V 72 no 2 2003

TAY periodical NO LOAN Wl UN9626B Un1vers1ty of Western Ontar1o medical JOUrnal UWOKJ.

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Volume 72 Number 2

u

OMJ Contents FEATURE ARTICLES

EDITORJAL

Do I look Fat in This?

Jason Ashley

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COMMENTS

Brian J Bigelow, Ph.D. , C.Psych.

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DEPARTMENT ARTICLES

Zebra Files A Review of the Etiology, Embryology and Management ofTrue Anophthalmia Chinedu Onochie, Meds 2005

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Ethics Patient-Centred Communication: An Emerging Medical Paradigm Adnan Pirbhai, Meds 2005 9 Diagnostic review Management of Severe Hypertriglyceridemia in Pregnancy Khalid Al-Shali and Rob Hegele Pro flies Interview with Dr. Cheril Clarson : A Pediatric Endocrinologist Magdalena Lipowska, B.Sc., Meds 2005 Clinical procedures An Introduction to the Lumbar Puncture Ryan J Punambo and Craig D. Ainsworth, Meds 2005

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Medicine on the Internet Implications of Internet use in both patient education, and continuing medical education for physicians Deric Morrison, Meds 2005 21 Medicine and the Law The Regulation of Physicians Leanne Tran, B.Sc., LL.B. (Uni versity ofToronto), Meds 2005 and Birinder Singh, B.Sc., LL.B. Meds 2004

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Health Promotion Primary prevention of Type 2 diabetes : Lifestyle interventions Anna Labuda, Meds 2005

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Thinking on Your Feet Lung Cancer and Ectopic ACTH: A Case Chris Chu, Meds 2004 and Jay Banerjee, Meds 2005 History of Medicine An Early Complex Emergency: The Plague of Athens Mar/is Saba, BSc, Meds 2005

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Prostatitis:Pathogenesis, Diagnosis and Treatment Orner Chaudhwy , MD, BA rtsSc, Meds 2003

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A Review of Diabetic Retinopathy Zishan Allibhai, Meds 2003, Husam Elkassem, B.Sc. and Farhan Siddiqui, Meds 2004

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Type 2 Diabetes Mellitus in Chi ldren and Adolescents: A Disturbing Trend Jaim e Blackwood and Ma ry Catherine Kerr, Meds 2003

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IS C-Peptide a Biologically Active Hormone?

Anile Mody

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X?: An approach to disorders of intersex Kirsten Grabowska, Meds 2003 and Erin Norris, Meds 2003

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Fetus-in-Fetu: A Diagnostic Challange Eve Fried, Meds 2003

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Turning up the heat in the OR: Brief Notes on Malignant Hyperthermia Joseph Kim, Meds 2003

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New developments in the Management of Osteoporosis Elizabeth Elliott

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Pheochromocytomas in Von Hippei-Lindau (VHL) disease Jill Shields. Chai1: Canadian VHL Family Alliance and Pierre Jacomet, Chile

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Polycystic ovary syndrome and the phenomenon of insulin resistance Sh oba Sujana Kumw; Meds 2003 62 Subclinical Hypothyroidism - Should We Treat?

Rania Rabie, Meds 2003

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The male andropause: a valid clinical entity?

Matei Andreoiu, Meds 2003

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The Atkins' Regime: A Critical Look at the ' Ketogenic ' Approach to Weight Loss Preet Virdee, BSc (Hans). Vikas Aganval, BSc (Hans) and Rishi Narine, BSc (Hans) 73 Renal Hormones and Hypertension Ali Namazie, Meds 2005

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The Effect of Protein Intake upon Osteoporosis Kristine L. Roth, BSc. and YoussefAlmalki, Meds 2004

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The debate continues: A review of current practi ces in the treatment of hyperthyroidism Nabil Sultan, Meds 2004 83 Š 2003 UWOMJ UWOMJ is published every 4 months.

Editorial Staff

Upcoming Issues:

EDITORIAL BOARD

The Joint and Obstetrics and Gynecology

COVER ART The cover art was designed and constructed by Mr. Ian Seo. Mr. Seo is a graduate of programs in both journalism and graphic design. His illustrative work covers a variety of styles in both traditional and digitally-based mediums. Mr. Seo can be contacted at seo@globility.com

..

Editor-in-Chief (middle) Senior Associate Editor (left) Junior Associate Editor (right) Managing Editor (not pictured)

Jason Ashley Shachar Sade Leanne Tran Chetna Tailor

Meds 2003 Meds 2004 Meds 2005 Meds 2004

DEPARTMENTAL EDITORS Ethics Sr.: Adnan Pirbhai, Meds 2005 Jr.: Amita Tanya Raha, Meds 2006

Medicine and the Internet Sr. : Deric Morrison , Meds 2005 Jr. : Arash Zohoor, Meds 2006

Clinical Procedures Sr. : Ryan Punambo, Meds 2005 Jr. : Mohammed Loubani , Meds 2006

Profiles Sr. : Magdalena Lipowska, Meds 2005 Jr. : Betty Lee, Meds 2006

Diagnostic Review Sr. : Nina Ghosh, Meds 2005 Jr.: Achinder Dhadwa r, Meds 2005

Thinking on Your Feet Sr. : Jay Banerjee, Meds 2005 Jr.: Sujiva Heyn , Meds 2006

Health Promotion Sr.: Anna Labuda, Meds 2005 Jr. : Nelvia Van Dorp, MMs 2006

Zebra Files Sr: Suzanne Richter, Meds 2005 Jr: Reem Nassur, Meds 2006

History of Medicine Sr.: Marli s Sabo, Meds 2005 Jr. : Amb rose Lau, Meds 2005

Senior Editors Chris Chu, Med 2004 Alan Khan, Meds 2004 Mary- Anne Rockx, Meds 2004 Elizabeth Au-Yeung, Med 2004 Bori So, Meds 2004

Medicine and the Law Sr. : Leanne Tran, Meds 2005 Jr.: Natasha Gakhal, Med 2006 Jr.: Lilian Barra, Meds 2006

UWOMJ ADVISORY COUNCIL Dr. Colby, Microbiology Dr. Wex ler, Anesthesiology Dr. Rieder, Paedi atrics

Dr. Silcox, Obstetrics I Gynecology Dr. Nisker, Obstetrics I Gynecology

ADVERTISING Kenmara Inc.

PRINTER Willow Printing Group Ltd.

UWOMJ Room MS-175 Medical Sciences Building The University of Western Ontario London, ON N6A SCI Phone/Fax : (519) 661-4238 Email: journal@uwo.ca URL: www.med.uwo.ca/medjrnl For information about writing for the UWOMJ, please follow the guidelines outlined on the website.

The UWOMJ is a peer-reviewed publication. All articles are reviewed by at least one external reader, in addition to the editorial staff. All editorial matter in the UWOMJ represents the opinions of the authors and not necessarily those of the editorial staff and advisory council. The editorial staff and advisory council assume no responsibility or liability for damages arising from any error or omission or from use of any information or advice contained in UWOMJ. Canada Post - Publication Mail Agreement Number 1720198 POSTMASTER: Undeliverable copies, please return to the address above.

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UWOMJ 72(2) 2003

Editorial

Do I look Fat in This?

Jason Ashley, Editor-in-Chief

This issue, dedicated to endocrinology and metabolism topics, further demonstrates the deep fryer that our western society is in. It is difficult to pinpoint a cause of the weight gain in our society, but it certainly is a problem. Obesity rates in adults increased by 60% between 1991 and 2000' , and rates doubled in children over the last 20 years2 . Rates ofType 2 diabetes rose 50% between 1990 and 2000 ' 路 In addition, Type 2 diabetes rates are increasing in children. While Canadian families are not far behind, obesity costs American families, businesses, and governments approximately $117 billion in health-care and related costs each year3 . Why is it that we have become so fat?

The pervasiveness of computers and the sedentary lifestyle associated with them is likely a culprit, but not the sole villain.

The fat content of the North American diet has climbed to the point that Americans spend more than $110 billion on fast food.

Furthermore, on any given day, about one in four individuals will visit a fast food outlet. These are staggering numbers. But spending this much on food does not necessarily equate to obesity. The disturbing trend is to "Super-size" one's meal. It has been ingrained in us to make the most of every dollar. Thus, in an effort to get the most for our money, we will increase the amount of food we get, if the perceived cost is minimal. The cost, it seems, is not financial. Most often, the cost of increasing the size of your portion is about 20%, while the caloric intake explodes by about 125%. Consider this example; at movie theaters, upgrading from a small to a medium-sized bag of popcorn without butter costs just $1 .10 more. However, it also adds an additional 500 calories (i.e., a 23% increase in price buys 125% more calories). If you pay yet another dollar, you can get a large, which brings the total to I, 160 calories. It seems that super-sizing applies to our food and to our belts.

Perhaps it is not our fault. We are bombarded by images of food throughout the day. If it 's not on a billboard, it's on the tele-

vision, or in a magazine. Are we warned of the perils that lie just beyond the succulent taste of a Cinnabon or are we at the mercy of the advertiser? Who is responsible for our overindulgent eating habits? Recently the placing of blame seems to be a bigger concern than addressing the actual problem of obesity. A family in New York filed a law suit blaming McDonald 's for failing to disclose that the ingredients they use could lead to diabetes , hypertension, and weight gain. Fortunately the judge ruled in favour of McDonald's. I wonder if the family has taken responsibility and adopted healthier eating habits.

Recently, obesity has been given the ominous privilege of being more damaging than smoking or problem drinking. Even after controlling for chronic conditions, obesity predicts physical health-related quality of life, in that case with an effect size similar to poverty4 . Furthermore, obesity is associated with more chronic conditions and worse physical health-related quality of life than smoking 4 . In addition, obesity is more costly than smoking. Obesity is associated with a 36% increase in inpatient and outpatient spending and a 77% increase in medications, compared with a 21 % increase in inpatient and outpatient spending and a 28% increase in medications for current smokers and smaller effects for problem drinkers. Also, obesity has roughly the same association with chronic health conditions as does twenty years ' agings. In an era of constrained health care spending obesity could break the scale, tipping us into mediocre health care.

How can medicine help? It is ineffective to tell people to "just lose the weight". Furthermore, obese individuals are often thought of as being victims of their own gluttony, a thought even seen in some medical professionals. It is through the partnerships that we build with patients that we must deal with this subj ect.

The approach to smoking and problem drinking is that of compassion and having the patient go through the stages of change.

Every visit, ideas and help is reinforced and reassured, showing a UWOMJ 72(2) 2003

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caring and compassionate view of the difficult struggle that lies before them . This is often missing in the treatment of obesity. All too often the obesity is seen as a weakness rather than a disease.

Alcoholism is a disease, then why not obesity? While it is easy to make such remarks, prejudice sti ll exists in our culture against those who are overweight. It will indeed be difficult to change the views of a society towards something as ingrained as obesity.

With that being said, I think I'll go for a coffee and a doughnut ... well ... maybe not the doughnut.

Jason Ashley Editor-in-Chief

REFERENCES 1.

Mokdad AH. Bowman B. Ford E. Vinicor F. Marks J, Koplan J The Continuing Epidemics of Obesity and Diabetes in the United States.

JAMA ; 286(1 0) :1195-1 200 2.

Natio nal Center for Health Statistics (NCHS), Centers for Disease Control and Prevention. "Prevalence of Overweight Among Children United States, 1999." Accessed at and Adolescents: http://www.cdc.gov/nchs/productslpubslpubdlhestats/overwght99.htm on Jun e 3, 2003 3. US Department of Health and Human Services (US DHHS). "The Surgeon General's Call to Action to Prevent and Decrease Overweight and Obesity 2001.'' Roc/.:ville, MD: US Department of Health and Human Services. Public Health Service, Office of the Surgeon General, 2001 4. Sturm R. Wells KB. Does obesity contribute as much to morbidity as poverty or smoking? Public Health ; 115(3) :229-35 5.

Sturm R. Th e effects of obesity, smoking, and drinking on medical problems and costs. Obesity outranks both smoking and drinking in its deleterious effects on health and health costs. Health Aff (Millwood); 21(2):245-53

Congratulations to all the students from: ~

WHITEHALL ROBINS TREATING YOU WITH CARE速

Makers of

Your #1 Analgesic Choice 4

VWOMJ 72(2) 2003

Comments

In response to comment in UWOMJ 72(1); 4-5, original article UWOMJ 71(2); 59-60 I felt compelled to respond to Dr. Wystanski 's Comment to Dr. Litman's article on "Differences in prescribing practice between board certified prescribing psychologists and psychiatrists", which appeared in UWOMJ (71 (2), 2001 ). As a full Professor of psychology, and both an academic as well as a clinician, I feel a certain acquired emotional detachment from scholarly debates, such as whether clinical psychologists or psychiatrists approach their patients any differently. Quite obviously, professions from several health disciplines serve patients effectively and a high level of "consociation", or what business people term as a 'good working relationship' , is to the benefit of the consuming public - our patients/clients. What I find disconcerting, however, is the invective tone of Dr. Wystanki's commentary. Namely, that Dr. Litman's views were not data based. Indeed, given the prestigious and rigourous references cited, it was clear to me that his opinions were not mere puffery.

In addition, Dr. Wystanki 's view that most of the world 's psychologists do not prescribe is simply wrong. According to my recent updates from the Prescribing Psychologists Register and from an article entitled "Psychology's first prescribers: DoDtrained psychologists have been paving the way so that others might one day prescribe", in The APA's Monitor on Psychology (34(2), pp. 36-39), American military psychologists have been prescribing in virtually all 50 states through the Department of Defense (DoD) since 1997, with a basic license through Guam.

Moreover, in March 2002 , New Mexico became the first state to enact a law that enables psychologists to receive post-doctorate training to prescribe psychotropics. This training includes, among other requirements, 450 hours of coarse work, and a I 00-patient practicum, taking about 400 hours under the supervision of a physician, and the requirement to pass a national certification exam. Moreover, my correspondence with the PPR informs me that about thirteen states have pending legislation and over 33 states have regional association task forces . In contrast, Ontario seems rather silent on the matter, but will no doubt jump on the proverbial band-wagon at the last possible minute. So, it seems that the facts are quite the reverse of those contended by Dr. Wystanki: no Canadian psychologists have the legal authority to prescribe at this point, but lots of American, and soon European, psychologists do in fact prescribe psychotropics.

As to the supposed dearth of biological training in clinical psychology, let me be clear that student psychologists do not work on cadavers - at least when I checked last - but they do take rigorous classes in biology, neurological psychology, and physiological psychology. But, to set the record straight, there is a lot more exposure to academic and experimental preparation in psychology than there is in medicine, which historically exposes trainees and residents to a grueling regiment of clinical cases. In my own

experience, psychological evaluations are much more time-consuming and expensive than are medical ones; that i , there is a natural tradeoff between volume and systemic prec ision, but so what? However, 1 would agree with Dr. Wystanski 's admonition that psychologists have better preparation in biology. For example, the adverse effects some antipsychotic meds have on the pericardium can be fatal. By implication, medical facilities should not be too far out of reach . But to engage in a ' we need them more than they need us ' debate is to drift out of consociation and into some of the counter-productive antics that we find so disappointing in some of our patients.

Sincerely, Brian J. Bigelow, Ph .D. , C.Psych .

(FSICPP, FPPR) Professor of Psychology Department of Psychology Laurentian University Ramsey Lake Road Sudbury, ON P3E 2C6

UWOMJ 72(2) 2003

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Zebra Files

A Review of the Etiology, Embryology and Management of True Anophthalmia

Chinedu Onochie, Meds 2004

Anophthalmia is a rare developmental disorder, with an incidence of 0.22 per 1000 births. 17 It is thought to be caused by various genetic defects and environmental insults.1 7 Embryologically, anophthalmia results from the inadequate development of optic and lens primordia cells or a disruption of the contact/interactions between optic and lens primordia, occurring at or before the the lens stage.1 7 The management of anophthalmia involves early orbital maintenance and expansion, followed later by surgical placement of an ocular implant and prosthesis. 10,17

INTRODUCTION Anophthalmia is an extremely rare developmental abnormality of the eye. True anophthalmia is characterized by the complete absence of all tissues of the eye (Figure 1). Clinical anophthalmia ranges from true anophthalmi a to extreme microphthalmia.

Microphthalmia descri bes an eye ranging in size from slightly sma ller than normal to an essentially empty orbit that simply contains remnants of ocular tissue visibl e only on microscopic study.

The incidence of clinical anophthl amia is 0.22 per 1000 births of which true anophthalmia makes up a small subset. 8,17 ETIOLOGY OF TRUE ANOPHTHALMIA It is thought that true anophthalmia is caused, at least in part, by geneti c abnormalities. However, the genetics of true anophthalmia are not completely understood . Genes responsibl e for the development of one form of anophthalmia have been mapped to region Xq27-q28 . The specific gene responsibl e for thi s X-linked form of anophthalmia has not been located.17 Another form of inherited anophthalmia is thought to be due to autosomal recessive genes, demonstrated by studies of iso lated Ami sh, Brazilian, and Arab families. The specific gene responsible for the phenotype is unknown .17

Figure 1. Bilateral Clinical Anophthalmia.

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UWOMJ 72(2) 2003

Pax6, a member of the homeobox transcription factor gene fami ly, has been implicated in the development of anophthalmia.

High levels of Pax6 activity have been observed in tissues of the lens, retina, nose, and brain. Anophthalmic phenotypes have been observed in homozygous Pax6 knockout mice. 6,7,17 In humans, Pax6 mutations are thought to be linked to anophtha lmia and other craniofacial abnormalities such as Peters anoma ly, nose defects, and brain defects .1 7 Insults to the intrauterine environment of a developing fetus are linked to the development of anophthalmia. Gestational exposure to toxic agents such as alcoholJ 6, retinoic acid(Acutane)5,9, LSD 11 , and hydantoin have been linked to the development of anophthalmia in animal studies. The drug Benomyl has been weakly linked to anophtha lmia in humans.14,17 Physical injury to the developing human fetus has also been linked to the development of anophthalmia. Specifically, cases of anophthalmia caused by amniocentesis needle trauma have been reported .2,17 EMBRYOLOGY Overview of Early Eye Development Late Gastrula Stage At less than one month post conception, the embryo is approximately three millimeters long. The dorsal surface of the embryo is made up of primitive ectoderm known as the epiblast (Figure 2). 1,3, 17 Along the epiblast runs a region of endoderm known as the primitive streak. At the most anterior part of this streak is Hensen 's node. Deep to the epiblast surface, at the anterior end of the embryo, is a region of mesoderm called the prechordal plate and the adjacent midline notochord. Epiblast adjacent to the prechordal plate makes up the gastrula eye field, the

optiC pnmorotum

opuc vestete lens primordium

eye field

M.loderm

notochord

late gastrula stage neural plate stage optic vesicle stage

primary precursor of ocular ti ssue .1,3,17 During the late gastrula stage, these embryonic structures begin to divide along the midline prechordal plate and notochord .17

Neural Plate Stage At this stage the notochord has lengthened and the first somite has formed . The eye field epiblast has now divided into four regions of tissue . These regions are the left and right optic primordium, derived from neural plate ectoderm, and the left and right lens primordium, derived from head ectoderm (Figure 2).8,15 By the end of the neural plate stage part of the dorsal ectoderm has differentiated into a central neural plate containing the two optic primordia deep to the surface.8, 15,17

Optic Vesicle Stage By this stage several somites have developed (Figure 2).17 Hensen 's node is now relatively large and transposed in position to the posterior region of the embryo. The notochord has grown and shifted, fu si ng with the primitive streak to form the neural tube . Of greatest importance to eye development is what is happening at the cranial end- bilaterally, each lens primordium is brought into contact with its corresponding optic primordium.

Bilaterally the optic primordia then differentiate into optic vesicles, while the lens primordia differentiate into lens placodes.17 It should be noted that these structures can develop to a large extent independently of one another, however, for complete development of the two primordia into the mature vertebrate eye, intermolecular signalling between cells of lens primordia/placodes and optic primordia/vesicles is necessary. 17,13 True anophthalmia is thought to be due to inadequate development of optic and lens primordia cells or a disruption of the contact/ interactions between the optic and lens primordia, occurring at or before the lens placode stage.17

Optic Cup S14gc

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R<ImaiPigrrn:nl Epitllcl ium Retina lens Placode Oplic

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Figure 2. Early eye development. Origin of the eye primordia in the chick embryo is depicted at the late gastrula, neural plate and optic vesicle stages. Embryo diagrams are drawn as if viewed from above (dorsa l face) , with underlying structures indicated in dash ed lines. Anterior is up. Late gastrula stage: The shaded oval area indicates the approximate extent of the eye field in the primitive ectoderm. Neural plate stage: Location of the pair of optic primordia, fated to become the optic vesicle and its derivatives is indicated. Approximate boundaries of the lens primordia are also inidicated. Optic vesicle stage: Lens placodes develop from Lens primordia in the head ectoderm that are brought into contact with the optic vesicle.

Lens Placode Stage During this stage the lens pl acode invaginates, forming a lens pit (Figure 3). Also, during thi s stage, the optic vesicle flatten s considerably. 17

Optic Cup Stage The ti ssue of the lens pl acode further differentiates to the point where it roughly resembles the structures that it will become; the lens and cornea primarily (Figure 3).1 7 The ti ssue of the optic vesicle further differentiates to the point where it roughly resembles its future structures; the ventral half of the eye (iris,/ciliary body, optic cup), retinal pigment epithelium, fibers of the optic nerve, and neural retina .17. 13 For the most part, the rest of the mi scellaneous ti ssues of the vasculature, sc lera, and choroid, are made up of a combination of neural crest and head mesoderm tissue, while the extraocular muscles are made up of paraxial mesoderm .17,4,12 Neural crest mesenchyme cells produce much of the vitreous and glycoprotein component.1 7.4

MANAGEMENT OF ANOPHTHALMIA Early Treatment To maintain a normal orbit, an eye orbit conformer is applied to the empty orbit soon after birth . The conformer is changed every one to two weeks for the first few months of life.s Later on, the conformer is changed every three to four months until the orbit size stabilizes. s If the orbit is abnonnally small and does not increase in size in response to the conformer, then an inflatable orbital tissue expander is used.17 This device adds more pressure to the orbit with the goal of stretching orbital tissue . If an inflatable tissue expander is not successful then surgical expansion of the four walls of the bony orbit is necessary.

Figure 3. Formation of the optic cup. Diagram showing key stages in the transformation of optic cup and lens placode into the optic cup and lens vesicle. Emb1yos are depicted as transverse sections through optic structures of the head. Depicted are the neural tube epithelium (inner tissue layer) and the su1jace ectoderm (outer layer/ Lens placode stage: Showing collapse of the optic vesicle into a paddle-shaped structure joined to the ven tral forebrain, and invagination of the lens placode to form a lens pit. Optic cup stage: Emb1yonic tissues are Labeled with the adult structures that they will Later generate.

UWOMJ 72(2) 2003

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ACKNOWLEDGEMENTS I would like to thank Dr. Christopher Anjema for hi s review of this article and several very helpful suggestions.

Figure 4A. Dermis fat graft.

Figure 4B. Graft sutured into anophthalmic socket.

Ocular Implant and Prosthesis If a suitably large and stable orbit size is reached, then a more permanent implant may be placed in the orbit. In the past, the standard implant types used were the methyl-methacrylate or silicone based spherical unit.1 7 These types of implants are sti II commonly used, however, in the early 1990s, newer hydroxyapatite and Medpore implants were introduced. IO Hydroxyapatite is an immunologically inert substance derived from a species of sea coral. The coral is heated, processed and shaped into a porous ocular impant 17,10. Hydroxyapatite 's primary advantages are its light weight and porous nature .

Because of its many pores, host blood vessels and tissues are able to infiltrate the porous spaces, resulting in a better f it, improved eye movement, less sagging/malposition, an da decreased rate of infection .IO Medpore is a porous polyethylene implant that also all ows for fibrovascu lar integration, however, Medpore is a little cheaper. It is not known which of the newer implants is more effective. IO Regardless of the type of implant used, the surgical principles followed during the insertion of the impl ant are the same. If deemed necessary by the surgeon, a fat graft from the lateral buttock is transferred to the back of the empty orbit to fill vo lume and decrease implant weight, thus decreasing the poss ibility of future implant extroversion (Figure 4 ). 17 Subsequently, a correctly sized implant is placed in the orbit, deep to the two layers of Tenon 's capsu le (if present) , then sutured in place. l7 Subsequently the conjunctiva l layer is sutured overtop (if present) . If present the latera l, medial , superior, and inferior recti , and uperior and inferior oblique musc les may be attached to the implant or a donor sclera, a ll owing for increased mobility and a more natural movement of the eye.17 It should be pointed out that all types of implants are simply space occupying objects that faci litate ocular motions- they are still quite cosmetically bare. A prosthetic eye "surface", painted to fit the patient, is attached to the anterior impl ant via a peg to comp lete the cosmetic presentation . Io

SUMMARY In recent years, anophtha lmi a 's poss ible associatiOn with man made toxins has placed it under intense scrutiny. However, it is a very rare developmental abnormality of the eye. Thi s di sorder is best comanaged by the patient 's pediatrician, fam ily practitioner, and ophthalmologist. It is important that all members of thi s team interact effectively to treat the primary defect and any comorbid conditions.

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UWOMJ 72(2) 2003

REFERENCES I. Adelmann H.B. Experimental studies on the development of the eye.//.

The eye forming potencies of th e median portions of th e urodelan neural Plate. J ofExp Zoology 1929;54:291-3 71.

2.

BenEzra D. . Seta M. Pe 'er J Bilateral anophthalmia and unilateral microphthalmia in two siblings. Ophthalmologica 1989; 198: 140-144.

3. Clarke L.F Regional differences in eye-fo rming capacity of the early chick blastoderm, as srudied in chorio-allantoic grafts. Physiol Zoot 1936;9:102-128.

4. Cook C.S. , O::anics V., Jakobiec FA. Prenatal development of the eye and its adn exa. in Duane :S Foundations of Clinical Ophthalmology, W. Tasman and E. Ja ege1; eds. Philadelphia: Lippincott; 1994.

5. Fraunfelder F , LaBraico J , MeyerS. Adverse ocular reactions possibly associated with isoretinoin . Am J Ophthalmoll985; 100:534-537.

6. Grindley JC.. Davidson D.R.. Hill R.E. The role of Pax-6 in eye and nasal development. Developm entl995;121 :1433 -1442.

7. Hogan B.L.M.. Horsburgh G.. Cohen J , Hetherington C.M., Fisher C..

Lyon M.F Small eyes (Sey): A homo::ygous lethal mutation on chromosome 2 which affects the differentiation of both lens and nasal pia codes in the mouse. J Emb1y ol Exp M01phol 1986;97:95- 110.

8. Katowitz JA ., Kropp T.M. Congenital and developm ental abnormalities of th e orbir: Synophtha lmos. anophthalmos, microphthalmos, e~yp toph­ thalmos. In Oculoplastic. Orbital. and Reconstructive Surge1y, vol 2, A. Hornblas , ed. Baltimore: Williams and Wilkins, 1990:817-825.

9. Lammer E. . Chen D.. Hoar R. , Agnish N , Benke P., et al. Retinoic acid emb1yopathy. New England Journal of Medicine 1985;3 13:83 7-841.

10. Levine M. R. Manual of Oculoplastic Surgery 2nd Edition . Boston: Buller>vorth-Heinemann ; 1996.

II . Margo lis S.. Martin L. Anophthalmia in an infan t ofparents using LSD. Ann Ophrhalm o/1980;13:78-8 1.

12. Noden D.M. Periocular mesenchy me: Neura l crest and mesodermal inreractions. in Duane s Foundations of Clin ical Ophrhalmology, W. Tasman , E. Ja eger. eds. Philadelphia: Lippincoll: 1994.

13. Saha M.S.. Spann C.L.. Gainger R.M. Emb1yonic lens inducrion : More rhan meers the optic vesicle. Cell Diff Dev 1989: 28:53- 172.

14. Spagnolo A., Bianchi F. Calabro A .. Ca lzolari E., Clementi M. , Mastroiacovo P.. era/. Anophthalmia and benomyl in Italy: A mulicenrer srudy based on 940 615 newborns. Reprod Toxicol 1994;8(5):397403.

15. Spema nn H. Embryonic Developmenr and induction. New Haven: Yale University Press. 1938.

16. Srromland K. Ocular In volvement in rhe fe tal alcohol syndrome. Surv Ophthalmol 1987:31 :277-283.

17. Traboulsi E.!. Genetic Diseases of the Eye. New York: Oxford University Press: 1998. â&#x20AC;˘Figures 1,2, 3, and 4: From TH E GENETIC DISEA E OF TI-lE EYE, edited by Ahmad S. Teebi & T.l. Farag, copyright - 1996 by Oxford University press, Inc. Used by permi ssion of Oxford Uni versity Press, Inc.

Ethics

Patient-Centred Communication: An Emerging Medical Paradigm

Adnan Pirbhai, Meds 2005

Patient-centred communication has emerged in the last few decades as the most preferred method of communicating in the clinical encounter. No longer based on the paternalistic model, or the informed treatment decision-making model, patient-physician relationships, based on patient centredness, are now epitomized by the shared treatment decision-making model. This paradigm shift is a result of both patients and physicians advocating for a method of communication that addresses the changing needs and desires of patients in such a way that still satisfies physicians and the greater medical community with regard to effective and efficient patient care. Until recently, however, the scholarly support for patient-centred communication was of a primarily theoretical nature. Recent studies showed that patient-centred communication yields tangible and measurable positive health outcomes for the patient while also being beneficial for the physician and the health care system. Physicians must ensure that these methods are widely and effectively incorporated into practice, and that the merits of patient centred communication extend beyond scholarly enthusiasm and into each patient-physician relationship.

The dynamics of health care delivery in the West have changed dramatically in the last century. Rapid technological advances have allowed for people to decide on treatment options that were never before considered. The clinical encounter, defined by the relationship between the physician and patient, is the context in which these decisions are often made. Although evolution within this context is slower compared to more scientific aspects of medicine, the shift in approaches to communicating with the patient that have occurred over the last few decades are no less significant. Whereas a mere thirty years ago the physician-patient relationship was defined as paternalistic, more and more scholars agree that in the best interests of care, a patient-centred approach should now epitomize communication in the clini cal encounter.

Patient-centred communication, best realized through the shared treatment decision-making model , allows physicians to address the changing needs and desires of patients. This will fu lfill not only the patients' expectations of the clinical encounter, but also the physicians' interests of patient care. With so much emphasis placed on achieving patient satisfaction in the clinical encounter, coupled with the medical community recognizing tangible benefits from pursuing that outcome, patient-centred communication has emerged in the last few years as the newest medical paradigm.

Changes in health care are often driven by changes in the needs of society and those served by the health care system.

Physician-patient interaction in Western medicine was characterized by a paternalistic approach up until the early seventies. In

response to the desire for more patient control in the clinical encounter, the informed treatment decision-making model , or consumer-sovereignty model , emerged in the last few decades.

Most recently, however, a patient-centred approach to communication in the clinical encounter has been widely advocated by both physicians and patients alike.

This most recent shift can be attributed to several reasons.

First of al l, it is obvious that in order to arrive at the best decisions for treating an individual, all information regarding that individual 's condition must be exposed. As has been argued by many scholars, a thorough exploration of the individual 's health condition can only proceed by incorporating components of the patient's illness experience. This is in stark contrast to previous models which focused on the disease explanatory model of health, a model which has characterized most advances in health care in the 20th century' . Such components include the patient 's f eelings about being ill, her ideas regarding causation and the impact the symptoms have had on her fun ctioning2. Although exploring the extent of the patient's disease is crucial for the physician in understanding the patient's problems, not all information can be elicited through tests and examinations or addressing physiological processes. Thus physicians must be able to effectively explore the patient 's self-reported symptomatology to enhance their own understanding3. Essentially what is required is an understanding of a patient's condition through a combination of the biomedical approach and illness explanatory model. This UWOMJ 72(2) 2003

9

combination fuses the disease explanatory model, of which physicians are trained experts, with the illness explanatory model, of which patients are the experts. Patient-centred communication facilitates thi s process.

A second reason why patient-centred communication is being enthusiastically embraced by the medical community and the public is in the way it addresses patients' expectations for care . Studies have shown that patient satisfaction is closely associated with having their expectations and preferences of the clinical encounter met. Additionally, patients often enter a relationship with a physician with an established set of problems that need to be addressed and a specific set of expectations in how to address them4. Patient-centred communication is particularly effective in revealing these expectations amidst a diverse and evolving patient popul ation, especially like that present in Canada. Such diversity lends itself to a large variety of expectations of care, despite simi lar conditions or symptoms3. Since patient-centred communication provides the framework for effectively exposing these expectations, it is evident why thi s approach has gained significant popularity.

One last reason why patient-centred communication has caught on is due to srufts in the dynamics of power amidst the clinical encounter and its impact on the goa ls of treatment.

Although patients desire more autonomy in their own care, other model s of communication do not result in the type of care that serves patients best. The paternalistic model of communication leaves the power to interpret and decide on treatment entirely in the hands of the physician . This relationship primarily reflects the disease explanatory model of the physician and does not all ow for the patient to express the components of her illness experience when deciding on treatments. The consumer-sovereignty model , at the other end of the spectrum, requires that patients assume the role of expert in understanding and managing their disease, absolving the physician of that role and lim iting her ro le to one of primarily information provision6. Although responding to patients' desires for increased control, thi s mode of communication places patients in the drivers' seat of what is essential ly the doctor's car. The information provided and explanatory mode l used to outline treatment options stem from the physician only.

Patient-centred communication, though , in its essence all ows both patients and physicians to maintain a deg ree of autonomy by arriving at mutually favourable treatment dec isions, or common ground. Reaching common ground entails a negoti ation of the exp lanatory model s, expectations and goa ls of treatment. Using this approach, patients are empowered to participate in crucia l determining aspects of their own ca re in consultation with the physician . Much of the responsibi li ty for hea lth and the maintenance of health shifts towards the pati entJ. Thus, patient-centred communication responds to a patient population th at desires more contro l in the clinical encounter by helping patients rea li ze treatment options and goals that correspond best with their illness expenence.

It has been shown that patients prefer components of the clinical encounter such as communication, partnership and hea lth promotion . Pati ents do not necessarily want their experience limited to a prescription , diagnosis or examination and appreciate having their specific feelings and expectations eli cited through 10

UWOMJ 72(2) 2003

communication with the physician 7. All of these preferences are reflected in the patient-centred approach to communication, exemplified by the shared treatment decision-making model. This framework, formally developed by Charles et al., is predicated upon the ultimate goal of reaching common ground. In this process, the physician relies on exploring and understanding all four components of the patient's illness experience (fears, ideas, functioning , expectations). Furthermore, shared decision making is described as a mechanism of increasing patients' "sense of autonomy and/or control over treatment decision that affect their well-being."S Thus, the shared treatment decision-making model addresses the various needs of patient's by providing a framework for effective communication between them and their physician, encouraging a partnership en route to common ground, which promotes control over their own health outcomes.

Although patient needs and preferences are well addressed in patient-centred communication, one should note that simply satisfying the pati ent alone is not the only reason why patient-centred communication is important in today's clinical environment.

There are several benefits in employing a patient-centred approach in the clinical encounter, ranging from improved health outcomes to even benefits borne exclusively by the physician.

Firstly, improved patient compliance with treatment regimens , the ability for physicians to make a more appropriate diagnosis, recommend more appropriate treatment, or better recognize signs of social and emotional di stress, are results of better communication in the clinical encounters. All of these factors can result in improved patient care and consequently improved health outcomes. Also, empowering patients to actively participate in decision making has been associated with beneficial outcomes in several chronic ailments. In patients with diabetes, hypertension and peptic ulcer disease, it was shown that pilot programs aimed at increasing patient participation in medical care resulted in improved function and health outcomes9. Furthennore, it has been suggested that patient satisfaction, as a result of improved conununication with their physician in itself can result in improve health outcomes2, 4 . In a landmark study done by Stewart eta!. , of London , Ontario, health outcome parameters such as level of discomfort, leve l of concern and mental health showed significant improvement with patient-centred conmmnication. They present a pathway that suggests that physician-patient communication " influences patients' health, by first influencing the patients ' perceptions of being a full participant in the discussions during the encounter."2 Although thi s process is not fully understood, the impact of the process is unmistakable: patient-centred communication improves health outcomes.

The benefits of patient-centred communication span beyond the patient as well. One can easily predict that patient satisfaction and improved patient health outcomes undeniably leads to higher physician satisfaction from the encounter. Establishing a better method of communication also improves the relationship between the physician and the patient, which leaves both parties further sati sfied with the encounter. Additionally, studies have shown that physicians who employ a patient-centred approach in their practice are subject to fewer malpractice claimslo. Patient-centred communication has also been proven to be more cost efficient as it reduces the number of referrals and diagnostic tests by half2.

Additionally, Rao et a!. report that patients with unrnet expectations from the clinical encounter are more likely to return to their physicians with similar symptoms as the previous consultation, thereby increasing the total number of visits and ultimately, adding a further financial burden to the health care system.

It is clear that patient-centred communication effectively addresses the needs of patients in the clinical encounter whi le also resulting in benefits to the physician and the health care system as a whole. Through the shared treatment decision-making model, both physicians and patients are able to deliberate in such a way that uncovers the fears , expectations and treatment goa ls of the patients and fuses them with those of the physician en route to a mutually agreeable treatment decision. This is a drastica lly different process compared to previous models of communication . And although changes to society's approach to the physician-patient relationship have been gradual , they are quite significant. In fact, the implications of these changes are so profound, that "just as the molecular and chemistry oriented sciences were adopted as the 20th century medical paradigm, incorporation of the patient's perspective into a relationship-centered medical paradigm has been suggested as appropriate for the 21st century." II In recognition of this medical paradigm shift, physicians are becoming increasingly aware of the merits of a patient-centred approach in the clinical encounter. Despite the widespread scholarly enthusiasm for patient-centred commun ication, however, the practice of this method has not diffused widely enough. In fact, close to one quarter of patients still leave the clinical encounter with unrnet expectations4. What is needed is more practical training within medical institutions that emphasize understanding the patient's unique illness experience in order to provide effective patient care. The University of Western Ontario, in particular, leads by example by incorporating both real and standardized patients in its education, in addition to explicitly focussing its curriculum around patient-centred methods. As more schools incorporate patient-centred approaches into their training, the medical community, through enhanced communication, will more effectively and efficiently fulfi ll its obligation to patient satisfaction and, ultimately, patient health.

REFERENCES I. 2.

3.

4.

5.

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7.

Helman C. Culture, Health and Illness. Oxford: Butterworth-Heinmann, 1994 Stewart, M. eta/. Th e impact ofpatient-centered care on outcomes. Th e Journal of Family Practice. 2000. 49 (9) : 796-804 Bensing J, Verhaak P. van Dulmen A, Visser A. Communication: the roy al pathway to patient-centered medicin e. Patient Education and Counseling. 2000, 39 (1) : 1-3 Rao J, Weinberger M, Kroenke K. Visit-sp ecific expectations and patient-centered outcomes. Archives ofFamily Medicine. 2000. 9: 11481155 Charles C. et al. Shared treatment decision-making: what does it mean ?. Social Science and Medicin e. 1997. 44 (5) : 681-692 Pellissier J, and Venia E. Introducing patient values into the decision making process for breast cancer screening. Wom en & Health. 1996. 24 (4): 47-67 Little P et al. Observational study of effect of patient centredn ess and positive approach on outcomes of general practice consultations. BMJ 2001 , 323: 908-9ll

King J Health beliefs in th e consulta tion. Docto r-Pa tien t Communication (Pendleton, D. an J Halser. ed.) Londo n: Academic Press, 1983 9.

Greenfield S, et al. Patient s participation in medical care: effects of blood sugar control and quality of life in diabetes. Journal of General internal Medicine 1998. 3: 448-454 I 0. Levinson W, Rorer DB, Mullooly JB. Dull VT. Frankel RM. Th e relationship with malpractice claims am ong prima~y care physicians and surgeons. JAMA 1997, 277. 553-59 II . Rorer D. Th e enduring and evolving nature of th e patient-physician relationship. Patient Education and Counseling. 2000. 39 (1): 5-15

8.

U.S.A. Immigration Law William Newell Siebert Attorney at Law 307 North Michigan Avenue Suite 924 Chicago, Illinois 60601 Voice: (312) 329-0646 Fax: (312) 553-4419 E-Mail: wsie bert@siebert-immigrati o nlaw. com

PRACTICE CONCENTRATED IN U.S. IMMIGRATION LAW SINCE 1969

UWOMJ 72(2) 2003 11

Diagnostic Review

Management of Severe Hypertriglyceridemia in Pregnancy

Khalid AI-Shali and Rob Hegele Robarts Research institute; and Division of Endocrinology, Department of Medicine, University of Western Ontario

Familial chylomicronemia is characterized by severe fasting hypertriglyceridemia, which is due to the massive accumulation of chylomicrons. Clinica l features include abdominal pain with or without pancreatitis, lipemia retinali s, eruptive cutaneous xanthomas and hepatosplenomegaly. Familial deficiency of lipoprotein lipase (LPL), a rare ( 1 per 1 million) autosomal recessive disease is the most common underlying molecular defect leading to the familial chylomicronemia syndrome.' The clinical diagnosis of familial LPL deficiency is confirmed by finding markedly reduced or absent LPL activity in plasma after a diagnostic heparin inj ection or by DNA analysis. Familial LPL deficiency results from having two mutant alleles of the LPL gene encoding lipoprotein lipase .2 Plasma triglyceride (TG) concentrations normally rise by 2- to 3-fold during the third trimester of pregnancy.3 This physiological TG increase has little clinical consequence when baseline TG is within the normal range. However, more pronounced TG increases have been reported in association with reduced or absent LPL activity, with variable pregnancy outcome.4-9 When severe hypertri glyceridemia during pregnancy is complicated by pancreatitis, there is a 2 1% and 20% risk of mortality for the mother and fetus , respectively.IO We describe the successfu l pregnancy outcome in a pati ent with documented severe hypertriglyceridemia since infancy due to LPL deficiency.

CASE REPORT At the age of three weeks , the patient presented with failure to thrive. Her blood had a milky lipemic appearance and plasma TG was 129 mmo l/L, of which -90% was chylomicrons. She was placed on a very low fat formula consisting of 13.3% of total calories from fat with medium chain triglycerides (MCT) and corn oil to prevent essential free fatty acid deficiency. This regimen resulted in good control of plasma TG . At age three, postheparin plasma LPL acti vity was found to be undetectable.

Between ages two and 17, on a diet with 10% of calories from fat, her plasma TG ranged between 11 .1 and 63.2 (median 29.0) mmol/L and total cholesterol between 2.2 and 16.1 (median 6.0) mmo l/L. She had normal growth and development. She remained

12

UWOMJ 72(2) 2003

asymptomatic with no clinical signs of chylomicronemia on two to three tablespoon s ofMCT oil once a day. DNA analysis showed that she was a compound heterozygote for two different loss of function mutations in the LPL gene encoding lipoprotein lipase.

At age 18, the patient became pregnant and MCT intake was associated with dyspepsia, which stopped upon its discontinuation . She required admission to St. Joseph 's Health Care Centre twice during the second trimester for management of high TG .

The first admission was at 16 weeks of ge tation for 11 days, and the second admi sion was at 19 weeks of gestation for 8 weeks.

During the third trimester, she required an admission at 36 weeks of gestation for one week in order to manage plasma TG > 50 mmol/L. On each admission, dietary intake was interrupted and intravenous (IV) administration of 5% dextrose in 0.45 % sodium chloride solution wa initiated and continued for between 2 and 4 days, until plasma TG levels fell by at least half. A low fat diet was also recommended on each admission, though compliance remained variable.

During the first admission, the patient 's diet contained 7 to 8.5% of energy from fat (16 to 18 g fat/day when total energy intake was 8600 kilojoules/day). During her second admission, fat intake declined to < 10 g/day. The diet was designed to meet essential fatty acid requirement. At 34 weeks of gestation, with persi tent TG >50 mmol/L, the patient was started on oral gemfibrozil 300 mg twice daily after giving consent for this treatment.

During the third admission , fat intake fell to 1 g/day. She was advised to apply corn oil to her skin to provide es entia! fatty acids transdermally, but compliance was not followed .

Throughout pregnancy, she had no clinical signs of hyperchylomicronemia, except for lipemia retinali s. Plasma TG ranged between 7.8 to 111.3 (median 31.8) mmol/L and during the third trimester ranged between 29.1 to 111.3 (median 50.6) mmol/L. Because of the very high pancreatitis risk and the normal maturation of the fetus, labour was induced at 38 weeks of gestation. A healthy 2.77 kg male infant was delivered vaginally. The patient had gained 15.5 kg since the start of her pregnancy. 24 hours after delivery, her fasting plasma TG concentration had fallen by 50% and continued to decrease to baseline during the following weeks.

DISCUSSION Successful pregnancy outcome in severely hypertriglyceridemic patients has been reported using various treatments. These include: an isocaloric NIH type V diet with 20% of calories as fat (-56 g fat/day) alone 11 , aggressive dietary therapy ( 10% fat diet equivalent to 10 to 15 g fa t/day) with intern1ittent IV supporti 2, very low fat diet (28 g fat/day), and n-3 fatty acids6. In our patient, severe fat restriction and intermittent hospitalizations with brief fasting and IV glucose helped to control plasma TG concentrations. This approach was based on a published observation that oral carbohydrate produces a greater rise in plasma TG compared with IV administration in normal individuals.I3 In this regard, total parenteral nutrition (TPN) is another therapeutic option. In another patient with pregnancy-induced hypertriglyceridemia, TPN use was associated with a significant reduction in plasma TG (from 60 to 20 mrnol/L over a few days) .9 In this same patient, IV heparin was used therapeutically following a diagnosis of pulmonary embolism, with a significant TG reduction (from 45 to 10.2 mrnol!L) once a partial thromboplastin time was therapeutically prolonged.

MCT nutritional support together with a low fat diet was previously reported in a patient with severe pregnancy-induced hypertriglyceridemia.I4 Although our patient was on MCT supplementation for most of her life, she discontinued this in early pregnancy because of associated abdominal pains, which dissipated once she stopped taking MCT. Noncompliance to the low fat diet was a concern, but was not unexpected. IS However, diet was reinforced on a regular basis by physicians, nurses, and dieticians who were involved in the patient's care.

Our patient had a significant increase in plasma TG concentration during the third trimester. Previous reports of patients with LPL deficiency demonstrated similar increases in plasma TG in late pregnancy.s. 6 This was consistent with increased secretion of TG-rich lipoproteins from the liver during this period.I6 A reduction in LPL activity, which is another mechanism for elevated plasma TG level in third trimester, 17 was unlikely to have played a role in our subject, since she was already completely LPL deficient.

Our patient was started on gemfibrozil at 34 weeks of gestation because of a significant pancreatitis risk. Patients with recurrent pancreatitis may respond to fibrate therapy with a mild reduction in plasma TG, but response varies'路 Although gemfibrozil's safety during pregnancy is not firmly established, there have been a few reports of it use in pregnancy with no apparent adverse effects.IS-2 1 In all but one of these reports, gemfibrozil was started after 20 weeks' gestation. Thorough review of the pharmaceutical literature regarding the efficacy, tolerability, and safety of gemfibrozil in pregnancies involving extreme TG elevation provided limited information, but revealed no serious adverse effects in patients taking gemfibrozil in the third trimester.

Furthermore, international experts in the field were consulted regarding gemfibrozil use in this patient. Interestingly, gemfibrozil did not affect plasma TG in our patient.

Omega-3 fatty acids at doses of 3 to 4 g/day can reduce TG by up to 25%22. Plasmapheresis would have been an option in our patient had she developed pancreatitis23-25. The approaches to

investigate and manage severe hypertri glyceridemia during pregnancy are summarized in table 1.

Thus, LPL deficient patients can have a successful pregnancy outcome. Ideally, they should receive careful preconception counseling, with optimization of plasma bi ochemi stry. Adh erence to a low fat diet, which is always important for these patients, becomes even more important during pregnancy. It is also important to ensure that proper nutrient balance and composition is being met. Frequent monitoring ofTG as an outpatient is important to detect increases before the development of complication s.

Hospitalization, with short-term periods offasting and IV support may be required . Also, the use offibric acid derivative during the latter stages of the third trimester may have a rol e in the management of these patients.

Table I: Investigation and management of severe hypertriglyceridemia in pregnancy History of:

- pancreatitis and/or abdominal pain - diabetes mellitus, hypothyroidism, renal disease - high TG prior to pregnancy - high TG in other family members - alcohol consumption - medication use: steroids, diuretics, beta-blockers

On examination:- xanthomata - eruptive and/or tubero-eruptive - hepatosplenomegaly - lipemia retinalis Laboratory:

-fasting plasma TG weekly (outpatient) and daily (inpatient) - serum amylase (if abdominal pain present) - Screen for primary causes of high TG: - Fasting lipids: total, LDL and HDL cholesterol, TG - VLDL cholesterol/TG ratio (for type III hyperlipidemia) - LPL activity in post-heparin plasma - Isoelectric focusing of apo E and apo CII - DNA sequencing of LPL - Screen for secondary causes of high TG : - Fasting plasma glucose, thyroid stimulating hormone - urea, creatinine, urinanalysis

Management:

- Admit to hospital if abdominal pain occurs or ifTG>40 mrnol/L - NPO, with IV glucose solution until symptoms resolve - Refer to registered dietician for very low fat diet (< 15 g fat/day) - Essential fatty acid requirement to be met at all times - Gemfibrozil (considered late in 3rd trimester), plasma exchange, IV heparin and/or total parenteral nutrition are each reserved for extreme, refractory cases UWOMJ 72(2) 2003 13

ACKNOWLEDGMENTS

19.

The following individuals provided assistance at various times in the diagnosis and management of this patient: Drs. Bernard Wolfe, Fraser Fellows, Jian Wang, Murray W. Huff and Jeff Mahon . We also thank Ms. Patricia Pauli and the medical and nursing staff of University Hospital of London Health Sciences Centre, and of St. Joseph 's Health Care Centre. Dr. John BrW1Zell, Professor of Medicine at University of Washington , Seattle WA, gave expert advice based upon his experience of managing type I hyperlipoproteinernia in pregnancy.

20.

21.

22.

23.

24.

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Foj o SS. Th e fa milial chy lomicronemia syndrome. Endocrinol Metab Clin No rth Am. 1998: 27: 55 1-67.

Murthy V, Julien P. Gagne C. Molecular pathobiology of the human lipoprotein lipase gene. Pharmacal Ther. 1996: 70: 101 -135.

Warth MR. Arky RA. Knopp RH. Lipid metabolism in pregnancy. ill Altered lipid composition in intermediate, very low, low, and high-density lipoprotein fractio ns. J Clin Endocrinol Metab. 1975: 41 : 649-55.

Henderson H. Leisegang F. Hassan F. Hayden M. Marais D. A novel glu42 1/ys substitution in the lipoprotein lipase gene in pregnancyinduced hypertriglyceridemic pancreatitis. Clin Chim Acta. 1998; 269: 1-12.

Walls GF. Morton K. Jackson P. Lewis B. Managem ent of patients with severe hypertriglyceridemia during pregnancy: report of two cases with fa milial lipoprotein lipase deficiency. Br J Obstet Gynecol 1992: 99: 163-6.

Glueck CJ. Streicher P. Wang P. Sprecher D. Fako JM. Treatment of severe fami lial hypertriglyceridemia during pregnancy with very-lowfat diet and n-3 fatty acids. Nutrition 1996: 12: 202-205.

Suga S, Tamasawa N, Kinpara 1, et a/. identification of homozygous lipoprotein lipase gene mutation in a woman with recurrent aggravation of hypertriglyceridemia induced by pregnancy. J Intern Med 1998: 243:317-321.

MaY. Ooi TC. Liu MS. eta/. Highfrequency of mutations in th e human lipoprotein lipase gene in pregnancy-induced chylomicronemia: possible association with apolipoprotein E2 isoform . J Lipid Res 1994: 35: 1066-1075.

Hsia SH. Connelly PW. Hegele RA . Successful outcome in severe pregnancy-associated hyperlipidemia: a case report and literature review.

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Montgomery WH. Miller FC. Pancreatitis and pregnancy. Ob tet Gy neco/19 70: 35: 658-64.

Glueck CJ. Christopher C, Miske/ MA . et a/. Pancreatitis. fa milial hypertriglyceridemia, and pregnancy. Am J Obstet Gyneco/1980: 136: 755.

Sanderson SL, l verius P-H. Wilson DE. Sue essfu l hyperlipidemic pregnancy. JAMA . 1991 :265: 158- 160.

DenBesten L. Reyna RH, Connor WE, Stegink LD. Th e diffe rent effects on the serum lipids and feca l teroids of high carbohydrate diets given orally or intravenously. J Clin invest 1973: 52: 1384- 1393.

Mizushima T. Ochi K. Matsumura N. eta/. Prevention of hyperlipidemic acute pancreatitis during pregnancy with medium chain triglyceride nutritional support. lnt J Pancreato/199 : 23:187-192.

Gasbarrini G, Mingron e G. Greco All, Castagneto M. An 18-year-o/d woman with fami lial chylomicronemia who would not stick to a diet.

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Herrera E. Gomez-Coronado D. Lasuncion MA . Lipid metabolism in preganacy. Bioi Neonate. 1987; 51: 70- 7.

Herrera E. Lasuncion MA , Gomez-Coronado D. Role of lipoprotein lipase activity on lipoprotein metabolism and the fa te of circulating triglycerides in pregnancy. Am J Obstet Gyneco/1 988; 158: 15 75-83.

Morse AN. Whitaker MD. Successful pregnancy in a woman with /ipoatrophic diabetes mellitus. A case report. J Reprod Med 2000: 45: 850852.

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Perrone G, Critelli C. Severe hypertriglyceridemia in pregnancy. A clinical case report. Min erva Ginecologica.l996; 48: 573-576.

Keilson LM, Vmy CP, Sprecher DL. Renfrew R. Hyperlipidemia and pancreatitis during pregnancy in two sisters with a mutation in th e lipoprotein lipase gene. Ann Intern Med 1996; 124:425-428.

Jaber PW. Wilson BB. Johns DW. Cooper PH, Ferguson JE II. Eruptive xanthomas during pregnancy. JAm Acad Derma to/. 1992; 27: 300-302.

Miller M. Current perspectives on th e management of hypertriglyceridemia. Am Heart J. 2000; 140: 232-40.

Lennertz A. Parhofer KG, Samtleben W. Bosch T. Therapeutic plasma exchange in patients with chy lomicronemia syndrome complicated by acute pancreatitis. Therapeutic Apheresis. 1999; 3:22 7-233.

Achard JM, Westeel PF. Moriniere PH, et a/. Pancreatitis related to severe hypertrig/yceridemia during pregnancy: treatment with lipoprotein apheresis. intensive Care Med 1991; 17: 236.

Yamauchi H. Sunamura M, Takeda K, eta/. Hyperlipidemia and pregnancy associated pancreatitis with reference to plasma exchange as a therapeutic intervention. Toh oku J Exp Med 1986: 148: 197.

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Profiles

Interview with Dr. Cheril Clarson: A Pediatric Endocrinologist

Magdalena Lipowska. B. Sc .. Meds 2005

Dr. Cheril Clarson is a Pediatric Endocrinologist. I spoke with her in her office at The Chi ldren 's Hospital of Western Ontario.

She describes her journey into this position as "not that typica l" .

Immediately after high school she entered a five year MD program in Nottingham, England, as a member of the inaugural class of the first new medical school to be opened in that country in over a hundred years. A new method of education was in use at the school and this, combined with being the first entering class at a brand new school , led to a lot of attention being focused on her and her classmates.

Pediatrics had always been an interest for Dr.Clarson so doing a Pediatric Residency, after graduating in 1975, was a natural choice. The five year residency, which she comp leted in Nottingham and Birmingham, culminated in a Registrar Job , a position in England 's fairly hierarchical residency system which would be most equivalent to a Senior Resident position here in Canada. At that time, Dr. Clarson chose to get some experience in another country, preferably an English speaking one. Her emp loyer in England knew someone at St. Joseph 's Hospital who was looking for Fellows in Neonatology and so Dr.Clarson arrived in London.

After a few months of neonatology, however, she decided that this area was not for her: "I liked kids you could talk to . I liked neonatology but I missed the follow up ." Some research on infants of diabetic mothers sparked an interest in endocrinology.

Unlike her initial choice of neonatology, whi ch involved a rather dramatic environment where kids were very sick and parents very distressed, she finds that endocrinology an aspect of the field which she very much enjoys. Endocrinology has elements of distress and acutely ill patients, but also allows one to build a longterm relationship with families. So, with the initial intent of coming to London for a few months as a Neonatology Fellow, Dr. Cheri! Clarson is still here, 21 years later, as a Pediatric Endocrinologist.

What factors about Endocrinology as a specialty led you to want to go down that path ? What was your motivation in pursuing this field?

I like the practical approach: you have a ch ild with growth hormone deficiency, you treat them with growth hormone and they grow. Hypothyroid is like that as wel l. Kids with endocrine problems can have lots of complaints, yet often these can be effectively dealt with. I wou ldn 't say they can be dealt with easily, but there are solutions and I think it is very satisfying watch ing kids progress. With diabetic kids it very clearly makes a difference for their childhood and short term health and life style, and also future health, if you work with them to encourage good control.

Tell me a bit about your practice? What is your patient popLdation ?

Probably about 30% of my practice is kids with diabetes. And what is interesting, when I first started in practice, in 1985, almost all of the chi ldren had Type I diabetes. And now we 're seeing more Type II Diabetes so that's interesting. It makes [my job] a bit more challenging. And with [diabetes] patients, we work as a team here, with a nurse clinician, a social worker and dietician.

Then I do two days a week of general endocrine clinic, so that's a mix : Kids with thyroid problems, delayed or precocious puberty, growth and short stature. That's a major part of it. So these are more straightforward issues. But then what can make this more challenging is that you also get kids coming in with something more uncommon, like adrenal disorders or neonatal period babies with ambiguous genitalia and then, in the teenage years, children with intersex.

I am also seeing more and more kids who are post-oncology patients : Kids who , for instance, had leukemia or brain tumours .

Survival rates [for these cancer patients] have improved tremendously but then many of these kids have endocrine sequelae such as Growth Hormone Deficiency or Hypogonadism, mostly as a result of radiation treatment.

Another one of the things I have done, for instance, is organize a joint endocrine gynaeco logy clinic with Dr. Maggie Rebel.

The purpose of that is transition. Children that I've been seeing for years with Turner's syndrome, can be seen by both of us as they 're coming up to seventeen or eighteen [years old]. And then UWOMJ 72(2) 2003 15

we can "hand them over''. So I think that improves the process in patient care. Also, we 'll see patients with complex problems li ke disorders of intersex and we have a fair amount of discuss ion around that so I think that's sort of in the interest of patient care.

Wha t does a typical week look like for you?

In a typica l week I'll spend two days see ing general endocrine patients. Half a day is spent in the diabetic clinic, and that's with the whole team. And after the di abetic clinic we always have a team meeting so you discuss any new patients, review a journal, and talk about pati ent probl ems. The medical part of diabetes is actually kind of straightforward. What are more difficult are all the psychosocial issues. I do outreach clinics in Diabetes in Sarnia, Chatham, and Stratford and then I do Endocrine clinics in Windsor. To practice Pediatric Endocrinol ogy you have to be in a terti ary centre. In Toronto there are a few people practi cing independently, but that's because of the size of the population. In general, to have a big enough popul ation you need to been in a tertiary centre. So there's no Pediatric Endocrinologist in Samia or Windsor. It 's us. So doing clinics there every two months means that patients don 't have to travel.

The other big advantage of those clinics is that I work with staff that is on site, meaning the other members of the diabetic team [such as] the nurse clinician and dietician. So it keeps the kids in the community. They're getting access to tertiary care. But they 're still known locally and they are linked up with the diabetes care specialists locally. So kids, who wouldn 't normally get seen, get seen.

So what I am now doing a lot of is clinical work because we are understaffed. But with the new alternate funding plan whi ch is suppose to be coming in next month, we should be able to hire a third person. So that will be a maj or advantage.

Wh.at are your other responsibilities?

Apart fro m clini cal work and admini strati on, I do a lot of teaching. Almost all the clinics that I do, I have somebody working with me, a res ident or a fell ow. And as we ll as the paedi atric residents, the adult endocrine res idents and fell ows, as part of their training, have to do pediatric endocrinology. And I enj oy them coming here because they tend to keep me up to date. I also do other teaching. For instance, next month I' m running a seminar for emergency fe llows.

Amongst this busy schedu le, do you find any time fo r research interests?

Not very much. We were more involved in research, as a section , up to a co upl e of years ago. That really has dimini shed in the last coupl e of years, with the increased c linical and teaching work. But with promise that we're go ing to get someone else (in the department) then we 've starting to get more invo lved. We're just getting into a few cl inical trail s. It 's very hard to do basic research when you've got major clinical commitments. So one of the clinica l tri als we 're getting involved in is for a new insulin and we 're also getting invo lved in tri al out of Ottawa on osteoporosis 16

UWOMJ 72(2) 2003

in kids on glucocorticoid therapy. There is a lot of opportunity and I enj oy being involved in the research. Of course, the clinical work has to come first.

How amenable would you say your chosen specialty is to fa mily life and a life outside of medicine?

I think it is pretty good and I think that's part of the reason that I chose endocrinology. I did not have a family at the time, but it was good just in terms of having a social life outside medicine.

One of the advantages of pediatric endocrinology is that it's not an emergency specialty. There are a couple of situations where I might get called by the resident for advice, which is fine , but I do not have to go rushing into the hospital. And because it is not an emergency specialty you can plan things . I just have one daughter who is now 15, but when she was younger I could plan things so that I could spend more time with her. There was a period of time where I could work shorter hours and I still can rearrange my schedule so that if there is something going on at school or if I need to take her somewhere I can do that.

How do you f eel the p ractice of endocrinology or p ediatric endocrinology is changing ?

I think the practice of medicine, generally, is changing. One of the major changes I've seen is patients and families wanting to be more involved in decision making. And I think that is pretty pervasive, not just in endocrinology. And I think this, in general, is a good thing. The patient profile have somewhat changed. Like I mentioned, more kids with Type II Diabetes, more PostOncology patients and in the female population I'm seeing a lot of adolescents with PCO (Polycystic Ovarian Syndrome).I ' m not sure that it 's any more common, but maybe because it has been diagnosed more frequently. The other big change that I've seen is that we admit very few children now. Certainly, in endocrinology and in paediatrics generally [there are] fewer admissions. When I started, we had a very large inpatient population and now, here at least, in 1993 we changed from inpatient management and diagnos is to outpatient management, and we were able to do that because the medica l day unit was opened. So prior to that time, a kid was diagnosed with diabetes and they would be in hospital for 5 days , and 20 yrs ago they were kept in hospital for 10 days or two weeks. For most famili es, diabetes is a devastating diagnosis and we were trying to convey the message that they can still have a normal childhood ... but then we would stick them in a bed for f ive days.

Describe to me the management of a typical case of a p atient that someone has referred to you?

I'll give you an example. Yesterday, a family doctor called me at about 2: 00 in the afternoon because she had a patient in her office that she suspected of having diabetes. A nine year old girl.

Her bl ood sugar leve l was 25 and she had polyuria, and polydypsia but [she was] not sick. So I gave the family doctor the option of me seeing that child yesterday afternoon or this morning. She wa very happy to send the little girl in yesterday afternoon. It

was not medically urgent, but for most fa mili es, once that di agnosis has been menti oned, they are anx ious and they want as much information. They want to pl an and move on wi th it. So the child and her mother came to my office yesterday. T did a hi story and physical , rev iewed the di agnosis and impli cati ons and then discussed the plan. The short term plan was to admit her to the day unit. So this child was admitted to th e day unit, the nursing staff up there did her bl ood sugar, ordered some insul in, and met with some of the other team members and she went home in the evening/ She came back thi s morning and they ca ll ed me with her blood sugar level, I ordered some more in sulin and then I' ll meet with them aga in today and she 'll go home this evenin g. Her mother will call me over the weekend with her blood sugar, I' ll order some more insulin and we 'll get home care to go in initi ally because she has not had much opportunity to lea rn insulin administration.

What advice would you give to Medical Students pursuing endocrinology as a sp ecialty? Are there personality characteristics that are particularly well suited fo r this fie ld?

Communication is very important. In paedi atri c endocrinology it is particularly important for two reasons. One, for paediatrics generally, you are talking to famili es . You are always dealing with more than one person. You have to address the child then you have to address the famil y. And secondly, there is a lot of information to convey. If I have a child diagnosed with Growth Hormone deficiency, I have to attempt to convey to the child and to the family what it means if the child doesn 't have treatment, in terms of their growth, and what we would expect from treatment.

What's the possible cause?

And, similarly, for kids with hypogonadism, there's a fa ir amount of counselling invo lved. So in one sense it's quite pragmatic: someone is hypothyroid, you give them thyroid hormone.

That 's pretty straightforward. But, on the other hand, there is a fa ir amount of discussion and counselling that I think are essential.

The other thing that is very important in paediatric endocrinology is teamwork. You need to be a team pl ayer. You need to work with a team. And not just parti cularly for diabetes but also fo r some of these other issue, such as girls w ith Turner's syndrome.

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Is there anything else you would like to share with me today about your field or what you do ?

I enjoy what I do. I wouldn 't choose any other part of medicine. It 's a specialty that I rea lly enj oy. Wh en I started in Endocrinology in 1985 I could have had a more genera l practice but I chose not to do that because I like foc using on an area.

I like working in a teaching hospital because I like to have the opportunity to teach residents and clerks. It keeps you on your toes a bit. Sometimes, you 've been doing things for years and someone questions you : " Why are you doing that", and you have to think about it. And so it stops you from taking shortcuts. And I also like the collegial atmosphere here.

UWOMJ 72(2) 2003 17

Clinical Procedures

An Introduction to the Lumbar Puncture

Ryan J. Punambo and Craig D. Ainsworth, Meds 2005

The lumbar puncture, a proced ure in which a fine needle is inserted into the vertebral L3-L4 interspace piercing the spinal ca nal, is an effective mea ns of collecting cerebrospinal fluid. The purpose of this paper is to introduce medical students to the lumbar puncture procedure by reviewing the relevant anatomy as well as the indications and risks associated with this procedure so that it may be performed safely.

Central nervous tissue samp les are seldom removed for analysis because any extracted or damaged neuron s will not be replaced. Instead, sma ll vo lumes of cerebrospina l fluid (CSF) are collected and analysed. CSF is intimately associated with the neural tissue of the central nervous system (CNS), and pathogens, cell debris, or metaboli c wastes in the CNS wi ll therefore be detectable in the CSF' . The co ll ection of CSF is performed as a bedside technique known as the lumbar puncture.

The lumbar puncture, or Quincke 's puncture I, was fir t performed by Heinrich Irenaeus Quinke ( 1842- 1922) in 1895.

Quinke, a German internist, observed that CSF could be uccessfully withdrawn from dogs. App lying this principle to human , he reasoned that by inserting a need le wi th a stilette into the lumbar interspace, he wou ld be able to co llect CSF wi thout causing substantial damage to the spinal cord. Quinke believed that thi s technique would be useful not only in all eviating hydrocephalu , but also in the ana lysis of the CS F whi ch would aid in the clin ical diagnosis of meningiti s2.

More than I 00 years after Quincke 's first lumbar puncture, his technique rema in s an important means of co ll ecti ng CSF and measuring intracranial pressure3. The purpose of thi s paper is to introduce medical students to the lumbar puncture procedure by reviewing the re levant anatomy as we ll as the indicati ons and ri sks associated with thi s procedure.

ANATOMY OF LUMBAR PUNCTURE The adult pinal cord ranges from 42 to 45 em in length and extends from the foramen magn um in the occipita l bone to approximately the L2 vertebra l leve l where the cord tapers into the conus medullari s. As such, there i a di sparity between the

18

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length of the spi nal cord and the bony vertebral column. This disparity in length begins as a fetu . U ntil the third month of fetal life, both grow at relatively the same rate and thus the cord occupies the entire vertebral can al. Thereafter, the vertebral column grows more rapidly than the spinal cord and by full maturation the cord usually tern1inates at the inferior border of the f irst lumbar vertebra or the uperior border of the second lumbar vertebra4.

For this reason, puncturi ng below the L2 interspace ensures that the spi nal cord will not be injured.

The remaining portion of the spinal canal, the lumbar cistern, which extends from the conus medullari s to the end of the dural sheath at vertebral level S2, is filled with a collection of dorsal and ventral roots bathed in CSF. The tern1inal region of the spinal cord resembles a horse's tail , hence it name - cauda equina (Figure I ). Consequently, a needl e carefully inserted into the lumbar cistern will pass harmlessly among the nerve roots, allowing for the safe sa mpling of CSf5.

.,;.

Subarachnoid -r.lr:'=,..-..:~ space 1â&#x20AC;˘ Dura mater

I

Figure 1. Anatomy of the distal ve rtebral column.

Lumbar spinal puncture is performed while the patient maintains back flexion . Flexion of the vertebra l column is necessary because it facilitates insertion of the need le by stretching the ligamentum flavum as well as eparating the spinous processes of neighbouring vertebral segments. As a result the inter-laminar foramina enlarge allowing for easier puncture6.

As the needle punctures the skin and moves towards the lumbar cistern, it must pass through three supporting ligaments of the vertebral column (supraspinous ligament, interspinous ligament and ligamentum flavum) and two of the spinal meningeal layers (dura mater and arachnoid mater). Collectively, the dura mater, arachnoid mater, and pia mater surrounding the spinal cord form the spinal meninges. These membranes in addition to CSF in the subarachnoid space surround, support, and protect the spinal cord and spinal nerve roots - including those in the cauda equina. In a lumbar spinal puncture, the needle traverses the dura and arachnoid mater and enters the space containing CSF6.

INDICATIONS The lumbar puncture is only indicated in clinical settings for which CSF findings have sufficiently high sensitivity and specificity to aid in diagnosis. For this reason, there are few clinical scenarios for which the lumbar puncture is clearly indicated (Table 1).

In contrast to these conditions, there are numerous diseases for which CSF analysis is of little diagnostic value. More specifically, conditions such as primary and metastatic brain tumours , brain abscess, subdural or epidural haematoma, have abnormal , but non-specific CSF findings. Consequently, a CT scan is necessary to confirm the presence of these diseases 3 .

Table 1. Indications for Lumbar Puncture

7.8

Absolute Indications Meningitis Encephalitis ..

Guillain-Barre syndrome (acute inflammatory polyneunt1s) Acute demyelinating disorders Benign intracranial hypertension Unexplained neurologic disorders -seizure, stroke, polyneuropathy, dementia, altered level of consciousness Therapeutic administration of antibiotics or antineoplastic agents ..

Diagnostic injections of dyes (myelography) or radiOISOtopes (CSF leak) Possible Indications (depending on the clinical scenario) Multiple sclerosis Subarachnoid haemorrhage

CONTRAINDICATIONS AND RISKS Much like any injection, a lumbar puncture is contraindicated in the presence of local infection at the proposed site of entry.

In addition studies have shown that a lumbar puncture performed in the pres~nce of severe bleeding leads to an increased risk of developing a spinal subdural haematoma 7.

Figure 2. Supporting ligaments of the vertebral column. From deep to superficial : (A) Ligamentum flavum , (B) Interspinous ligament, (C) Supraspinous li gament.

However, Eng & Seligman ( 1981) emphasize that the presence of septicemia is not a contraindication since the incidence of meningitis among a cohort of septic patients who underwent a lumbar puncture was no different compared to controls 8 .

In general, the lumbar puncture is considered a safe procedure. The post-lumbar puncture headache (also known as the postdural puncture headache), which occurs in 10-25 % of patients, is the most common complication of this procedure 3 .

The headache is described as "usually but not always bilateral and may be characterized by frontal or occipital pressure and throbbing occurring when the patient is upright, and diminishing when supine"2. Using a smaller gauge needle and placing the patient in a prone position following the procedure can minimize the risk of headache7. In addition, to the post-lumbar puncture headache, another common complication is severe bleeding particularly among those using anticoagulants.

A rare but potentially lethal complication of lumbar puncture may arise among patients with raised intracranial pressure. These patients are at an increased risk of tonsillar herniation, a condition where the cerebral tonsils are compressed downward into the foramen magnum , placing patients at risk of cardiorespiratory arrest. Although the incidence of tonsillar herniation following lumbar puncture is unclear, some studies estimate an incidence of < 1.2%3.

THE APPROACH As with any clinical procedure, the student must begin by thoroughly explaining the risks and benefits to the patient and obtaining consent.

In the event that the patient is suspected of having a defect in coagulation, a platelet count and prothrombin/partial prothromboplastin time may be obtained. In addition, a careful fundoscopic and neurological exam should be performed to rule out papilledema or a focal neurological deficit. Usually no intravenous pain medication is required3.

The most important aspect of this procedure is ensuring that the patient is properly positioned. Place the patient on a firm surface in the latera l recumbent position, with knees curled towards the chest. Further, ensure that the patient's lumbar region is close to the edge of the bed and the plane of the back and shoulders per-

UWOMJ 72(2) 2003 19

Figure 3. Proper positioning of patient for lumbar puncture.

pendi cular to the bed (Fi gure 3 ). The student should not continue with the preparati on until thi po ition has been achieved, otherwise the line for the puncture needle is unpredictable.

THE TECHNIQUE An imaginary line joining the posterior iliac crests roughly identifies the L3-L4 interspace, the target area for the lumbar puncture. In situations where a patient 's vertebral landmarks may be difficult to identify (such as in obese patients or those suffering from ankylosing spondyliti s), the student may opt to place the patient in a seated position with neck and spine maximally flexed with arms relaxed and then identify the L3-L4 interspace using the approach described above. Once the target area has been identi fied, the area hould be cleaned and draped with a portal exposing the area just identified.

Again identi fy the L3 and L4 pinous processe by placing fin ger o f the left hand on each, tretching the skin between.

Therea fter, try to keep th ese fin gers on the pines to maintain the

Table 2. Contents of a commercial lumbar puncture kit.

Materials for Local An estheti c: 5 mL syringe, 25 -gauge needl e, 22-ga uge needl e, I % lidoca ine so lution Ma ks, steril e glove and drapes A lcohol swab Spinal needl es (2 0-gauge needl e, 22-gauge needl e ) Manometer and three-way stopcock Three steril e co llecti on tubes Steril e gauze sponges Tincture of iodine (Betadine)

depth of approximately 4 to 5 em.? The needle should be para_llel to the ground at all times . Continue inserting the needl e until a li ght "pop" or "give" is experienced, indicating that the dura mater has been pierced4.

If the needle strikes bone or if no fluid is tapped within 10 mm of the "pop", consider withdrawing the needle to just below the skin, asking the patient to further flex the spine, and reinsert the needle, pointing slightly more towards the head as necessary.

The CSF is classically described as " gin clear" in appearance' . Once CSF ha been identified in the hub of the needle, reinsert the stilette to avoid further flow until a manometer can be attached to the needle using a three-way stopcock. Remember the pre sure should always be measured, saving the fluid passing through the manometer for analysis . If the manometer indicates a normal opening pre sure (80-180 mm CSF)?, the student may proceed in collecting CSF in the three (or more) sterile tubes (equivalent to a total volume of 10 mL) 2 .

Finally, after the manometer has been reconnected and a closing pressure recorded, the manometer, stopcock and the needle may be carefully removed. Apply pressure over the puncture site and dress the puncture site. The patient should then be instructed to remain prone for 2-3 hour following the procedure in order to minimize post-lumbar puncture headache9.

CONCLUSION The lumbar puncture is an effective procedure for the collection of CSF. Although it is considered safe, the lumbar puncture is not by any means a routine procedure. In order to perform the lumbar puncture, the student must have an approach grounded in a thorough understanding of its relevant anatomy, indications, contraindications and potential risks .

REFERE CES I. 2.

3.

4.

5.

6.

7.

8.

re lation ship whil e anaestheti zing th e skin and later inserting the lumbar pucture needl e. With the Lidoca ine, infiltrate the skin midway between these f ixed po int using the right hand, ensuring th e left hand remains on th e two spinous processes.

After havi ng anesthet ized the target area, in ert the lumbar puncture needl e with a rotary moti on into the target area, angling the needle along an imaginary lin e running from the site of entry to the umbilicus (pointing the needl e about 5路 headwards) to a

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9.

Rubin E. Farber JL. Eds. Pathology. 3rd ed. New York: LippincottRaven Publishers 1999: 14 75- I 4 77.

Brocker RJ. Techniq ue to avoid spinal tap headache. Journal of th e American Medical Asso iation 1958: 68:261-263.

Simon R, Brenner B. Emergency Medicine. Baltimore. MD: Williams & Wi lkins 1982: 156- I 67.

Moore KL. Persaud TVN. Th e Developing Hum an: Clinically Oriented Embi)'Oiogy. Philadelphia, PA: WB. Saunders ompany I 998.

No lte. J. The Hum an Brain: An Introduction to its Functional Anatomy.

4th ed. Sr Louis: Mosby Inc. I 999.

Moore KL. Dalley II, AF Clincal/y Oriented Anatomy, 4th ed. Baltimore, MD: Lippincott Wi lliams & Wi/A:i ns 1999.

Braun wald E. Fa uci AS. Ka per DL. Hauser SL. Longo DL. Jam eson JL Eds. Harrison :S Principles of Internal Medicine, 13th ed. McGra w-Hill, Inc. 2001: 232 -233 1.

Eng RHK. Seligman SJ. Lumbar puncture-induced meningitis. Journal of the American Medical Association I 98 I ; 245:1456- 1459.

Marton KJ. Gean AD. Th e spinal tap: A new look at an old test. Annals of Internal Medicine 19 6: I 04:840-848.

Medicine on the Internet

Implications of Internet use in both patient education, and continuing medical education for physicians

Deric Morrison, Meds 2005

Over the past decade Internet use has evolved from a relatively obscure practice, to a common activity impacting heavily on many areas of society. The internet has especially had a profound effect on medicine. The emergence of the Internet has helped to provide an environment where advances in clinical practice and biomedical science can occur at a remarkable pace. There are numerous resources devoted to patient and physician medical education. This information has become widely available at a time when the medical profession has adopted a patient-centred, informed consent based model, in response to pressure from patients who desire more control over their health care. Relevant patient education can be valuable to care, but the unregulated nature of the Internet makes it a potentially dangerous landscape marked with information that ranges from helpful to dangerous. This article reviews methods to promote efficient use of the Internet by patients, and advocates physicians ' use of the Internet as a mode of life long learning and continuing medical education.

INTRODUCTION

PATIENT EDUCATION ON THE INTERNET

Not since Guttenberg 's development of the printing press has something revolutionized communications and information dissemination like the Internet. After a relatively slow thirty year evoluti on from its humble beginnings in 1962 to its state in 1992 when the first graphics based web browsers were introduced, the Internet has become so ubiquitous that its impact can be seen today in almost all facets of society. The delivery of health care is no exception. Widespread use of the Internet has come at an opportune time for the medical profession . Over the past few decades western medicine has undergone a metamorphosis from a paternalistic physician-patient relationship model to a patientcentred approach, based on informed consent of the patient. The Internet has the potential to be an invaluable mode of patient education and allow patients to take a more active role in decisions regarding their care. As well as helping to educate patients, the Internet can also be used as a tool for health care providers to maintain current medical knowledge in an era where advances in medical science are occurring at an amazing pace. Unfortunately, in addition to the promising potential the Internet offers, there are great concerns about the effectiveness of its use. The Internet is a vast landscape of health care information, some timely, accurate and valuable, while some is out of date, misleading or even dangerous. Sifting through the dunes of sand to find the gold can be an incredibly daunting task. However, the Internet is here to stay and it is up to the health care community to undertake the task of using this potentially valuable resource for the benefit of patients, whi le protecting them from its lurking dangers .

Already the reality is that a primary use of the Internet among consumers is to illicit hea lth care related information . In the US in 1999 between 30-60 million people u ed the Internet to re earch di sease, look for nutrition and fitness information, research drugs and drug interactions, locate medical care or use online medical support groups. I This clearly indicates that today's patient wishes to have more informati on on, and assume more control over their general health and medical interventions. This desire is evidenced by the vast amount of health care information provided on the World Wide Web. It is estimated that there are 100 000 Internet sites containing heal th care inforn1ation ,2 some of which is of high quality, but other can be, misi nformation, good information that is unsuitable to the patient, or questionable information designed to se ll products 3 Determining what information is valuable can be difficult for patients as there is no standard of validation required to post information on the Internet. A lso, it is difficult to di sti ngui sh between sites that are oriented to patients, and those that are geared for physician use .4 This could cause confusion for patients who are ill equipped to deal with specialized information which is provided for use by medical experts. To combat these diffi culties it is important that physicians are able to help in clarifying information that their patient bring to them from the Internet and that they are able to help guide a patient's search more efficiently through the immense amount of health information on the World Wide Web. This need can be seen in the fact that 89% of doctors claim that patients ' use of the Internet affects their practice.l Unfortunately, most physicians asserted UWOMJ 72(2) 2003 21

that this influence could be negative more often than positive, citing that patients often brought misleading information or information which was not relevant to their situation. Another concern that physicians voiced was that there were instances where patients would bring in information that physicians were not aware of, and that this would harm patients ' confidence in their doctors . In order to address these concerns the physician can take many simple approaches . Firstly, physicians must create an atmosphere where patients feel comfortable telling their physicians about the information they have located on the Internet.

This step allows doctors to evaluate patients' resources and protect them from potentially misleading, irrelevant or dangerous information, and it gives physicians the option of trying to help patients find reliable information that will be of use to them , save time for both the doctor and patient, and even possibly allow the patient to become a resource for the doctor, if the patient can find quality information that the doctor and patient can then critically evaluate together. One potentially helpful resource that physicians can provide their patients is the use of ethics sites, such as eHealth Code of Ethics (www. ihealthcoaltition.org), Health on the Net (www.hon.ch), and Truste (www.truste.org). These sites give guidelines that are based upon the notion that health care websites should provide timely and accurate information, as well as disclose conflicts of interest, authorship and attribution , and flow of information to third parties.3 However, whereas these guidelines are a good start, consumers still need to be wary, as it is difficult for these sites to police health care websites that claim to conform to their guidelines. In response to this problem the American National Institute of Health has designed a new web page (www.medlineplus.gov), that places sites that comply with its ethical guidelines, directly on the page, creating a safe and reliable resource for patients.s An area of special concern is regarding complementary and alternative medicine (CAM). The Internet is a breeding ground for information on CAM, and many patients do not disclose their CAM practices to their physician. This can be very dangerous as the sites on the Internet devoted to CAM can range from research based information to blatantly mi sleading information designeq to make money from unsuspecting patients. It is important that physicia ns are aware of their patients CAM practices and ideas, so that they can provide insight into treatments and direct patients to reliabl e information on CAM. A reliable site can be found on the National Center for Complementary and Alternative Medicine (http://nccam.nih .gov). 6 The fact is increasing numbers of patients are using the Internet to find health information, and while there are some problems, there are many benefits if thi s trend is used to its potential.

Accurate patient education has been shown to save time, give patients more reali stic expectations, more appropriate use of health care resources by pati ents,s and even improve patient outcomes.?

PHYSICIAN EDUCATION ON THE INTERNET It is not only patients that need to be educated when it comes to health care and the Internet. With the immense and rapidly evolving body of medical knowledge it is imperative that physicians continue to learn throughout their careers. It ha been found that in an average day more than 50% of visits to a family practi-

22

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tioner will generate a medical question for the physician, however only 30% of these questions are pursued, with 26% being answered.8 In a study of general internists an average of 12 questions per day was found, with answers being sought for 33% of these questions.9 Clearly, medicine is a knowledge intensive profession and physicians need access to relevant information every day.I O, II , 12 The most common way that doctors go about answering their medical questions is through asking colleagues, 10 â&#x20AC;˘ 12 ¡ 13 and while this may be acceptable in some circumstances, this information may be lacking, is difficult to validate and may be biased. In the past, the other ways to locate medical information were through textbooks, published journals and continuing medical education (CME) courses and conferences. However, a major problem with these methods was accessibility, it simply took to much time and effort to access these options for each patient question, and unfortunately it has been found that often, due primarily to time constraints, accessibility of medical information is more important to physicians than its quality.14 For this reason traditional methods of CME do not significantly affect physician behaviour. 15 However, the Internet could be a great way to improve CME. Already, in 2000 66% of family physicians used the World Wide Web, and this number continues to climb.16 The advantages of using the Internet for CME are multiple; the specific content desired can be searched for easily, the information can be found from any computer wired to the Internet eliminating travel time and costs to attend seminars, conferences or libraries, and the research can be conducted at anytime that is convenient. However, many of the same problems that affect patient education on the Internet also confront on-line CME for physicians. The information must be easy to locate or it will suffer the same fate as traditional CME, although it may be easier for physician to distinguish good information from bad, if it is too difficult to find relevant information the Internet becomes a poor resource. In a study to determine what physicians would require for useful resources in the Internet it was found that the premium resource would contain brief summaries of important information with links provided to more detailed information.16 Already, there are many great resources for physicians on the internet, Pubmed/Medline (www.pubmed.gov) is a great, free, index of journal articles, however for many journals it is impossible to obtain more than abstracts to obtain complete articles, as well as access to online textbooks, clinical practice guidelines and patient handout sites like MDConsult (www.mdconsult.com) are excellent, though membership fees are often required. Another emerging option is accessing websites provided by universities and medical schools.

An exan1ple of this is the University of Iowa 's virtual hospital where CME modules are provided for physicians to complete for credit. This project has been very successful in that many physicians have visited the virtual ho pita! as a resource. However, few physicians complete entire modules for credit. In order to make this option more enticing it ha been proposed that credit be offered based on the amount of time the system is used so that doctors can use the vittual hospital to answer questions pertaining to their practices while working toward credit without having to complete an entire module, which may or may not apply to their current information needs.l5 Overall, there are many great references on the Internet that could make CME easier, more accessible and more valid than simply asking colleagues or using old textbooks, but in

order to make the best use of these resources some background research must be put into finding and evaluating sites that can be of use in the future. This background research could save much time floundering around in cyberspace in the future and could dramatically improve physician knowledge and clinical dec ision-making.

CONCLUSION The Internet is a doubl e-edged enti ty, which could pose serious problems for the health care professions if it is permitted.

However, if used wisely, physicians themselves can benefit from or even develop quality methods of CME that wi ll help to advance the medical profession . In addition , physicians have the ability to help gu ide their patients use of health care information on the internet, helping to develop a critical approach to Internet health care, thereby perhaps limiting the success and spread of sites with questionable material and promoting a popul ati on armed with quality hea lth care knowledge and resources to an extent never before imagined.

REFERENCES I. 2.

3.

4.

5.

6.

7.

8.

9.

10.

11 .

12.

13.

14.

i 5.

16.

Fotsch E, The effect of the World-Wide Web on you and your patients.

Ophthalmol Clin No rth Am 2000 Jun : 13(2) :261-269.

Eysenbach G. Consumer health informatics. Br Med J 2000:320:17i 3- i 7i 6.

Mazzini MJ. Glode LM. lnrernel oncology: Increased benejir and risk for parienrs and oncologists. Hematol Oncol Clin North Am 200i Jun ; 15(3) :583-92.

Kim Mi . Endocrinology resources on the internet. J Clin Endocrinol Metab 2001 Jul;86(7):2 942-5.

Ullrich PF Jr. Vaccaro AR. Patient educarion on rhe intern et: opportunities and pitfalls. Spine 2002 Apr i ;27(7) :Ei 85-8.

Bouch B, Mc Waters DS. In adequate intern et Resources Cited.

Pediatrics 200i No v;i 08(5): i 23 7-8.

Jones JM, Nyhof- Young J. Friedman A, Calton P More than just a pamphlet: development of an innovative computer-based education program for cancer patients. Patient Educ Couns 200i Sep;44(3): 27i-81.

Gorman PN, Helfand M. Informa tion seeking in primwy care: how physicians choose which clinical questions to pursue and which to leave unanswered. Med Decis Ma/..:i ng 1995:15:ll3-i 19.

Covell DG, Uman GC, Manning PR. Informati on needs in the office practice: are they being met? Ann i ntern Med 1985;103:596-599.

Dee C, Blazek R. Information needs of th e rural physician: a descriptive study. Bull Med Libr Assoc i 993:8i :259-264.

Ely .rw, Burch RJ. Vinson DC. Th e information needs of family physicians and other health care practitioners: case-specific clinical questions. J Fam Pract 1992:35:265-269.

OsheroffJA , Forsyth e DE, Buchanan BG, eta!. Physicians路 information needs: analysis of questions posed during clinical teaching. Ann intern Med i 99l;ll 4:576-581.

Hayward RSA, Guya/1 GH. Moore KA , Carter AO. Canadian physicians ' attitudes about pref erences regarding clinical practice guidelines.

CanMedA ssoc J 1997; 156:i 715-23.

Verhoeven AA , Boerma EJ. Meyboom-de Jong B. Use of information sources by fam ily p hysicians: a literature survey. Bull Med Libr Assoc 1995;83(1) :85-90.

Peterson MW. Galvin JR. Dayton C, D 'Alessandro MP. Realizing the promise: Delivering pulmonwy continuing medical education over the internet. Chest 1999 May: ll 5(5) :i 429-36.

Feightner Jw. Marshall JN, Sangster LM, Wath en CN, Quintana Y. Evidence-based preventive practice Guidelin es: Qualitative study of useful resources on th e Intern et. Can Fam Physician 2001 Aug;47: 1577-83.

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UWOMJ 72(2) 2003 23

Medicine and the Law

The Regulation of Physicians

Leanne Tran. B.Sc., LL.B. (University ofToronto) , Meds 2005 Birinder Singh. B.Sc .. LL.B. Meds 2004

In Canada, the actions of physicians are regulated through two major mechanisms: (1) the courts, by means of civil liability and negligence litigation, and (2) through disciplinary action by the Colleges of Physicians and Surgeons of the various provinces. Negligence in a medical context has many unique characteristics that general negligence claims do not deal with. The regulation of physicians by our regulatory bodies is for the purpose of protecting the public, and is geared towards dealing with indivi dual physicians, as opposed to litigation which is concerned with redressing wrongs done to patients by providing financial compensation.

The regu lation of physicians can be clas ified into two categories : (I) civil liability or negligence litigation and (2) di cip li nary action for fa ilure to meet professional standards. Both categories are important for they can each affect the practicing phy ician in a multitude of ways . A such, a comprehensive understanding of their mechani sms i vital for all physician .

CIVIL LIABILITY Although several a pects of a medical negligence suit are unique, it shares the rationale and basic elements of any negligence claim. The medical negligence c la im has two goa ls: ( I) to compensate the victims of substandard medical practice and (2) to deter future negligence. To thi s end, the plaintiff (patient) must prove (I) a duty of care exi sts, (2) that the duty was breached, and (3) the defendant 's (physician's ) negligence caused the plaintiff's injury.' Each of these components wil l be examined in turn .

I. Duty of Care

The first condition which must be ati sfied in a medical negligence action is that the physician owed the patient a duty of care.

Thi is rarely an issue. Once a doctor-patient relation hip ex ists, a duty of care exists. In recent years, third party liabi lity has become an increasingly important issue. There have been evera l ca e in which physician were found not on ly to be liable to their patient but also to third parties injured as a result of the negligence.2 For instance, in Pittman Estate v. Bain ,J a fami ly phy ician was li able to the wife of a patient. The patient had received HIV contaminated blood and later infected hi s wife. The physician was found to be negligent for not telling the patient that he had contracted HIV from the tran sfu ion . The court determined that if the patient had been told thi s information, hi s wife wou ld not be infected . Another examp le wou ld be a physician not report24

UWOMJ 72(2) 2003

ing a patient who i medica lly unfit to drive . In two Ontario cases,4 plaintiffs injured in a car accident obtained damages aga in t the other driver' physician on this basis.

II. Standard of Care

A. General Principles The law does not require phy icians to be infallible. Rather, a physician must demon trate the level of knowledge, skill and care that would rea onably be expected of a physician of the same experience and standing. Therefore, it follows that the reference for the tandard of care of a pecia list would be a rea onable practitioner of the same pecialty. However, a phy ician without the qualification s or training of a pec ialist who a sumes the responibilitie of a specia li t or hold him elf/herself out to be a specia li t, is held to the tandard of care of a specialist s It i a! o well e tabli hed that the medical knowledge and tandards of practice that ap ply are those that are in place at the time of the alleged neg li gence. This is significant as the knowledge and tandard may change while the case makes its way through the co urt sy tern . Furthermore, the applicable standard of care i determined w ith reference to the resources available to the physician . For exa mple, a physician cannot be liable for failure to use a certain apparatu (e.g., MRI) if it was not avai lable. A related i sue invol ves budgetary concerns - a physician i negligent if a certa in procedure or test was available but it was not performed becau e of the costs.6 Moreover, a physician who cannot access testing or equipment may be found negligent if he/ he doe not refer the patient to the proper facilities . This also applie to the duty to refer to a specia li st - the law expects physicians to know their own limits.

B. Error of Judgment

An error of judgment by a physician does not necessa rily translate to negligence. It is not sufficient for the patient to establi sh that the physician was mistaken; it must also be shown that a reasonabl e physician in the same circum tances would not have made the same error.? The most common example of this pri ncipl e is mi sdiagnos is. It should be noted that although the ini tial mi staken di agnosis may not constitute negli gence, a phys ician may be liable if he/she does not re-evaluate the di agnosis especially if the pati ent is deteri orating or treatment appears ineffective .& C. Approved Practice In general, when a physician acts in accordance with "accepted medical practice", he or she will not be fo und negligent .ix However, there are some exceptions to thi s: ( I) where there are obvious ri sks and (2) where non-technica l matters are at issue so that the trier offact (i.e., judge or jury) despite its lack of medi ca l knowledge can conclude that the approved practi ce was not reasonable and hence the physician was negli gent to fo llow it.

III. Causation The patient in a medical negligence case has the onus of proving (on a balance of probabilities) that the physician 's negli gence caused the injury. The leading med ical malpracti ce case on causation is Snell v. Farrell.IO The Supreme Court in this case stressed that tri al judges in medica l negligence actions should not be disinclined to assume a " robust and pragmati c approach" and infe r causation from the evidence. Sopinka J. wrote:

The legal or ultimate burden remains with the p laintiff, but in the absence of evidence to the contrary adduced by the defendant, an inference of causation may be drawn, although positive or scientific p roof of causation has not been adduced. I I Sn ell v. Fa rrell seems to have lowered the bar fo r patients to prove causation in malpracti ce suits.

IV. Injury A monetary award will not be given without proof of damage, even if negligence is established. In the maj ority of cases, th e injury will be obvious. However, there are occasions where thi s becomes an issue such as in claims fo r "wrongful birth" and "wrongful life". The characteri stic case invo lves a phys ician who performs a sterilization procedure on the pati ent (e.g. , vasectomy or tubal ligation). However, because of the physician's negli gence, the procedure is not effective and the patient (or his/her partner) becomes pregnant and gives birth. Have the child or the parents suffered any " injury"?

With respect to the child 's claim, most courts have held that one cannot establish whether the child has been injured (even when the child has severe di sabilities) because thi s would entail a compari son of the child 's current ex istence with a situation where the child did not exist (i.e., would the child be better off if he/she had never been bom ?). 12 As for the parents' claim (e.g. , the monetary costs of rearing the child), the view has changed recently. In the 1970 's, Canadian courts held that it was contrary to public policy to award damages for the birth of a healthy child.13 The U. K. courts have recently rejected thi s position and have given damages to the parents,xiv

and Canadian courts seem to be fol lowing suit. For instance, in Suite v. Cookel5 and Joshi v. Woo/ley,16 the Canadi an courts awa rded damages for the birth of a healthy child including the cost of ra isi ng the chil d to the age of majority.

V. Defences Certain defences are available in the negli gence action. The most common one in med ica l malpractice suits is the limitat ions defence, a compl ete defence to the p lai ntiff 's cla im. A negligence action in genera l and aga inst a physician must be commenced by a certain time. In most prov inces the li mitati on period is one to two years and it can begin fro m the time professional ervice end regardl ess of whether the patient is aware of an inj ury. TI1U , many patients are time-barred before they even know that they have a cause of acti on (a lthough in Ontario the time start fro m when the pati ent knew or ought to have kn own the facts upon whi ch the neg li gence claim is based). Thi s is different fro m most general negligence cases where the limitati on period beg in s when the cause of acti on ari ses. 17 Another defence is contributory negligence. Thi s is not a complete defence but rather reduces the damages in accordance w ith the shared fault between pl aintiff and defendant. Although thi s defence is not common in med ical negligence suits, 18 there have been some cases in whi ch it has been raised successfu lly. For instance, a pati ent who did not use crutches after a bone bi opsy (and then fe ll and broke her leg) was held to be one-fift h contributorily negli gent.1 9 Such cases indicate that the courts are not only looking at the patient's behaviour but are also more criti cal of it. "As patients strive for (and achieve) a more equal ro le in their medi cal care and in the doctor-pati ent relati onship , it is predictabl e and just that there will be more patients fo und to be contributorily negligent, with a consequential reduction in the compensati on awarded."20

VI. Class Action Litigation In certain cases, class acti on proceedings may be used in order to most efficiently utili ze judicial resources, as well as to increase access of individuals to the court system . By going forward with class acti ons, courts can answer lega l questions of importance to many peopl e in a single proceeding, thereby sav ing time and money for all invo lved. As well , lawyers in class action proceedings work on a contingency basis, thereby all owing econo mically di sadvantaged pl aintiffs more equitabl e access to the system. For a class acti on to proceed, there needs to be an identif iable class, and there must be a representative plainti ff who wi ll bring the matter before the courts on behalf of the class members .

An exampl e of class acti on proceedings in a clinical situation is fo und in Anderson v. Wilson21. In thi s case, negligent sterilization techniques at an EEG clinic led to Hepatitis B preva lence in the clinic's population to be 500 times that of the general population.

Common issues that the court heard in class proceedings dealt with the breach of standard of infection control procedures, that there was a single infection carrier (a technician), the treatment modality used (EEG), etc. Ind ividual issues left over were things like damages, and whether the patient indeed received the Hepatitis B from the clinic, or whether it was from some other source. Ultimately the court fou nd in favour of the class participants fo r a total of $95 mill ion in compensatory damages , and

UWOMJ 72(2) 2003 25

$ 10 mi ll ion in punitive and exemplary damages. Other examples of the use of class proceedings invo lved the infamous breast implant cases against Dow Coming.

DISCIPLINARY ACTION Thi s is to highl ight an exampl e of di sciplinary and refl ects actions and procedures taken in Ontari o. This does not necessarily refl ect the respective colleges of all provinces.

The College of Physicians and Surgeons of Ontario The di sciplinary process, unlike civil li ability, is controlled by the profess ion itself. In Ontario, the professional body is the College of Physicians and Surgeons of Ontario (CPSO). Also, unl ike the negli gence action, the di sciplinary process does not compensate victims monetaril y.

The CPSO sets the tandards of practi ce and guidelines for ethical conduct which are enfo rced by the di sciplinary process.

The aim is to prevent threats to the publi c welfare. The CPSO al so controls who enters the profession (input regulati on) and monitors their competence and conduct after professional admittance (output regulati on). Compli ance w ith standards can be checked by peer review and by compl aint investi gation .

The CPSO di sciplines three classes of intolerabl e conduct: inco mpete nce, misconduct a nd conduct unbecoming.

Incompetence refers to practice which does not meet a generally accepted level. Incompetence includes incapacity (e.g., addiction, illness). Professional mi sconduct invol ves unacceptable behaviour within the professional practice. Misconduct includes sexual acts with patients, improper billing practices and income tax evasion. Conduct unbecoming usually concerns actions outside the professional practi ce that could bring the profess ion into disrepute.22

The Discipline Process The pro fess ional di scipline process has four stages : detection, investigati on, hearing, and appeal. The primary method of identify ing probl ematic behaviour in physicians is through patient complaints. It should be noted that many compl aints to the CPSO invo lve poor commun ication between the pati ent and the physiCia n .

Once a complaint has been f il ed, an investi gation (usually mandatory) is started . The obj ective o f the investigati on is to di spose of or reso lve some charges in a timely manner, and to co llect evidence for the next stage of the process. If an investigation concludes that a complaint has merit, it w ill advance to a hearing with a panel. The panel usually consists of3 practi sing phys icians and 2 members of the publi c. Evidence is presented at the hearing and a decision is made regarding whether or not the conduct was improper and what, if any, sanction should be imposed.

Sanctions include remedial education or training, a fine, a reprimand on record, suspension, license conditi ons or revocation.23 The last stage is the appea l, either to a court or to an appea l committee of the professional body. In additi on, a phys ician may have the opti on of applying fo r j udicial review of a dec ision.

REFERENCES 1. See genera lly L. KIGI: Tort La w, 2nd ed. (To ronto: Carswell, 1996).

2.

See E. Picard & G. Robertson. Legal Liability of Doctors and Hospitals in Canada. 3rd ed. (Toronto: Carswell. 1996) at 180-84.

26

UWOMJ 72(2) 2003

3.

4.

5.

6.

7.

8.

9.

10.

11 .

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

(1994), 11 2 D.L.R. (4th) 257 (Ont. Gen. Div.).

Toms v. Foster (1994), 7 M. V.R. (3d) 34 (Ont. C.A.): Spillane v.

Wasserma n (1992) , 42 M. V.R. (2d) 144 (Ont. Gen. Div.).

Poole v. Morgan, [1987] 3 W.W.R. 217 (A lta. Q.B.).

Law Estate v. Simice (1994), 21 C.C.L. T. (2d) 228 (B.C. S.C.) : affd [1996] 4 W.W.R. 672 (C.A.).

Wilson v. Swanson (1956), 5 D.L. R. (2d) 11 3 (S. C. C.) at 120. This standard was reaffirmed in Lapointe v. Hopita / Le Gardeur (1992). 90 D.L. R. (4th) 7 (S.C.C.).

Bergen v. Sturgeon Gen eral Hospita l (1984), 52 A.R. 161 (Q.B.). rer Neuzen v. Korn [1995] 10 W.W.R. 1 (S.C.C.) at1 5.

(1 990). 72 D.L.R. (4 th) 289 (S.C. C.).

Ibid.. at 301.

McKay v. Essex A .H. A .. [1982] 2 W.L.R. 890 (C.A.): Catafo rd v. Mo reau (1978), 11 4 D.L.R. (3d) 585 (Qu e. Supp. Ct.).

For example, see Doiron v. Orr (1 978) , 86 D.L.R. (3d) 719 (On t. H. C.); Colp v. Ringrose (19 76) 3 Leg. Med. Q. 72 (A lta. S.C.) .

Emeh v. KensingtonA .H. A .. [1985] 2 WL. R. 233 (C.A.); Wa tkin v. South Ma nchester Health Authority, [1995] 4 A ll E.R. 132 (C.A.).

(1993). 15 C.C.L. T. (2d) 15 (Que. Supp. Ct.); affd [1 995] R.JQ. 2765 (C.A.) .

(1995). 4 B.C.L. R. (3d) 208 (S.C.) .

Kam loops (City) v. Nielsen. [1984] 2 S.C.R. 2; Centra l Trust Co. v.

Rafuse. [1986] 2 S.C.R. 147: M.(K.) v. M.(H.), [1992} 3 S.C. R. 6; Murp hy v. Welsh. [1993} 2 S.C. R. 1069; Peixeiro v. Haberman. [199 7] 3 S.C. R. 549.

See Picard & Robertson, supra. note 2 at 283-86.

Brushelt v. Cowan (1990), 69 D.L. R. (4 th) 743 (Njld. C.A.).

Picard & Robertson. supra. note 2 at 284.

(1998) . 156 DLR (4th) 735 (Ont. G.D.). varied (1999), 175 DLR (4 th) 409 (Onr. C.A.).

G. Sharpe, The La w and Medicine in Canada. 2nd ed. (Vancouver: Butterworths. 1987) at231 .

Sibbald B. "He aid. she said: demystifying the dreaded di ciplinaiJ' hearing " (2000) CMAJ 162(8): 1199.

Health Promotion

Primary prevention of Type 2 diabetes: Lifestyle interventions

Anna Labuda, Meds 2005

Type 2 diabetes, which is reaching epidemic proportions in our society, has long been linked to behavioural and environmental factors such as diet, obesity and physical activity. This article present lifestyle modification as an effective primary prevention against diabetes. A few of the major recent studies are reviewed, which show that, a prevention effort for diabetes may well be justified.

Type 2 diabetes is one of the most costly and fastest growing diseases of our time 1.2. Estimates show that between 1995 and 2025 , the number of people diagnosed with diabetes will increase by 42% (to a total of 71 million) in industrializes countries, and by 170% (to a total of 228 million) in developing countries 3.

Diabetes is a chronic disease, which manifests itself in illness, economic consequences, loss of quality of life, and death 3.

Complications of diabetes are microvascular and macrovascular, leading to damage or failure of organs such as kidneys , nerves and eyes I, 2. Individuals with impaired glucose tolerance (IGT) also have a higher risk of cardiovascular disease 1. Though treatments that prevent the devastating complications of diabetes do exist, they are suboptimally used, and the disease is progressive and degenerative 3.

The rationalization for the prevention of type 2 diabetes is the prevention or postponement of complications arising from this disease. This is intended to reduce human suffering as well as the socio-economic burden on the society 1. It is estimated that at the time of type 2 diabetes diagnosis, only 50-60% of pancreatic Bcell capacity is left, as the disease has already been present for over a decade 4. This leads to the conclusion that the most effective approach to decrease the burden of type 2 diabetes is primary prevention 1.

Primary prevention can be defined as all measures that aim to reduce the risk of disease onset, by modifying the underlying factors for type 2 diabetes I . Thus, the goal of primary prevention of type 2 diabetes is to control the worsening of glucose intolerance before the damaging effects of hyperglycemia become permanent 1. There are 5 main conditions that should be satisfied, in order to justify a prevention program 2. Firstly, the target disease should be a health problem that is a significant burden on the affected population. The early development of the disease should

be understood well enough to identify parameters that measure its advancement to disease. Thirdly, a safe and predictive test should be available that detects the predisease state. There should also exist safe, effective and dependable methods that prevent, or at least delay, the progress from the predisease to the disease state.

It is known that diabetes satisfies all four of these criteria. It is the fifth condition, that the cost of finding high-risk individuals and the cost of the intervention should be cost-efficient, that has not yet been determined. Even though the cost-effectiveness of intervention strategies is not completely elucidated yet, the tremendous burden resulting from the complications of diabetes and the potential benefits of some interventions suggest that a prevention effort for diabetes may well be justified 2.

As type 2 diabetes is a multifactorial disease, prevention programs shou ld be based on the modification of several risk factors concurrently. However, recent research suggests that even a single intervention can lead to a significant decrease in the risk for type 2 diabetes s, 6, 7, 8. One of the most beneficial approaches that have recently shown to be effective in preventing diabetes has relied on lifestyle modification, and a growing number of studies show that lifestyle interventions can lead to improved glucose tolerance in individuals at high ri sk for developing type 2 diabetes 2.

Although evidence exists that genetics play a role in the development of type 2 diabetes, recent increases in diabetes prevalence throughout the world point to the importance of environmental factors 9. Research has clearly identified obesity and a sedentary lifestyle as two of the most crucial modifiable factors associated with the development of diabetes 9. Several interventions based on weight loss, increased physical activity, as well as behaviour change strategies have emerged. Unfortunately, it has proved complicated to prevent obesity or to effectively decrease body weight, and especially difficult to maintain the weight off UWOMJ 72(2) 2003 27

permanently. Furthermore, many lifesty le intervention studies have not been properly designed to provide a definite explanation to what extent the primary prevention of type 2 diabetes is likely1. Despite this, several recent studies have shown the possibility for moderate and sustained weight-loss to signifi cantly reduce the risk of type 2 diabetes .

In 1991 , Eriksson and Lindgarde s from Sweden reported on their 6-year lifesty le intervention study in subjects with IGT. Diet and exercise interventions were compared to a no-intervention reference group . As the reference group consisted of men who chose themselves not to join an intervention, the groups were not randomly assigned. Weight loss and improved fitness were associated with reduced incidence of di abetes, and the occurrence of type 2 di abetes was significantly reduced from 4.3 % per year to 1. 3% per year. In 1997, Pan et al. 6 reported from China that a 6year lifestyle interventi on based on diet and exercise reduced the progression to diabetes in 577 subj ects from 68% to approximately 43 %. However, the subj ects were not individua lly all ocated to the interventi on and control groups; instead, the participating clini cs were randomized. More promi sing results come from the Swedish Obese Subj ects Study IO, in which the 2-year incidence of diabetes was 30 times lower in overweight individuals who mai ntained we ight loss following post bariatric surgery.

Two recent we ll-contro ll ed studies include the Finnish Diabetes Preventi on Study?, and Th e Diabetes Prevention ProgramS. In the Finnish Diabetes Prevention Study, which studied 522 individuals at high risk for type 2 diabetes over 5 years, subj ects were randomly allocated to the control or intervention groups '路 7. The intervention group rece ived seven sess ions with a nutritionist the first year and one sess ion every three months afterwards . They also received counseling on increasing their phys ica l activity, free membership to a fitness club was offered, and over half the interventi on subj ects received personal training sessions. The contro l group subj ects received general advice about hea lthy lifestyle at the annual visit to the study clinic.

Overall, the cum ul ative incidence of type 2 diabetes in the interventi on group was 58% lower than in the control group.

The Di abetes Preveotion Program s was a randomi zed trial that focused on 3234 hi gh-ri sk individual s, and compared the efficacy and safety of three interventions: an intensive lifestyle intervention, or standard li festy le reco mmendations combined with either metformin (a biguanide antihyperg lycemic agent) or placebo I , s. The intensive lifesty le intervention group met with a case manager 16 times over the first 6 months, and then generally every month. Telephone contact was made monthly, and group co urses on exercise and weight-loss lasting 4-6 weeks were offered every three months . Two supervised exerci se sess ion were offered each week , and incentive such as exerci se tapes, equipment, fitness club memberships, free low-ca lorie foods and home visits for cou nse ling were offered. The metformin and placebo groups also received yearly encouragement to lose weight and exercise, but without individuali zed discuss ion of how to achieve these goa ls. The results of the study howed that the intensive lifestyle intervention reduced the incidence of type 2 diabetes by 58%, and metformin reduced the incidence by 3 1%, as compared to pl acebo .

In conc lu ion , there exists a vast amount of data which shows 28

VWOMJ 72(2) 2003

that lifestyle factors such as physical inactivity and obesity are increas ing in our society, and that thi s is being accompanied by an increased number of clinical diabetes diagnosis ' 路 Similarly, many studies suggest that lifestyle modifications that target these factors should be the first choice in the primary prevention of type 2 diabetes. Lifestyle intervention to prevent diabetes should theoretically be relatively easy to ap ply, as it sati sfies the necessary conditions in order to justify a primary intervention. Furthermore, lifestyle interventions, such as exercise and diet, have not only been shown to delay or prevent diabetes, but also provide a variety of other health benefits, both physical and psychological. As well , many of the high-risk indiv iduals are already frequent users of the health care system, enabling primary care physicians to urge all overweight or sedentary indi viduals to adopt the necessary lifesty le changes. However, va lid concerns do arise that lifesty le intervention may not be the best primary prevention program. For example, the hi ghly specific and individually tailored lifesty le counseling performed in the discussed studies was done by special educators, who were highly qualified motivated, and compensated. One question that arises is whether this could be reproduced in an ordinary general practice setting . Finally, a bigger obstacle still may be that factors such as phys ical inactivity and obesity may not be under vo luntary control, and so the preventi on of diabetes would also need to address societal and cultural norms.

REFERENCES Eriksson J. Lindstrom J. Tuomilehto J Potentia/for the prevention of type 2 diabetes. British Medical Bulletin 2001 :60:183-199 2. American Diabetes Association and National institute of Diabetes, Digestive and Kidn ey Diseases. Th e Prevention or Delay of Tj1pe 2 Diabetes. Diabetes Care 2002: 25(4): 742-749 3. Narayan KM. Bowman BA. Engelgau ME. Prevention ofType 2 diabetes. British Medical Journal 2001 ;323:63 -64 4. UKPDS Group. UK Prospecti ve diabetes study l 6: overview of six years路 therapy of type 2 diabetes - a progressive disease. Diabetes 1995:44:1249-1 258 5. Eriksson KF Lindgarde F Prevention of type 2 (non-insulin dependant) diabetes mellitus by diet and physical exercise. Th e 6-year Ma lm o f easibility study. Diabetologia 1991 :34(1 2):891-898 6. Pan ).'R. Li G W. Hu YH et a/. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing JGT and Diabetes Study. Diabetes Care 1997: 20(4) :53 7-544 7.

Tuomilehto J. Lindstrom J. Eriksson JG. eta/. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolera nce. New England Journal of Medicine 2001 :344(18): 134350 8. Diabetes Prevention Program Research Group. Reduction in th e incidence of type 2 diabetes with lifesty le intervention or metformin. New England Journal of Medicine 2002:346(6):393-403 9. Birkeland Kl. Berg JP Type 2 diabetes - preventable, but how?

European Journal of Endocrin ology 2001: 145(5) :5 73-575 10. Sjostrom C, Li sner L. Weedel H. Sjostrom L. Reduction of incidence of diabetes, hypertension and lipid di turbances after intentional weight los induced by bariatric surge1y: the SOS Intervention Study. Obesity Research 1999;5:477-484 1.

Thinking on Your Feet

Lung Cancer and Ectopic ACTH: A Case

By: Chris Chu, Meds 2004 and Jay Banerjee, Meds 2005

A 6 1-year-old patient, named Mr. Brown, presents to the Thoracic Surgery clinic. His referral note states that he is a fo rmer heavy smoker (7 5 pack-years, quit 2 years ago), with a recently worsening cough and some shortness of breath on exertion. The attached chest x-ray report indicates a 4 to 5 em illdefined lesion in the region of the left upper lobe.

1) Give a differential diagnosis for a solitary pulmonary mass seen on chest x-ray.

On compari son to a chest x-ray performed two years ago, this appears to be a new lesion. A CT scan of the thorax has also been performed, which shows the mass encroaching on the left upper lobe bronchus, and evidence of lymphadenopathy in the subcarinal and paratracheal areas. When asked about hi s symptoms, Mr. Brown now says that hi s shortness of breath has been worsening to the point where he cannot climb even one flight of stairs. He describes two recent episodes of coughing up blood-streaked sputum, and says he may have lost between 10 and 20 pounds over the past month.

2) What are common clinical features of lung cancer?

3) Outline possible diagnostic tests for a patient suspected of having lung cancer.

Based on the suspicious nature and the location of the lesion, bronchoscopy is ordered and performed by the consulting surgeon. Transbronchial needle biopsy speci mens taken of the lymph nodes in the subcarinal area are positive for small cell lung cancer.

4) Discuss appropriate tests for staging small cell lung cancer.

While staging tests are being carried out, Mr. Brown is referred to the regional cancer center fo r discussion of treatment options. The results of the staging tests reveal metastatic foc i in Mr. Brown 's liver and brain. Interestingly, hi s lab results show severe hypokalemi a, and moderate hyperglycemia. In addition, physical examination of the patient at the cancer center reveals a new onset of hypertension, peripheral edema in the lower extremities, and a somewhat "puffy" face . The perceptive clinical clerk

on the Oncology service wonders why the patient appears to be presenting with Cushing's Syndrome

5) What is the association between small cell lung cancer and Cushing's Syndrome?

6) What tests can be used to determine the etiology of Cushing's Syndrome?

The appropriate tests are ordered, and indeed confi rm an ectopic origin of ACTH. In the meantime, Mr. Brown has been started on therapy fo r his cancer.

7) What is the current first-line treatment for small cell lung cancer?

8) What impact does the ectopic ACTH syndrome have on Mr. Brown 's prognosis?

ANSWERS 1) In assessing a so litary pulmonary mass, the firs t step should be to detem1ine if the mass is visi bl e on any prev ious chest x-rays .' Assuming that the les ion is either new or changed in appearance, or that previous f ilms are not availabl e, the next factor which should be taken into account is the size of the lesion. If the diameter of the lesion is greater than 3 em, it has a very high probabili ty of malignancy, and should be managed with prompt diagnosis and staging.2 Small er lesions (3 em in diameter or less) are commonly referred to as solitary pulmonary nodules (SPN), and generally fa ll into either infectio us or neoplastic categories. Infectious etiologies account fo r approximately 50-55% of SPNs (including TB granul omas, histoplasmosis, and coccidiomycosis). The remainder are almost all of neoplastic origin, including primary bronchogenic cancer (30%), so litary metastasis (5%), and benign growths such as hamartomas and lipomas (10%).3 In general, benign lesions on chest x-rays tend to be round, w ith a smooth, regular border, and are often calcified. Malignant lesions tend have an irregular, spiculated border, are rarely calci-

UWOMJ 72(2) 2003 29

fied, and can be associated with findings such as lymphadenopathy or pleural effusion.4 Clinical correlation is always necessary; factors such as a positive smoking history and respiratory symptoms (see next question) can increase the suspicion of malignancy in a SPN. It should be noted that with the advent of improved technology and the concept of CT screening for lung cancer, new, very small pulmonary nodules are often now first detected on CT scan.

Despite the higher likelihood of malignancy in larger (> 3 em) nodules, it is still necessary to investigate and follow these very small new lesions. s 2) Common symptoms of lung cancer at presentation include cough (especially persistence or worsening of cough), dyspnea, chest pain, and hemoptysis. Clubbing of the digits can be seen, as well as constitutional symptoms such as anorexia, weight loss, fever, and anemia. Symptoms and signs can also be seen as a result of tumour spread, either local (e.g. pleural effusion, dysphagia, hoarseness, Horner's syndrome), or distant (notably, bony pain and/or CNS manifestations such as headache, nausea, and vomiting).' 路 3 3) After history, physical examination, and imaging (i.e. chest x-ray and CT scan), several diagnostic tests for lung cancer exist. Sputum cytology is a simple, non-invasive test, which has a good diagnostic yield for centrally located tumours.' However, more invasive modalities are currently preferred. Flexible bronchoscopy is especially useful for centrally located lesions, with biopsy via direct sampling, transbronchial needle aspiration, brushing, or saline lavage.' For peripheral lesions, transthoracic needle aspiration (under fluoroscopic or CT guidance) is very good for obtaining tissue samples for diagnosis . However, a negative needle biopsy cannot rule out the presence of malignancy, and therefore surgical resection of a solitary nodule can be performed for diagnosis, in patients with a high index of suspicion for early-stage lung cancer.6 4) The primary goal of staging small cell lung cancer (SCLC) is to determine if di stant metastases are present, as this has implications for the management of the disease. The most commonly used staging system involves two categories. Limited disease denotes tumour confined to one lung and any regional lymph nodes (i ncluding contralateral hilar nodes) , with all cancer encompassed in one radiotherapy portal. Extensive di sease denotes cancer not encompassed in one radiotherapy field, or the presence of metastatic disease. 7, 8 Therefore, staging procedures should include a CT scan of the thorax and abdomen (to assess the mediastinum, liver and adrenals), liver ultrasound if indicated, bone scan, and CT scan (or MRI) of the head. Routine hematological tests, liver function tests, serum electrolytes, and alkaline phosphatase (for bony metastases) should also be checked.?. 8 5) Small cell lung cancer is derived from cells of neuroendocrine origin, and therefore has a particular tendency to act as an ectopic source of naturally occurring hormones (the so-called paraneoplastic syndromes)8 Ectopic secretion of ACTH occurs in 30

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5% of SCLC cases. It is thought to be due to the expression of the proopiomelanocortin gene (the precursor to ACTH), and subsequent aberrant processing resulting in the release of these ACTH precursors into the circulation.9 This in tum stimulates release of corticosteroids from the adrenal glands, causing the clinical features of Cushing's syndrome.

Interestingly, ectopic ACTH in SCLC tends to cause atypical presentations of Cushing's syndrome, often with only metabolic abnormalities seen as opposed to classic physical findings (i.e. weight gain, truncal obesity, abdominal striae). This is attributed to both the catabolic effects of SCLC, the relatively rapid onset of disease, and the short life span of these patients (classical Cushing 's syndrome tends to develop only after a prolonged period of hypercortisolism).I O 6) With clinical suspicion of hypercortisolism based on history and physical examination, 24-hour urinary free cortisol is measured to confirm the diagnosis of Cushing's syndrome. In addition, a low-dose dexamethasone test can be used (normal suppression of serum cortisol levels by dexamethasone is not seen in patients with Cushing's syndrome).

Next, plasma ACTH levels should be measured. Low levels of ACTH suggest an adrenal (ACTH-independent) origin of the hypercortisolism, while high ACTH levels suggest either a pituitary or ectopic origin (ACTH-dependent).

ACTH-dependent tumours can be further characterized with various methods. The high-dose dexamethasone test is often useful , since suppression of hypercortisolism from pituitary origin is still seen, unlike in ectopic cases. CRH stimulation can also be performed, with pituitary tumours showing an elevation in serum cortisol and with little response in ectopic ACTH-secreting tumours . Finally, CRH stimulation coupled with inferior petrosal sinus sampling directly measures the release of ACTH from the pituitary. This is the most powerful test available to distinguish between pituitary and ectopic sources of ACTH, but is invasive and requires specialized expertise." , 12 7) Combination chemotherapy is currently the first-line treatment for SCLC. Agents which are used include cisplatin, cyclophosphamide, doxorubicin, etoposide, and vincristine.

Many different combinations are used, with the most popular being etoposide-cisplatin, as well as cyclophospharnide-doxorubicin-vincristine.7. s In patients with limited-stage disease, the addition of radiation therapy can provide a modest increase in long-term survival, while in patients with extensive disease, radiation therapy may be useful for palliation of symptoms (for example, superior vena caval obstruction) . In addition , for patients who achieve a complete response to primary chemotherapy, prophylactic cranial irradiation is recommended to reduce the possibility of brain metastases. 7 Small cell lung cancers are rarely surgically resectable, due to the frequency of disseminated disease at the time of presentation. However, solitary pulmonary nodules presenting as SCLC can be surgically resected, followed by combination chemotherapy with or without thoracic and cranial irradiation.?

8) The prognosis for SCLC is in itself inherently poor.

Patients with limited-stage SCLC have five-year survival rates of between 20 and 30%, while patients with extensive SCLC have a mean survival time of less than 12 months even with treatment.8 Clinically apparent ectopic Cushing's syndrome can adversely affect the prognosis of patients with SCLC, especially by increasing the risk of infectious complications (since hypercortisolism is associated with immunosuppression). In addition, metabolic abnormalities such as hypokalemia and hyperglycemia can be difficult to manage. Therefore, control of Cushing's syndrome via cortisol synthesis inhibitors (ketoconazo le, metyrapone) has been suggested to improve the care of SCLC patients with ectopic ACTH production. I o ACKNOWLEDGMENT Special thanks to Dr. Richard Inculet for reviewing this case.

Dr. Inculet is a thoracic surgeon, and the head of the Divisions of Thoracic Surgery and Surgical Oncology at the London Health Sciences Center, Victoria Campus.

Building Opportunities . ..

Site preparation for a new Peterborough Regional Health Centre (PRHC) is underway.

The new hospital will allow for improved health care delivery to the more than 300,000 residents of the region. There will be space for more than 500 beds and expanded services.

PRHC has a blueprintt hat will guidethe growth of its health care team ... we will be looking to hire up to a thousand people.

It is PRHC's mission to be a centre of excellence in the delivery of comprehensiveand accessible health care.

References Maddaus MA , Ginsberg RJ. Clinical features, diagnosis, and staging of lung cancer. In: Pearson FG, et a!., editors. Thoracic Surgery.

Philadelphia: Churchill Livingstone; 2002. p. 8i3-836.

2.

Ost D, Fein A. Evaluation and Management of the Solitwy Pulmonary Nodule. Am J Respir Crit Care Med 2000; i62: 782-787.

3. Panu N, Wong S, editors. MCCQE Review Notes & Lecture Series.

Toronto : MCCQE Notes Ltd; 2002.

4.

Ginsberg MS, Erasmus JJ, Patz ER, Herman SJ Imaging of the lung. in: Pearson FG, et al. , editors. Thoracic Surgery. Philadelphia: Churchill Livingstone; 2002. p. 443-498.

5. Discussion with Dr. Richard inculet, Thoracic Surgeon, London Health Sciences Center- Victoria Campus (Sep tember 23, 2002).

6. Slovis BS, Brigham KL. Neoplastic diseases of the lung. in: Andreoli TE. Carpenter CC, Griggs RC, Loscalzo J Cecil Essentials of Medicine.

Philadelphia: W.B. Saunders Company; 200i. p. 206-209.

7.

Feld R. Ginsberg RJ. Small cell lung cance1: In : Pearson FG. et al., editors. Thora cic Surge1y. Philadelphia: Churchill Livingston e; 2002. p.

925-946.

8. Griggs JJ, Desch CE. Solid tumors. in: Andreoli TE. Cwpenter CC, Griggs RC, LoscalzoJ Cecil Essentials ofMedicine. Philadelphia: W.B. Saunders Company; 200i . p. 493-504.

9. Terzolo M, et al. Ectopic ACTH syndrome: Molecular bases and clinical heterogeneity. Annals of Oncology 200i; i 2 (s uppl.2) : S83-S87. iO. Delisle L, et at. Ectopic Corticotropin Syndrome and Small-cell Carcinoma of the Lung. Arch intern Med 1993; 153: 746-752.

1i . Newell-Price J, Train er P, Besser M, Grossman A. The Diagnosis and Differential Diagnosis of Cushing's Syndrome and Pseudo-Cushing's States. Endocrine Reviews 1998; 19: 647-672.

12. Ross RJ, Trainer PJ Endocrine Investigation: Cushing's Syndrome.

Clinical Endocrinology i998; 49: 153-155. i.

For career opportunities, visit www.prhc.on.ca.

UWOMJ 72(2) 2003 31

History of Medicine

An Early Complex Emergency: The Plague of Athens

Martis Sabo, BSc, Meds 2005

Complex emergencies are significant public health challenges, but are not a new phenomenon. The Plague of Athens (430-426 BC) is a classic example of a complex emergency. A combination of factors helped form a situation that promoted the spread of infectious disease. Today, we have increased knowledge, resources, and agencies that are attempting to manage the public health crises of complex emergencies around the world.

INTRODUCTION

CITY LIFE AND INFRASTRUCTURE DURING THE WAR

War and di sease have long been intimate partners causing death and destructi on in human history. Even today, despite all the advances in treatment and prevention , once infrastructure collapses, di sease runs rampant. The combination of viol ence, stress, relocati on, poor nutrition and sanitation , and abnormal populati on density, serve as an idea l breeding g round for epidemic di sease and presents a sign ifica nt public hea lth chall enge . Among the more hi stori cally fa mous epidemi cs, the plague of Athe ns is a classic example of how these fac tors interact. The probl ems faced then are essenti ally the arne problem faced in refugee ca mp and war zones today.

Housing in Athens was generally simple, with walls made of mud .4 Once the war began, the degree of crowding meant that many people lived in shelters in streets .S Piraeus had many synoikai: cramped apartment blocks.4 In addition to the poor housing, air pollution in the city was so severe due to fires , lamps, charcoal burning, furnaces and dust that the sun was obscured.6 ot only was the air befouled, but the streets were routinely ankl e-deep in waste.4 Men would relieve themselves in the street , although ophi sticated sorts would use chamber pots.4 There was no garbage disposal as such, although garbage and the dead were supposed to be removed beyond the city walls .6 However, the war likely put a damper on this, and the plague would have made it worse. Thucydides observed that the dead were often left unburied or we re cremated, contributing to the smoke problem. ?

The traditional crop of Attica was barley, since the oil was too poor and alkaline to support wheat. As Athens grew, it began to rely more on imported wheat, available mainly to the wealthy.

Once the war began and the fam1land was razed, the city was periodica lly compl etely dependent on imported food . The main source of the imported food was from the Black Sea gained by an arrangement made by Pericles prior to the outbreak of war.'

Athens had a diversified water supply consi sting of public founta ins, pri vate well s and c iste rns to collect rainwater.4 Fountains were located in high traffic areas and had flowing water whil e well and cisterns were located in courtyards or next to individual dwe llings .4 Thi should have protected the population from a single point of contamination and from shortage during the iege. s However, Thucydides observed that

THE PELOPONNESIAN WAR At the time of the mid-fifth century BC, Athens was the dominant city-state of Greece and what had been a relatively democrati c alli ance of other city- tates had become an empire. Hostilities grew between Athens and Sparta, another powerful city-state.

Atheni an leaders had expected war several years before hostiliti es actually broke out. Pericles, the city leader, decided that the city would prepare for a siege and wage the war using their superior naval capabiliti es. ' The city had erected wall encl osing Piraeus, the road between it and Athens, and Athens itself. Prior to the outbreak of war, the popul ati on of the city was around 155 ,000 peop! e2 In 430 B , the entire population of Attica, the surrounding countryside, was moved inside these wa ll s, pu rung the populati on density up to I 00,000 persons per square mil e.J Thi s extreme overcrowding Ia ted for 2 to 5 years contin uously.3 The Spartans laid waste to the crops and farml and in Atti ca in 430 and 427/6 BC I, but invasion were not continuous during thi s time.

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... the victims could not endure the laying-on of even the lightest wraps and linens .. . but must go naked, and a plunge into cold water would give th e greatest relief. Many who were left unattended actua lly did thi s, jumping into we ll s, o unquenchable was the thirst which possessed them ... s He also observed that the ill lay in pi les around the fountains.s Even a water supply o decentrali zed co ul d have been compromised by the presence of the ill.

COMPLEX EMERGENCIES The situati on in Athens duri ng the early years of the Peloponnesian War was grim . By today 's nomenclature, it was a complex emergency - a situation affecting a large civili an population invo lvi ng a combinati on of factors including war, food shortages, and population disp lacement, resul ti ng in significant excess mortality.I O In fact, the situati on into which the plague arrived was very similar to recent examples of complex emergencies in regions such as Rwanda or Somali a. One major difference between then and now is our ability to intervene to stave off the disintegration of infras tructure and to prevent the mass outbreaks of infecti ous di sease.

There are several levels of prevention in compl ex emergencies. The first level, primary prevention, invo lves stopping the violence in the region, preferably before the co llapse of the government and the infrastructurei O. Meeting basic needs cannot happen while a region is too unsafe to enter. Intervention has been limited by the national sovereignty embodied in the Uni ted Nations Charter, limiting the degree of primary preventi on possible because frequently, situations have degenerated to the point where involvement is riskyi O. Secondary prevention involves early detecti on of confl ictrelated food shortages and popul ati on movements, and invo lves being prepared for interventions to mitigate publ ic health problems that ari se I 0. Very few contingency plans exist on a global scale to handle major public health crises. In Za ire in 1994, a maj or cho lera epidemi c wreaked havoc in a Rwandan refugee camp, highlighting inadequate sup plies and equipment, lack of safe water suppli es, and a lack of un ified plann ing iO Tertiary preventi on invo lves prevention of excess morta lity and morbidity once the disaster or emergency has occurred I 0.

According to Too le and Waldman, most deaths in refugee camps and displaced populati ons are preventabl e w ith availabl e and affordable techno logyiO. The key is to get those with the know ledge together with those with the resources iO.

rapid spread of communicable di sea eiO. Agenci es hould a lso be prepared to handle epidemics of infect ious di sease with appropri ate treatment and preventative measures li ke vaccinatio ns or drugs 10.

These interventi ons are easy to li st but difficult to impl ement. However, the last decade has seen considerable improvement in standardi zing approaches to emergencies and to the de livery of reli ef to the areas that need iti O. It is not a simpl e matter to contend with, and the process of responding to comp lex emergencies continues to evo lve.

Compl ex emergencies have ex isted fo r mill enni a. Th e plague of Athens in 430-426 BC is a class ic examp le of a vari ety of factors co uld lead to mass outbreaks of infecti ous di sease. Disease broke out in Athens de pite some attempts at maintaining a supply offood and water. However, these plans were foiled by publi c chaos, overcrowdin g, and a lack of med ical know ledge2. It ha taken time, but we now have the knowledge, resources, and cooperati on to begin to combat the problem . It is conce ivable that in th e near future, comp lex emergencies that end up in mass ive excess mortality and morbidity may be successfu lly managed by effective public health.

REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

9.

Bellemare J. Plant IM, Cunningham LM. 1994. Plague of Athens Fungal Poison? Journal of the History of Medicine. 49:521-45.

Relief FP, Cilliers L. 1998. Th e ep idemic ofA thens. 430-426 B C. South African Medical Journal. 88(1) :50-3.

Morens DM . Littmann RJ 1994. "Thu cydides Sy ndrome " Reconsidered: Nev.1 Th oughts on th e "Plag ue of Athens." A merican Journal of Epidemiology. 140(7) :62 1-8.

Garland R. 1998. Daily Life of th e Ancient Greeks. Greenwood Press.

Westport. pp. 86- 7.

Th ucydides. 1993. On Justice. Po l路Vel~ and Human Na ture. Translated by Woodruff P (ed) . Hackett Publishing Company. In dianapolis. pp. 46-50.

Hughes JD. 1994. Pan s Tra vail. John Hopki ns University Press.

Baltimore. pp. 156- 165.

Langmuir AD, Wo rthen TD. Solomon J. Ray CG. Petersen E. 1985. Th e Th ucydides Sy ndrome. Th e New Eng land Journ al of Medicin e.

313(16) :102 7-30.

Crouch DP 1993. Water Ma nagement in Ancient Greek Cities. Oxford Uni versity Press. New York. p. 284.

Toole MJ. Wa ldman RJ 1997. Th e Public Health Aspects of Comp lex Emergencies and Refugee Situations. Annual Review of Public Health .

18.路283-3 12.

PREVENTING THE PLAGUE? Supposing for a moment that the situation in Athens was developing in 2002 AD and not in 430 BC, what interventions would be indicated? Each of the problem areas has to be addressed. A balanced diet with at least 2000 kcal per person per day distributed fairly to households is critical, since good nutrition involves adequate protein and micronutrients such as vitamin A 10 .

Adequate clean water is also essential: at least 15 L per person per day for domestic needsi O. The water need not be microbe-free , just relatively clean. This should be done in partnership with hygiene education and access to soap iO. These measures go a long way to ensuring increased resistance to disease and to preventing

UWOMJ 72(2) 2003 33

Feature Articles

Prostatitis: Pathogenesis, Diagnosis and Treatment

Omer Chaudhmy, MD, BArtsSc, Meds 2003

Prostatitis encompasses a wide range of disorders that involve inflammation of the prostate gland. These disorders have recently been categorized by the National Institutes of Health International Prostatitis Collaborative Network as acute bacterial prostatitis, chronic bacterial prostatitis, chronic nonbacterial prostatitis and asymptomatic inflammatory prostatitis. According to modern theories, the major etiological factor of the acute form of prostatitis is reflux of infected urine into the prostatic and ejaculatory ducts.

Diagnosis is made most easily in these cases as it involves typical findings of urinary tract infections (UTis) as well as a tender and firm prostate on rectal exam. First line therapy for acute bacterial prostatitis involve quinolone antibiotics for one month duration. Chronic forms of prostatitis, on the other hand, are less well understood and may occur because of reflux of sterile urate, stasis of prostatic fluid, calculi development and fibrosis. Furthermore, occult bacterial infections have been identified as possible culprits behind chronic nonbacterial cases. Presentations of chronic prostatitis include less prominent UTI symptoms and essentially an endless variety of pelvic and genitourinary symptoms from suprapubic to testicular complaints. The prostate on rectal exam is most often normal. Treatments of these situations also vary, from quinolones, septra and transurethral prostatectomy in cases of chronic bacterial prostatitis to tetracyclines, macrolides, allopurinol, NSAIDS, anticholinergics and alpha-blocking agents and transurethral microwave therapy in chronic nonbacterial prostatitis. Long-term complications of all forms of prostatitis include abscess formation , pelvic pain syndromes, UTis, infertility and possibly benign prostatic hyperplasia.

INTRODUCTION Prostatiti s includes a wide range of di sorders that invo lve the infl ammation of the prostate gland.1 .2 Unfortunately, mo t of these di sorders have a poorl y defin ed pathogenesis, are diffi cult to diagnose due to a lack of di stingui shing characteri tic , and are often res istant to modern treatments路2,3 Such ambi guity ha bee n the cause of much fru stration for both phys icia ns and their pati ents,4.5,6,7 and has led one author to go so far a to describe prostatiti s as "a wastebasket of clini ca l ignorance." I ,4.8 Due to the eni gmatic nature of prostatiti s, it is use ful to review modern ways of diagnosing and treating the condition .

EPIDEMIOLOGY The widespread preva lence of pro tatiti s has put increas ing pressure on the medical community to find effective treatments for these ill-characterized disorders. Studies have shown that protatiti s has a 9% overall preva lence in adu lt males and that prevalence increases with age.1 .2 The ri sk also tends to increase with pati ents who have had a previous hi story.1 ,9 Prostatitis can accounts for up to 25% of outpatient visits for men presenting

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with genitourinary ymptom .2 Of particular note, one out of eleven men by the age of80 will have prostatitis and most of these ca e wi ll be in the management of primary care physicians.2. JO

CLASSIFICATION In 1998, the National Institutes of Health International Prostatiti s Co llaborat ive Network divided prostatitis into four categories; acute bacteria l prostatiti s, chronic bacte rial prostatitis, chroni c nonbacterial prostatiti s (inflammatory and noninflammatory) and asymptomatic inflammatory prostatiti s. 2,4,11 ,12 Of these the most common and least understood form is chronic nonbacterial prostatitis and it accounts for greater than 60% of prostatitis cases. 2 On the other hand, acute bacterial prostatitis accounts for only 1.5% of case and only 5-l 0% of prostatiti are known to have a bacterial etiology.12

PATHOGENESIS The most accepted mechani sm behind the pathogenesis of acute prostatitis invol ves the reflux of infected urine into the prostatic and ejacul atory ducts .2.JJ ,J3 Other postulated mechanism inc lude the spread of infection to the prostate from hematogenous

or lymphatic sources, from an infec ti on of the external meatus ascending through the urethra, fro m the epididymi s in cases of epididymitis, from direct invas ion via the rectum , and fro m prostatic inflammation from urethral catheters. 2,11 In the case of chronic prostatitis, recurrent reflu x of steri le urine or urate into the prostate has been proposed as a mechani sm of inflammation without an infectious agent.2 On the other hand, conditions of prolonged stasis of prostati c fluid, the deve lopment of calculi ,'' 路' 4 fibrosis of prostati c ducts, and secretory dysfunction 15 may all help to reduce the prostate's abi I ity to eradicate infectious organisms and result in chronic bacterial infecti ons.

Other mechanisms of chronic prostatitis include alteration of the natural pH of prostati c fluid and loss of intrinsic antimicrobial substances.z

DIAGNOSIS Although there is no gold standard to diagnose prostatiti s, the Meares-Stamey four glass test urinary tract locali zation technique has been used for the diagnosis of chroni c bacterial prostatitis since 1968.1,2,11 ,16 The procedure involves taking four urine specimens; an initial urethral spec imen, a midstream specimen, a prostatic massage specimen and a post prostatic massage specimen.

Essentially, white blood cells and bacteria in only the last two specimens are diagnostic of chronic bacterial prostatiti s.

Leukocytes and organisms in the initial urethral sample suggest urethritis, while the same findings in midstream specimen indicate cystitis. Due to the associated discomfort to the patient, the difficulties in obtaining prostatic fluid samples, and the cost, the Meares-Stamey technique has been scarcely employed in clinical practice.

Other tools used to aid in the diagnosis of prostatiti s include Prostate Specific Antigen (PSA) levels and transrectal ultrasound.ll,l6 The former may help to diagnose prostatiti s and monitor the success of treatment if they can me compared to previous values. Isolated PSA counts, however, often prov ide little diagnostic value. Similarly, transrectal ultrasound is useful in revealing cysts and abscesses within the prostate that my symptomatically mimic features of prostatitis.

ACUTE BACTERIAL PROSTATITIS Ironically, the least common form of prostatitis, acute bacterial prostatitis, is the most easily diagnosed and treated.3, 4 ,11 ,12 Patients present with typical symptoms of an urinary tract infection (UTI). These include fever, chills, low back pain, perinea l or ejaculatory pain, dysuria, frequency, urgency, arthralgia, myalgia and possibly obstruction.' On rectal examination, the prostate is tender and may be warm, swollen, firm and irregular. Leukocytes and bacteria in the urine are also present, but diagnosis is essentially made on clinical grounds.

To pass the blood prostate barrier, antibiotics successful in treating bacterial prostatitis need to be lipid soluble, have low protein binding and a high dissociation constant (pKa).3,ll Included in this profile are drugs such as trimethoprim-sulfamethoxazo le (TMP-SMZ), the tetracyclines and the quinolones. Approved alternatives include carbenicillin, doxycycline and various penicillins and cephalosporins, but are less desireable due to their reduced prostate penetrations.

In the case of acute bacterial prostatiti s, firs t line drugs include ciprofloxacin (500 mg BID), norfloxac in (400 mg BID) or ofloxaci n (400 mg BID)." TMP-SMZ ( 160 & 800 mg BID) has also been shown to be as effective but has not received FDA approva l specifica lly for prostatit is in th e Un ited States. 2 Antim icrobi al therapy is initiated as soo n as a clini cal diagnos is is made and sensitiviti es are used to later guide therapy if necessary.11 ,16 The durati on of therapy is typ ica lly fo ur weeks. In the case of acutely ill patients with bacteremia, an intravenous drug effective against urinary pathogens is ind icated (i.e. cefuroxime, cefotaxime) . Causative organisms are Eschericia coli 80% of the time and less commonly Pseudomonas aeruginosa, Serratia marcescens, Klebsiella spp, and Proteus mirabilis.z Men at increased ri sk of sexually transmitted disease may benefit fro m antibi otics that also cover Chlamydia inf ections.'

CHRONIC BACTERIAL AND NONBACTERIAL PROSTATITIS Chronic prostatiti s is di fficult to di agnose because of the w ide vari ety of pelvic and genitourinary symptom that may be associated. Pain may occur on ejaculation and in any of the suprapubic, perineal, penile, rectal, inguinal or testi cul ar areas路2,11 In the case of chroni c bacterial prostatiti s, the spectrum of symptoms can range fro m being asymptomatic to presenting much like an acute bacterial prostatitis, although generally the UTI symptoms tend to be much Jess prominent. " ,12 Typical symptoms of chronic nonbacterial prostatitis include urgency, weak stream , nocturia, hesitancy and sexual dysfunction.12 Rectal examination often reveals a normal prostate, although it may sometimes be boggy and tender in chronic bacteri al prostatiti s. Often it is the urine culture that is required to clari fy the diagnosis since the presence or absence of bacteria distinguishes between chroni c bacterial versus nonbacterial prostatiti s.z Likewise, the presence or absence of leukocytes differenti ates between chroni c inflammatory vs. noninfl ammatory prostatitis.

The treatment for chronic bacteri al prostatiti s is similar to that of its acute counterpart except that treatment is usually guided by sensitivity test results on the outset and that the duration of therapy lasts for at least 3 months.' ' However, due to the limited ability of the prostate to eradicate infectious organi sms, reinfection is common.2 Transurethral prostatectomy (TURP) can be therapeutic in cases of prostati c ca lculi invo lvement and, in rare circumstances, can even be curative if all the infec ted tissue is removed.l,l3,16 In both extreme and rare cases, total prostatectomy is needed to prov ide a definitive cure.

Surprisingly, although chroni c nonbacterial prostatitis is diagnosed in the absence of bacteria on urine culture, studi es using transperineal needle biopsy for culture have suggested that occult bacterial infections may play an etiological role.' ,17 As a result, an antibiotic tri al may be reasonable in such cases.

Because Chlamydia trachomatis, Ureaplasma urealy ticwn and Mycoplasma hominis have been identified as potential culprits, antimicrobial treatment is geared towards covering these organisms. Good options include doxycycline ( 100 mg BID), rninocyc line (I 00 mg BID) and erythromycin (500 mg QID) for at least 2 weeks. Other therapies that have shown to be effective for chronic nonbacteria l prostatitis include transurethral microwave

UWOMJ 72(2) 2003 35

therapy, allopurinol , NSAIDS , antichol inergics (i.e. oxybutynin) and alpha-blocking agents (i.e. doxazosin, prazosin, tamsul osin or terazosi n).

13.

14.

ASYMPTOMATIC INFLAMMATORY PROSTATITIS

15.

Asymptomatic inflammatory prostatitis is most commonly diagnosed by observing signs of inflammation on prostate biopsy for prostate cancer or following a tran urethra l resection of the prostate for bladder outlet obstruction. Physica l exam is usually non-specific and all cu ltures are us ually negative.1 6 Treatment for asymptomatic inflammatory pro tatiti i generally not indi cated unti l the patient is symptomatic or an identified pathogen is fo und.2 In such cases, antimicrobial treatment is targeted agai nst the causative organism. As with chronic non-bacterial prostatit i , NSAIDS and alpha blockers have al o been hown to be u efu l in therapy.

/6.

17.

Meares, EM. Prostalitis and Rela!ed Disorders. Campbell s Uro logy 7th ed. 1997; 1:807-22.

Lipsky BA . Prostatitis and urinary rracl infeclion in men: What s new: what s /rue? Am J Med 1999: 106(3);327-32.

Meares EM. Acute and chronic prostalitis: Diagnosis and treatmenl.

Infect Dis Clin Norlh Am 1987: 1(4):85 5-73.

Britlon JJ Jr & Carson CC. Prostatitis. AUA Upda le Series. Lesson 20.

Vol XVII. Houston, TX 1998.

Berger RE et a/. Bacleria in the pros tale /issue of men with idiopalhic prostatic inflammation. J Uro/199 7; 157:863-5.

CONSEQUENCES Acute or chronjc bacteria l prostatitis infrequently leads to abscess formation that can re ult in pe lvic pain symptoms.2 Treatment inevitably involve drainage via fine needl e aspiration.

In addition , chronic bacterial or nonbacterial prostatitis may result in chronic pelvic pain syndromes, repeated urinary tract infections and infertility. There is also some hi stological evidence that prostatitis may play an etio logic role in the development of benign prostatic hyperplasia (BPH). In the end, chronic fo rms of prostatitis and their sequelae can have a dramatic effect on fu nctiona l status and quality of life.

ACKNOWLEDGEMENT The author would like to thank Dr. Jonathan Izawa fo r hi s revision of thi s manuscript. Dr. Izawa is an Assistant Professo r of Surgery and Onco logy in the D ivision of Urology at the University of Western Ontario and is a member of the fac ulty at the London Hea lth Sciences Centre, Westm inster Campus.

REFERENCES Stevermer JJ & Easley K. Trearm enr of Prostatiris. Am Fam Physician 2000: 6 1{10) :3015-22.

2.

Chow RD. Prostatiris- Work-up and treatment of men with telltale symptoms. Geriatrics 2001: 56(4) :32-6.

3. Anderson John. Prostate disease: an overview. Hospital Medicine / 999: 60(1 0):698-9.

4. Collins MM. Ma cDonald R. & Wilt TJ. Diagnosis and treatment of chronic abacrerial prosratitis: a systemaric review. Ann Intern Med 2000: 133:367-81.

5. Meares EM J1: Prosratiris. Med Clin North Am 1991: 75 :405-24.

6.

Nickel JC. Prostatitis: myths and realities. Urology 1998: 51:362-6.

7. Meares EM Jr. Bacterial prostatitis vs "prostatosis " - A clinical and bacteriological study. JAMA 1973; 224:1372-5.

8. Stamey TA. Urinmy tract infections in males. in : Stamey TA . ed.

Path ogenesis and Treatm ent of Urinmy Tract infections. Baltimore: Williams & Wilkins / 980: 342-429.

9. RoberIs RO et a/. Prevalence of a physician-assigned diagnosis of proslatilis: !h e Olmsled Counly Sludy of UrinGiy Symptoms and Heallh Status Among Men. Uro logy / 998: 51:578-84.

I 0. Roberts RO el a/. A review of clinical and pathological prostalitis syndromes. Urology 1997; 49(6):809-21.

11 . Thin RNT. Pros/ali/is. Hospilal Medicine / 999; 60(10) ;710-3.

12. Epperly TD & Moore KE. Health issues in men: Part ]. Common genilourinmy disorders. Am Fam Physician 2000: 61(12): 3657-64.

I.

36

VWOMJ 72(2) 2003

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A Review of Diabetic Retinopathy

Zishan A/libhai, Med 2003 Husam Elkassem, B.Sc. Farhan Siddiqui, Meds 2004

At various stages of the disease, diabetic retinopathy (DR) targets many worldwide. Both type I and type II diabetics are susceptible to acquiring DR after the age of puberty. The lack of sufficient oxygen to the blood vessels and the transformation of glucose into sorbitol in diabetics cause interrupted normal function in the walls of the blood vessels in the retina. This causes the blood vessels to weaken creating microaneurysms that can easily rupture thus hemorrhaging surrounding areas. Effects of this disease range from slight blurring to legal blindness. A close monitoring of one's blood glucose levels delays DR symptoms. Early diagnosis of the disease by frequent visits to one's eye-care professional can completely eradicate or reduce the effects of DR.

At various stages of the disease, diabetic retinopathy (DR) targets many worldwide. Both type I and type II diabetics are susceptible to acquiring DR after the age of puberty. The lack of sufficient oxygen to the blood vessels and the transformation of glucose into sorbitol in diabetics cause interrupted normal function in the walls of the blood vessels in the retina . This causes the blood vessels to weaken creating microaneurysms that can easily rupture thus hemorrhaging surrounding areas. Effects of thi s di sease range from slight blurring to legal blindness. A close monitoring of one 's blood glucose levels del ays DR symptoms. Early diagnosis of the di sease by frequent visits to one 's eye-care professional can completely eradicate or reduce the effects of DR.

INTRODUCTION Diabetes mellitus (DM) is a major medical problem throughout the world. It causes an array of long-term systemic complications, which have considerable impact on both the patient and the society because it typically affects individuals in their most productive years. Ophthalmic complications of diabetes include corneal abnormalities, glaucoma, iris neovasculari zation , cataracts, and neuropathies. However, the most common and potentially blinding of these is diabetic retinopathy.

Diabetic retinopathy is responsible for 12% of all cases of blindness, and is the leading cause of new blindness in persons aged 25-7 4 years in the developing world. 1 It is defined as the progressive dysfunction of retinal vasculature caused by. the chronic hyperglycemia of diabetes.' In the initial stages, patients are generally asymptomatic; however, in more advanced s~ages of the disease, patients may experience increas ing v1sual acmty loss.

RISK FACTORS The most significant determinants of retinopathy are the duration of diabetes and the degree of blood glucose control.' 路 2 Tight control of glucose leve ls within the recommended range has been shown to delay both the onset of retinopathy as well as the progression of established retinopathy. Hypertension, if poorly controlled, has been associated with not only the worsening of retinopathy, but particularly with the development of proliferative di sease.' Diabetic women without retinopathy have a 10% ri sk of deve loping background retinopathy during pregnancy. Women with background retinopathy at the onset of pregnancy may show progress ion of thei r retinopathy, although there is genera lly some regression after delivery.'

The presence of renal di sease, as evidenced by proteinuria, augmented blood urea nitrogen and increased blood creatinine is an indication of increased risk for the development of retinopathy.' ,2 Other adverse factors include smoking, obesity, anemia, and hyperlipidemia.' 路 2, 3

PATHOGENISIS Fundamentally, DM causes abnormal glucose metabolism as a result of decreased levels or activity of insu lin. Increased levels of blood glucose are thought to have a structural and physiologic effect on retinal capillaries causing them to become functionally incompetent. A persistent increase in blood glucose levels shunts excess glucose into the aldose reductase pathway in certain tissues, which converts sugars into alcohol (eg. glucose into sorbitol).' Intramural pericytes of retinal capillaries seem to be affected by this increased level of sorbitol, eventually leading to

UWOMJ 72(2) 2003 37

the loss of its primary function (i.e. autoregulation of retinal capillari es). Loss of function of pericytes results in weakness and eventual saccular outpouching of capillary walls.'

These microaneurysms are the earliest detectable signs of DM retinopathy. Ruptured microaneurysms (MA) result in retinal hemorrhages either superficially (flame-shaped hemorrhages) or in deeper layers of the retina (dot-and-blot hemorrhages) .' 路 2 Increased permeability of these vessels results in leakage of fluid and proteinaceous material , which clinically appears as retinal thickening and exudates. If the swelling and exudation happen to involve the macula, a diminution in central vis ion may be experienced.' Macular edema is the most common cause of vision loss in patients with nonproliferative diabetic retinopathy (NPDR) ; however, it may also complicate cases of proliferative diabetic retinopathy (PDR).

As the disease progresses, eventual closure of retinal capillaries occur, leading to hypoxia . Infarction of the nerve fiber layer leads to the formation of cotton-wool spots (CWS) with associated stasis in axop lasmic flow.' More extensive retinal hypoxia triggers compensatory mechanisms within the eye to provide enough oxygen to tissues. Venous caliber abnormaliti es, such as venous beading, loops, and dilation, signify increasing hypoxia and almost always are seen bordering the areas of capillary nonperfusion. Intraretinal microvascular abnormalities (IRMA) represent either new vessel growth or remodeli ng of preexisting vessels through endothelial cell proliferation within the retinal tissues to act as shunts through areas of nonperfusion .'路 3 Further increases in retinal ischemia trigger the production of vasoproliferative factors that stimulate new vesse l formation .

Neovascularization represents progression to the proliferative form of Diabetic Retinopathy, and is observed at the borders of perfused and nonperfused retina, most commonly along the vascular arcades and at the optic nerve head .3 The new vessels break through and grow along the surface of the retina and into the scaffold of the posterior hyaloid face . By themselves , these vessels rarely cause visual comprom ise. However, they are fragile and highly permeable, and these delicate vesse ls are easi ly di srupted by vitreous traction, leadi.pg to hemorrhage into the vitreous cavity.1路 3 Traction may also cause retinal edema and retinal heterotropia, as well as retinal tears and tractional retinal detachments.

Thus, the microan giopathic changes associated with diabetic retinopathy can be attributed to either microvascular occ lusio n or microvasc ular leakage.

DIAGNOSIS All diabetic patients should have regu lar op hthalmologic screening exams for diabetic retinopathy.2. 3 Vi sual acuity testing for both near and di stant vision , as well as a fundo scopic inspection with pupil dilatation , fonns the basis of an effective screening method for diabetic retinopathy. Tonometry, a standard test that determines the fluid pressure inside the eye, is used to detect elevated press ure, another potential problem in diabetics ) Fluorescein angiography is an invaluable adjunct in the diagnosi s and management of diabetic retinopathy. Microaneurysms appear as pinpoint areas ofhyperfluorescence that do not enlarge, but rather fade during the later phases of the test. Dot-and-blot

38

UWOMJ 72(2) 2003

hemorrhages can be distinguished from microaneurysms because they appear as hypofluorescent rather than hyperfluorescent.

Areas of nonperfusion appear as homogenous dark patches bordered by occluded blood vessels. 3

CLINICAL COURSE The clinica l course of diabetic retinopathy does not appear until 3 to 5 years after the onset of type I diabetes. Onset in type II diabetes is probably simi lar but more difficult to pinpoint because of difficulty establishing onset of the underlying disease.' 路 3 Type I diabetics tend to progress more rapidly to proliferative retinopathy, with an incidence of 50% after 15 years. Older type II diabetics have a higher incidence of macular edemainduced vision loss.3 The prognosis for diabetic retinopathy used to be dismal.

Today, the best hope for diabetics remains prevention, with elimination of associated risk factors , most importantly, strict control of their blood sugar leve ls.3 This will help to delay not only the onset of the retinopathy, but also to slow the progression of the visual symptoms. On the other hand, a patient that has experienced neovascularization from diabetic retinopathy may benefit from timely laser photocoagulation, which can reduce severe visual loss by 95 %. Neverthe less, many diabetics still become legally blind because they are not regularly examined by their eye-care professionaJ.3 While all agree that screening of asymptomatic diabetic patients is critical, the mo t cost-effective timing remains controversial. It is generally agreed that adu lt-onset diabetics should be examined at the onset of their disease, then yearly thereafter.

Juvenile-onset diabetics do not have to be examined until 5 years into their disease course, but no sooner than puberty, then yearly thereafter. 3 If retinopathy is detected, the frequency of examinations should be increased appropriately.

TREATMENT DM and diabetic retinopathy are both progressive conditions.

Accordingly, regular follow-up care with an optometrist or ophthalmologist is crucial to detect any changes that may be amenable to treatment.

Medical Care: One of the mo t important aspects in the management of diabetic retinopathy is patient education. Patients who are well informed a n~ comp liant with therapy can then play an integral role 111 their own eye care. The Diabetes Control and Comp li cations Trial (DCTT) clearly demonstrated that intensive control of blood glucose in diabetics is associated with a reduced risk of ne~l~ diag~osed retinopathy as well as reduced progresSion of ex1stmg retmopathy, especia lly in Type I Diabetics.4

Surgical Care: Laser photocoagulation is an effective treatment modality for macular edema that ha a significant degree of success with a relative ly low com~ lication rate . It involves directing a highlyfocused beam of hght energy at the areas of the leaking blood vesse ls to create a coagulative response.4 The strategy for treating macular edem~ depends on the type and extent of vessel leakage.

If the edema IS due to leakage of spec ific microaneurysms, the

leaking vessels are treated directly with focal laser photocoagulation. In cases where the foci of leakage are nonspecific, as is usually the case in proliferative retinopathy, a grid pattern of laser bums is applied.

A vitrectomy is performed if a lot of blood is present in the vitreous. This process involves removing the cloudy vitreous and replacing it with a salt solution. Because the vitreous is mostly water, no change between the salt solution and the normal vitreous will be noticed.

CONCLUSION Diabetic retinopathy remains the number one cause of new blindness in most industrialized countries. The vast majority of diabetic individuals who lose vision do so not because of an inability to treat their disease, but rather due to a delay in seeking medical attention. The key to sight preservation for diabetic patients is routine examinations to detect the earliest signs of retinopathy. Appropriate referral to an ophthalmologist for retinal evaluation and treatment is both necessary and cost-effective in reducing the burden of this devastating complication of diabetes.

REFERENCES 1. Klein R. eta/. Diabetic eye disease. Lancet. Jul. 1997: 350(9072) : 197204 2. Palmberg, P. Screening for diabetic retinopathy. Comment on: Diabetes Care. Ma r. 2001 ; Vol 24 (3) : 522-6 3. Owens D.R. et a/. Diabetic retinopathy screening. Diabetic Medicine.

Jul. 2000; Vo l 17 (7) : 493-4 4.

Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group. Ophthalmology 1995; 102(4) :647-61

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UWOMJ 72(2) 2003 39

Type 2 Diabetes Mellitus in Children and Adolescents: A Disturbing Trend

Ja ime Blackwood and Mary Catherine Kerr; Meds 2003

Type 2 Diabetes Mellitus (DM) can be a devastating disease with long-term complications such as retinopathy ', coronary artery disease (CAD)2, nephropathy and neuropathy. The clinical entity of type 2 DM is likely a compilation of genetic, environmental, and behavioural factors. However, the underlying metabolic pathology involves insulin resistance coupled with pancreatic beta cell failureJ. Recent studies show a trend toward increasing incidence and prevalence of Type 2 DM in child ren and adolescents, particularly those of Pima Indian descent in the Arizona region, where the prevalence of type 2 DM in 15-19 year-olds has reached 50.9 per 1000 4â&#x20AC;˘ Given that complications generally increase with longevity of the disease and particularly untreated disease', the implications for children and adolescents, who will potentially have the disease for decades longer t han the average adult, is frightening. Should this trend continue, the potential burden of disease on both the patients and health care providers is concerning. In an attempt to decrease this problem, prevention a nd ea rly education and lifestyle modifications are instrumental.

As health care providers, it is necessary to think of the possibility of the disease in a patient, accurately diagnose it, and subsequently educate and treat the patient appropriately.

PATHOPHYSIOLOGY

INCIDENCE

Pancreati c beta cell s normally sec rete insulin in response to elevated bl ood glucose levels. In sulin binds to insulin receptor on musc le and fat cell s, whi ch fac ilitates the uptake of g lucose by those ti ssuesJ. Type 2 Di abetes Mellitus is an endocrine di sorder invo lving insulin res istance, pancreati c beta ce ll fa ilure, and dysregul ated hepati c glucose producti on3.

Di so rders of glucose metaboli sm consti tute a spectrum , ranging from in ulin res istance with normoglycemi a to overt diabetes4. Pati ents initi ally demonstrate in sulin res istance but are able to compensate with increased insulin secreti on (hyperinsulinemi a), and therefore are normoglycemi c. However, as the in sulin res i tance prog resses, beta ce ll s become less abl e to compensate, to the point that fasting hyperg lycemi a i present.

Increased hepati c glucose producti on fu rther contributes to the hyperglycemi a due to lack of the normal inhibitory effect of in sulin on the liver secondary to res i tance in indi viduals with the di sease 4.

Given that type 2 DM is a relatively newly recognized disease in thi s young age group, literature regarding incidence and preva lence is somewhat limited. However, some groups have been studi ed more extensively, such as the Pima Indian population in Ari zona. Of the g roups studied thus far, they are believed to have the hi ghest preva lence of the disease. In an analysis from 19921996, the preva lence in l 0- 14 year-olds and 15 - 19 year-olds were fo und to be 22.3 per! 000 and 50.9 per 1000, respectively4. Of note, it was more likely to affect individual of mothers with DM or ge tational DM, who may have experienced a diabetic intrauterine environment?.

The incidence of type 2 DM in I 0-19 year-olds in Cincinnati, Ohio rose from 0.7 per 100 000 in 1982 to 7.2 per 100 000 just over a decade later in 19944. Similarly, a Canadian study of a First Nations population studied in Manitoba reflects a high incidence 36.0 per l 000 g irl s aged 10-19 in 1996-974.

A lthough further study is indicated, enough data exists in the literature to draw attention to an alam1ing trend - Type 2 DM is increasing in children and adolescents.

40

UWOMJ 72(2) 2003

PRESENTATION

TESTING

Children and/or adolescents with type 2 DM can present with a full range of symptoms, from an incidental finding of hyperglycemia to ketoacidosiss. As a clinician, it is important to realize that it may be difficult to distinguish between the different types ofDM upon initial presentation. A child with type 2 DM may initially require insulin to treat hyperglycemia and as a result, the child may be believed to have type I DM. However, if insulin is no longer required the child may actually have type 2 DM and can be treated with ora l hypoglycemicss. Thus, the final diagnosis and classification of the type of DM may occur only after following the clinical course of the illnesss.

Although not always present, there are some differences between the presentations of the various types of DM that one must keep in mind while classifying the illness. First, type 2 DM often has an indolent presentation, as opposed to the acute presentation of type I 4. Second, it is more likely that type 2 DM wi ll be found incidentally on routine urinalysis where one may find glucosuria without ketouria4. Third, a key discerning feature of children/adolescents with type 2 DM is obesity7. Up to 85% of children affected with type 2 DM are either overweight or obese4.

Finally, a feature that may be noted on physical examination in 85% of patients with type 2 DM is acanthosis nigricans6. This sign of long-standing hyperinsulinism is a cutaneous finding characterized by velvety hyperpigrnented areas found on the nape of the neck, in the antecubital areas and along the inner thighs6 A thorough family history must be obtained for any chi ld where DM is being considered as a diagnosis, as 45-80% of children with type 2 DM have at least one parent with DM and they may have a family history of DM over several generations6.

There is insuffici ent data to make definite guide lines for the screening of chi ldren for type 2 DM. However, the American Diabetes Association recommends that if children are overweight (defined as a BMI > 85 th percentile for age and sex, weight or height > 85 th percentile or weight > 120% of ideal for height) and have two further risk factors , they should be tested for DM regularly4. Ri sk factors include: I) family hi story of type 2 DM in a first or second degree relative, 2) race/ethnicity (American Indi ans, African-Americans, Hi spanics and Asian are at an increased ri sk) and 3) signs of insulin resistance such as acanthosis nigricans or polycystic ovary syndrome4.

Screening should be initiated at I 0 years old or at the onset of puberty (whichever occurs earlier) and should be done every two years2. Testing should consist of a fasting bl ood glucose since this test is both cost effective and convenient2.

DIAGNOSIS The diagnosis of diabetes mellitus (DM) is based primarily on blood glucose measurements. These measurements may be obtained randomly, in the fasting state or during an oral glucose tolerance test6. The classification of DM is based on the clinical presentation, lab values and course of the disease. Figure 1 outlines the criteria for the diagnosis of type 2 DM.

Figure 1. Criteria for the Diagnosis of Diabetes Mellitus Symptoms of DM plus a random blood glucose level of > 11 .1 mmol/L

Classic symptoms of DM include poly uria, polydipsia, and weight loss.

OR: Fasting Plasma Glucose (FPG) > 7.0 mmo l/L

Fasting involves no caloric intake for 8 hours.

OR: 2-hr. Post-Prandial Glucose > 11 .1 mmol/L during an OGTT (Oral Glucose Tolerance Test) Adapted from Expert Committee on the Diagnosis and Classification of DM6

MANAGEMENT The treatment goal for type 2 diabetics is the nom1alization of blood glucose, for the purpose of decreasing long-term complications4 . The Diabetes Control and Com pi ications Trial (DCCT) showed that intensive therapy of adu lt type 1 DM delayed the onset and slowed the progression of early diabetic complications. This premise was tested in children by completing separate subset analyses in 195 patients between the ages of 13 and 17 included in the DCCT. Intensive therapy lowered the risk of developing retinopathy by 30% and of developing microalbuminuria by 40% '路 This may prove to be even more important in children with type 2 DM, since early onset of the di sease may increase the possibility of microvascular complications.

The initial treatment of type 2 DM is dependent upon the clinical presentation of the child. Patients who are not serious ly ill may be managed initially with diet and exercise. However, most eventually require medical treatment4. Meanwhile, if children present with dehydration and ketoacidosis, the initial treatment will be medical therapy, and likely insulin. It is important to note that insulin is the only drug approved by the Food and Drug Administration for the treatment of diabetes in children. Even so, most endocrinologists use oral hypoglycemic agents in children with type 2 DM and believe them to be equal in efficacy to insulin 4. The oral hypoglycemic agents commonly used for children include metformin , glyburide and meglitinide4. The first line oral agent should be metformin because of its ability to decrease blood glucose levels without causing hypoglycemi a. However, metformin should not be used if there is known hepatic disease, severe infection or hypoxemic conditions4.

Regardless of the type of treatment initiated, the most important component of this treatment is lifestyle changes, which may include referral to a dietician and increasing levels of physical activity6. In order to follow the course of their disease, children must be taught how to monitor their own blood glucose levels and physicians should always closely monitor hemoglobin A I C levels as an indication of overall blood glucose contro\6.

Finally, the child's overall well-being shou ld be followed, paying close attention to psychosocial factors , and their reaction to the diagnosis of a life long di sease. A close relationship between the treating physician and the child and his/her fami ly is UWOMJ 72(2) 2003 41

an integral part of the treatment. A ' team ' ideally consisting of a physician , dietician , diabetes nurse and social worker is necessary to ensure the best possible care for the child.

CONCLUSION Based on the cutTent trend toward an increased incidence and prevalence of type 2 DM in children and adolescents, it is pertinent that health care providers are aware of the disease and the potential devastating consequences of poor management. One must consciously consider the diagnosis and screen susceptible individuals. Upon diagnosis, the key to management is education and self-monitoring by the patient, as well as the promotion of healthy eating and exerc ise, and the introduction of appropriate pharmacological agents. In addition, it is hoped that community strategies aimed at the promotion of hea lthy eating and increased physical activi ty mi ght play a role in prevention of type 2 DM in the future .

REFERENCES 1.

2.

3.

4.

5.

6.

7.

Prevention and Treatment of Diabetes in Children. Journal of Clinical Endocrinology and Metabolism. 85 (2) . February 2000.

Strategies f or Reducing Morbidity and Mortality fro m Diabetes Through Health-Care System Interventions and Diabetes Self-Management Education in Community Settings: A Report on Recommendations ofthe Task Force on Community Preventive Services. Morbidity and Mortality Weekly Report. 50 (RR-16) , September 2001.

Andreoli, T , Carpenter C. ,Griggs, R., Loscalzo, J Cecil Essentials of internal Medicine. Fifth Edition. Toronto: WB. Sa unders Company, 2001, 586-588.

American Diabetes Association: Type 2 Diabetes in Children and Adolescents. Pediatrics. 105 (3) . 2000.

Dabelea, Dana. MD, PhD, et a/. Type 2 Diabetes Mellitus in Minority Children and Adolescents: An Emerging Problem. Endocrinology and Metabolism Clin ics. 28 (4), December 1999.

Nes mith, J Darrell, MD, MPH. Type 2 Diabetes Mellitus in Children and Adolescents. Pediatrics in Review. 22 (5) , May 2001.

Fagot-Campagna, Anne, MD. PhD, eta/. Type 2 diabetes among North American children and adolescents: An epidemiologic review and a public health perspective. Journa l of Pediatrics. 136 (5). May 2000.

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IS C-Peptide a Biologically Active Hormone?

Anile Mody

It has long been the general consensus that the connecting peptide (C-peptide) of proinsulin is essential in

insulin biosynthesis, but it is biologically inert. Recent evidence however, shows that C-peptide exerts important physiological effects. It has been shown to bind to cell surfaces through an unidentified surface receptor, with subsequent intracellular signal transduction. Furthermore, administration of C-peptide causes increased bloodflow in skeletal muscle and skin, decreased glomerular hyperfiltration, diminished urinary albumin excretion, and improved nerve function, all in patients with Type 1 diabetes mellitus (DM) who lack the peptide. Thus, connecting peptide can no longer be considered a biologically inert marker of insulin production. This statement has tremendous therapeutic implications. If C-peptide is indeed a biologically active hormone, then giving it in physiological doses, concomitantly with exogenous insulin may retard or even prevent the long-term microvascular complications in patients with Type 1 DM.

INTRODUCTION Type 1 diabetes mellitus (DM) is an endocrine disorder in which insulin is functionally absent because of autoimmune destruction of the pancreatic beta cells. Patients require exogenous insulin to reverse this catabolic condition, decrease hyperglucagonemia, normalize lipid and protein metabolism and prevent ketosis. Hence this condition is also referred to as Type I DM. However, it is well established that some patients with Type I DM retain a measurable level of pancreatic beta-cell activity for many years after onset of the disease. 1 Residual insulin secretion in these patients has been suggested to be associated with improved blood glucose controJ.2 Likewise, early signs of microvascular complications (nephropathy, retinopathy, neuropathy) are seen less frequently in patients with signs of residual beta-cell activity.3 Also, a negative relationship has been shown between endogenous beta-cell activity and early signs of diabetic retinopathy; this relationship is more prominent than that found between glycaemic control and early retinopathy.2 The above findings have generally been interpreted as indicating that remaining endogenous insulin levels exert a beneficial effect on glycaemic control and a protective influence with regard to the development of diabetic complications.3,4 In trying to understand why endogenous insulin is more beneficial than exogenous, one can theorize that residual beta-cell activity implies remaining insulin as well as Cpeptide. Exogenously administered insulin has no C-peptide.

Thus, perhaps it is the C-peptide, rather than the endogenous insulin itself, that is exerting a beneficial influence both on blood

glucose control and on the development of microvascular complications in Type I DM.4 This hypothesis is fascinating and a great deal of research is currently underway to determjne the true significance of this elusive clipping of the proinsulin molecule. This paper will review the history of C-peptide, recent evidence that questions whether C-peptide is truely a biologically inert protein, and the potential therapeutic advantages of C-peptide.

HISTORY OF C-PEPTIDE Although Banting and Best first discovered insulin in 1921 , it was not until 1967 that the biosynthesis of this essential hormone was clarified.3 Steiner eta! found that preproinsulin is synthesized in the beta cells of the islets of Langerhans.4 This single-chain polypeptide is subsequently converted to proinsulin, a molecule consisting of an A and B chain linked by a connecting peptide (Cpeptide). It was thought that the main function ofC-peptide was to join the A and B chains in a way that allows correct folding and inter-chain disulfide bond formation. s C-peptide is ultimately cleaved from proinsulin and released in equirnolar amounts with insulin into the circulation, following stimulation by glucose.

In the setting ofType I DM, C-peptide is used in the evaluation of residual insulin secretion and has provided an important research tool in the study of the natural course of beta-cell destruction and of therapeutic interventions to deter or halt tills process.3 Subsequent to its discovery, C-peptide was investigated for possible metabolic effects. Specifically, research focused on any potential insulin-like effects of this molecule in healthy humans

UWOMJ 72(2) 2003 43

and animal model s, but none were found.6 Molecular studies were disappointing as well. Traditionally, a bioactive peptide is thought to exert its effects through ligand-receptor interactions. A specific part of the ligand termed the " active site" is directly involved in this binding. This "active site" is usually conserved across species boundari es.-~ However, the C-peptide molecular structure was found to vary greatly between different species with regard to both its chain length and its amino acid composition.S This finding, coupled with repeated negative experimental results supported the opinion that C-peptide is a biological inert molecule .J.s However, evidence with in the last decade que tions this conclusio n.

EVIDENCE IN SUPPORT OF C-PEPTIDE AS A BIOLOGICALLY ACTIVE HORMONE Research has centered on C-peptide admini strati o n in patients with Type I DM as well as experimental animal mode ls both with little to no endogenous C-peptide product ion. The following is a synops is of the most sa lient findings that suggest Cpeptide may be biologically active.

Binding and Intracellular Signal Transduction Recent binding studies usi ng advanced technology have actua lly demonstrated the presence of signi f icant C -peptide-ce ll membrane interactions.6 There is direct evidence of stereospecific binding of C-peptide to a ce ll surface receptor, different from that of insu lin and other related hormones .? Furthermore, Ohtomo eta! has shown that C-peptide activates calcium-dependent intrace llul ar signalin g pathways with subsequent stimul ation of sodium-potassi um adenosine triphosphatase (ATPase) and endothe li al nitric oxide synthase (eNOS) activity.8 The latter enzyme is invo lved in bal ancing vasc ular tone, coagul ati on and inflammation .9 These enzyme systems are well known to show decreased activity in Type I DM, particu larly in renal and nerve ti ssue. IO These effects are negated when pertussis tox in (known to interfere with the alpha subunit of Gi protein s) is added to experimental mode ls prior to C-peptide ad mini stration. 9 Thus, althoug h a specific ce ll surface receptor has not yet been identified, G proteins may be invol ved. Furthermore, a COOH-terminal pentapeptide segment has been fo und in C- peptide, whi ch is essenti al for binding and constitutes an active site.''

The above results suggest that C-peptide binds to a ce ll- urface receptor in a li gand-receptor interact ion, and may exert bi ologica l effects through a n intrace llul ar signal tran duction pathway. It may be that thi s receptor is saturated by norma l C-peptide concentrations in healthy individuals, and thus no additi o nal bi ological activity can be expected from further C-peptide admini stration .3 Thi s hypothesis would ex plain why the early studi es that invo lved givi ng C-peptide to hea lthy humans and anim als yie lded negative results.

Beneficial Systemic Effects Admini stration of C-peptide to pati ents with Type I DM is accompanied by numerous physio logica l responses. increased blood flow to skeletal musc le at rest and during exerc ise, redistributi on of skin microvascul ar blood flow, and increased rena l bl ood flow can be seen after C-peptide admini stration for 1-3 hours.I2 Johansson et al found that combi ned treatment with Cpeptide and insulin for 3 month s improved rena l function by

44

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diminishing urinary albumin excretion and g lomerular hyperfiltration and ameli orated autonomic and sensory nerve dysfunc' tion . 13 In contrast, no beneficial effect was seen in the same group of patients during a control period of insulin therapy alone.' 3 Therefore, these preliminary studies of C-peptide demonstrate that it improves may have a role in the associated neural, renal and vascular dysfunction ofType 1 DM .

FURTHER STUDIES Therefore, C-peptide may offer an intervention for glycaernic control and microvascular complications in Type 1 DM. However, there is also a population of Type 2 diabetic patients who require exogenous insulin for optimal glycaernic control. Few studies to date have examined tills group of patients, and tills represents a populati on for future study. In addition, C-peptide studies thus far have been conducted in relatively small groups for short durations of time. The evidence summarized in till s paper is promising preliminary data provi ding a basis for larger and more prolonged trial s.

CONCLUSION In conclusion, C-peptide may not mere ly be a marker for insulin secretion, but also may have therapeutic implications complementary to exogenous insulin in the treatment of Type I DM . Future research may have important implications for the interventions into compli cations in Type 1 DM. REFERENCES 1.

2.

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Madsbad S. McNair P. Faber OK, Binder C. Beta-cell f unction and metabolic co ntrol in insulin-dependent trea ted diabetics. Acta Endocrin e. 93: 196-200: 1990.

Sjoberg S. Berglund L. Moller E. Residual C.-peptide excretion is associated with a betrer long-term glycemic control and slower progress of retinopa thy in type 1 (insu lin-dependent) diabetes mellitus. J Diabetes Complications. 5: 18-22: 1991.

Wahren J. Gohansson B. Wallberg-Henriksson H. Does C.-peptide have a physiological role? Diabetologia. 37: 99- 107; 1994.

Wahren J. Johansson B. Linde B. C.-peptide revisited- new physiological effects and therapeutic implications. Journal ofinternal Medicine. 240: 11 5-124.

Kitabchi E. Proinsulin and C.-peptide. Metabo lism. 26: 54 7-87; 1977.

Steiner D. Rubenstein A. Proinsulin C.-Peptide-Biological Activity?

Science. 277: 531-532: 1997.

Rigler R. Pramanik A. Jonasson P. Kratz G. Jan sson 0. and Wahren J Specific binding of proinsu/in C.-peptide to human cell membranes.

Proc Na t/ Acad Sci USA . 96: 1318-1323: 1999.

Djemli A. Gal/ice P. Coste. and Jann ot M. Ex vivo and in vitro effects of insulin and C.-peptide on Na/K ATPase activity in red blood cell membranes of type I diabetic patients. Diabetologia. 42: A 154: 1999.

Pieper G. Review ofAlterations in Endothelial Nitric Oxide Production in Diabetes. Hypertension. 31: 1047- 1060: 1998.

Honing M. Morrison P. Banga 1 Nitric Oxide Availability in Diabetes Mellitus. Diabetes Metabolism Reviews. 14: 241-249: 1998.

Wahren J. Ekberg K. Johansson J. and Pramanik A. Role ofC-peptide in human physiology. Am J Physiol Endocrinol Metab. 278: ÂŁ 759-ÂŁ768; 2000.

Johansson B. Linde B. Wahren J Effects ofC-peptide on blood f low. capillmy diffusion capacity and glucose llfilization in th e exercising fore arm of type 1 (insulin-dependent)diabetic patients. Diabetologia. 35: 11 51-11 58; 1992.

Johansson B. Borg K. Fernqvist F C.-peptide improves autonomic nerve fun ction in patients with type 1 diabetes. Diabetologia. 39: 687-695: 1996.

X?: An approach to disorders of intersex

Kirsten Grabowska, Meds 2003 and Erin Norris, Meds 2003

A diagnosis of intersex has implications for the individual and the family from the delivery room onwards.

The clinician must be able to recognize the condition in a newborn, initiate necessary investigations, and arrive at a diagnosis in order to guide management. This article reviews normal sexual differentiation, and contrasts this to pathophysiology of various intersex disorders. The etiologies and presentations of disorders of sexual differentiation, broadly divided into disorders of genetic sex, chromosomal sex, and phenotypic sex, are delineated. Finally, clinical evaluation of the newborn with ambiguous genitalia is examined, and management of this condition is discussed.

EVENTS OF NORMAL SEX DIFFERENTIATION Chromosomal Sex: Chromosomal sex is established at fertilization when the haploid genetic content of the ovum combines with the hap loid genetic content of one sperm ' 路 Fo llowing fertilization, embryonic cells multiply by mitosis. Nondisjunction events during meiosis and early mitosis can result in mosaicism, where different cell lines express a different karyotype.

Gonadal Sex: Primordial germ cells migrate to the genital ridges between 4 to 6 weeks of life, at which time the gonads are bipotential 2. The trigger for differentiation lies in the sex determining region of the Y chromosome, the SRY gene. If this gene is present, the gonads will become testes. In the absence of this gene, an ovary develops 3.

Other genes necessary in normal testicular development encode for transcription factors associated with SRY or downstream events 4 .

Phenotypic Sex: At eight weeks, the genita l tracts are bipotential, comprising the Wolffian ducts and the M ullerian ducts. Differentiation is due to either the presence or absence of a functional testis 2 . If there are functional Leydig cells, testosterone is produced, with levels peaking between 15- 18 weeks. This promotes the development of the Wolffian duct into the epididymis, vas deferens, and seminal vesicles. The testicular Sertoli cells synthesize antimullerian hormone (AMH), which promotes both regression of the mullerian ducts and transabdominal movement of the testes. In the absence

of a functional testis, the absence of testosterone and AMH causes regression of the Wolffian ducts and the development of the Mullerian system into fa llopian tubes, uterus, and upper vagina.

For viri lization to occur in the bipotential external genitalia, 5-alpha-reductase in these ti ssues must convert testosterone into dihydrotestosterone. Without this androgen effect, external genitalia develop into fema le structures.

Gender and Sexual Behaviour: There is growing evidence that the development of sexual behaviour is under neuroendocrine control. Work done on estrogen receptor knockout (ERKO) mice has demonstrated an estrogenic effect on female reproductive behaviour, moreover, male ERKA mice lacked typical male behaviours 5. A study of social behavior among girls with congenital adrenal hyperplasia demonstrated a correlation between prenatal androgen exposure and male-like behaviour 6, lending favor to the theory of testosterone imprinting of the feta l brain.

DISORDERS OF CHROMOSOMAL SEX These are abnormalities of the X or Y chromosome, either in number or in structure; not all disorders of chromosomal sex result in ambiguous genitalia.

Klinefelter Syndrome (47XXY): This syndrome is characterized by small testes, azoospermia, elevated plasma gonadotropins, and gynecomastia, but not ambiguous genitalia. Other features include developmental delay (s) and endocrine abnormalities of the thyroid and pancreas. This disorder results from an excess of one or more X chromosomes in

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an otherwise XY individual. The extra X chromosome(s) accumulate either by translocation during gametogenes is or by nondisjunction during mitosis of embryonic cells. In the latter case, the child will exhibit genetic mosaicism, and will often have a less severe form of the syndrome: in such a case, the diagnosis is often not made unti l puberty or adu lthood.

Turner Syndrome (45XO) As with Klinefelter syndrome, an infant born with Turner syndrome does not have ambiguous genitalia. The syndrome includes abnormaliti es of skeletal and connective tissues (webbed neck, widely spaced nippl es, prominent ears, short fourth metacarpals, limb lymphedema), short stature, bilateral streak gonads, and hypergonadotropic hypoestrogenism at puberty.

Chromosomal loss occurs either during gametogenes is or during embryonic mitosis; severity of the syndrome depends on what percentage of the X chromosome is miss ing, and whether some or all cell lines are affected.

Mixed Gonadal Dysgenesis Mixed gonadal dysgenesis is the result of Y-chromosome mosaicism. The phenotype depends on the di stributi on and proportion of 46 XY cells; affected individuals often have both a streak gonad and an intraabdominal testi s. A streak gonad is ovarian stromal ti ssue without oocytes, elongated along either the broad ligament or the pelvic wall. External genitalia are ambiguous, and there exists almost always internal female genitalia. Two thirds of affected children are reared as females; in these, it is important to remove testicular ti ssue prior to puberty, for both reasons of malignancy potential and to avoid virilization at puberty.

XX Male Syndrome The 46 XX karyotype in phenotyp ic mal es does not present with ambi guo us genitali a; rather, the phenotype is that of Klinefelter syndrome without an increased ri sk of deve lopmental problems. Pathophys iology is usually an abnormal X chromosome that contain s Y-related DNA, due to meiotic translocation.

True Hermaphroditism By definiti on, a true hermaphrodite must have hi stologically documented ovarian and testicul ar ti ssue, including oocytes.

Tissue can be either lateralized (i .e. an ovary on one side and a testi s on the other) or occur together in an ovotesti s. Internal genitalia usually correspond to the adjacent gonad, and ex ternal genitalia phenotype is usually ambi guous to some degree. Genotype in these individuals is variabl e, and mechani sm of gonadal deve lopment is unknown. Assignment of sex is vari able and difficult in such individuals DISORDERS OF GONADAL SEX Disorders of Gonadal sex are those where genotype does not correspond the gonad of the individual: Pure Gonadal Dysgenesis This disorder is one where phenotypic fe males with internal and external genitali a similar to Turner syndrome have either a 46 XX or 46 XY phenotype. It is distinguishabl e fro m Turner's based on karyotype and a lack of somatic abnormalities. The mutation in XY individuals is in the SRY sequence or downstream genes 46

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that render it non-functional; in XX, the mutation null s one X chromosome.

Dysgenetic Testes The syndrome of dysgenetic testes is a spectrum of disordered testicular development, and due to any of several genes known to be involved in testicular development. Because the involved genes regulate other systems, there are frequent systemic abnormalities associated with thi s condition. Syndromes that fa ll under Dysgenetic Testes include Denys-Drash (Wilms ' tumours) and Fras ier syndrome (focal nephrosclerosis). SFl mutations are associated with adrenal insufficiency, and SOX9 mutati ons are assoc iated with skeletal abnormalities 4 .

Testicular Regression Syndrome Individuals with thi s syndrome are 46 XY with bilaterally absent testes, although there is phenotypic evidence of testicular functi on during fetal development. An absence of Mullerian duct structures ind icate the presence of AMH at the appropriate time in deve lopment. The spectrum of the disorder ranges from phenotypic females with absence of any internal genitalia (testicular failure prior to testosterone secretion) to phenotypic males with bilateral anorchia only. Those individuals in the middle of the spectrum will have ambiguous genitalia.

The cause of testicular regression may be due to several mechani sms, including genetic mutations, ischemia and congenital infection.

DISORDERS OF PHENOTYPIC SEX (PSEUDOHERMAPHRODITISM) These occur when the gonads and sex chromosomes correspond, but the urogenital tract does not.

Female pseudohermaphroditism refers to the virilization of female infa nts who are 46 XX and who have bilateral ovaries.

Congenital Adrenal Hyperplasia: CAH is the most common cause of female pseudohermaphroditi sm. It is a genetic disorder resulting from the deficiency of an enzyme involved in steroid horn1one biosynthesis, most commonly 2 1-hydroxylase with an incidence of I in 14,500 3. Other enzyn1e defi ciencies which may cause CAH and ambiguous genitali a in gonadal fe males are noted in Table I. In 2 1-hydroxylase defi ciency, 17-0H Progesterone cannot be converted to the glucocortico id corti sol or the mineralocorticoid aldosterone. It is therefore metabolized to androgen by the only ava il able pathway. In normal steroid hormone biosynthesis, cortiso l and aldosterone feed back to the anterior pituitary to inhibit the secreti on of adrenocorticotropic hormone (ACTH) and therefore stop steroid hormone biosynthesis. Without thi s negative feedback, the stimulati on of steroid hormone synthesis remains unchecked. At birth, androgen excess causes virilization to varying degrees, and aldosterone defi ciency, present in 50-75% of infa nts with CAH, can cause potentially fatal hyponatremia and hyperkalemia 3.

Although CAH commonly manifests at birth, other non-classic or late forms are possible. These may present in adolescence with signs of hirsutism or menstrual dysfunction , or even later with infertil ity. Males affected with CAH do not have ambiguous genitalia, but present with precocious puberty.

Table 1: Disorders of Sexual Differentiation Disorders of Chromosomal Sex Kleinfelter syndrome (47 XXY) Turner syndrome (45 XO) Mixed gonadal dysgenesis (45 XO, 46XY) XX Male syndrome True Hermaphroditism Disorders of Gonadal Sex Pure Gonadal dysgenesis Dysgenetic Testes Testicular Regression Syndrome Female pseudohermaphroditi sm Congenital adrenal hyperplasia 21-hydroxylase 11-alpha-hydroxylase 3-beta-hydroxysteroid dehydrogenase P450cc (cholesterol side chain cleavage) Placental aromatase deficiency Gestational hyperandrogenism Male pseudohermaphroditism Deficiencies of testosterone biosynthesis 3-beta-hydroxystero id dehydrogenase P450scc (cholesterol side chain cleavage) 17-alpha-hydroxysteroid dehydrogenase 17 ,20-lyase Syndromes of incomplete androgen effect Sa Reductase Deficiency Disorders of Mullerian duct regression

Placental aromatase deficiency: Mutations in the gene encoding this enzyme, which converts androgens to estrogens, results in elevated fetal levels of testosterone. Enzyme deficiency persists in later life, causing hirsutism and polycystic ovaries.

Gestational Hyperandrogenism: A hyperandrogenic state during pregnancy can be due to either exogenous or endogenous hormones, and results in virilization of the female fetus . Male fetuses are not affected. Causes include ovarian luteomas, theca-lutein cysts, and administration of progestins and androgens, and degree of virilization depends upon the timing of exposure. Conditions of hyperandrogenism must develop during pregnancy, as excess of androgen prior to pregnancy would induce infertility 7.

Mullerian Agenesis (Meyer-Rokitansky-Kuster-Hauser Syndrome) Developmental disorders of the Mullerian ducts should also be considered as disorders of phenotypic sex, although females with these disorders do not exhibit viri lization and usually present at puberty with primary amenorrhea. The severity depends on the extent of the mullerian tract involved. The hypothesized etiology is a mutation activating the AMH gene or its receptor 3. Renal anomalies need to be investigated as they coexist in one-third 4.

Male pseudoherm aphroditism refers to 46 XY male infants who are incompletely virili zed.

Deficiencies of testosterone biosynthesis: CAH can lead to male pseudohermaphroditism when excess adrenal androgens inhibit anterior pituitary secretion of luteinizing hormone, resulting in decreased testicular testosterone production . Most disorders are inherited as autosomal recessive. In some, affected individuals have iso lated androgen deficiency without symptoms or signs of mineralocorticoid or glucocorticoid deficiencies. The characteristics of males with these deficiencies vary from mild hypospadias to incomplete virilization and, in more extreme cases, ambiguous genitalia. Affected individua ls may also present later in life with precocious puberty or male infertility4.

Incomplete Androgen Effect: Sa-reductase deficiency Males deficient in thi s enzyme, necessary for male external genitalia development, present with ambiguous genitalia at birth, with perineoscrotal hypospadias, micro phallus, a blind-ending vagina, cryptorchid testes and an immature prostate. Since Wolffian duct development is not dependent on DHT, internal genitalia are intact male structures s. At the time of puberty, DHT deficiency is overcome by a relative increase in testosterone, and these males undergo virilization to resemble normal males of their age3.

Complete Androgen Insensitivity (Testicular Feminization) These XY infants resemble phenotypic females to the extent that they may present in early childhood with an inguinal hernia, or after puberty, when investigated for primary amenorrhea.

These patients lack a functioning androgen receptor, such that testosterone secreted by the testes cannot act on its target tissues.

The internal genitalia are absent because the Wolffian tracts have not been stimulated, however AMH is sti ll produced, and so the Mullerian tracts have regressed. Without testosterone or DHT influence, the secondary sex characteristics are clearly female , including the external genitalia and breast formation . Only the lower vagina develops, if at all 9. Specific care must be taken in this patients, as cryptorchidism is a major risk for developing testicular tumours. Psychological development is female, presumably because of a lack of testosterone imprinting on the fetal brain.

Reifenstein Syndrome, a partial defect in the androgen receptor, presents with incomplete virilization of a phenotypic male, including perineoscrotal hypospadias, azoospermia, and gynecomastia. In contrast to males with complete androgen insensitivity, the psychological development of these individuals is generally male 4.

Persistent Mullerian Duct Syndrome These patients have normal male external genitalia, and intact internal male structures. However, the testes are undescended, and there exists persistant mullerian structures including the uterus and fallopian tubes. A defect of AMH or its receptor, which is responsible for both descent of the testes and regression of the mullerian tract, is responsible3.

UWOMJ 72(2) 2003 47

CLINICAL EVALUATION History Important information to so li cit on history of the child with ambi guous genitali a include maternal androgen exposure in pregnancy (exogenous or endogenous), family or maternal history of an excess of miscarriages, and family hi story of ambiguous genitali a, hypospadia , etc. A family with a large number of females , some of whom are infertile, is perhaps suggestive of complete androgen insensitivity yndrome 10. A hi story of teratogen exposure may suggest an etiology in testi cular reg ression syndrome.

Physical Exam Physical exam should carefu lly document and descri be the genitalia, as well as any other abnormalities or dysmorphic features that may suggest a di agnosis. The most important element in the physical examination of a newborn with ambiguous genitali a is the pre ence or absence of palpabl e gonads 11. "Federman's rule" states that a gonad palpated below the inguinal ligament is a testi s until proven otherwise 10, as ovarian descent is exceptionally rare. Moreover, a single palpable gonad, or asymmetry in the external genitalia, are both clues that should alert the physician to the possibility of true hermaphroditi sm, or mixed gonadal dysgenesis.

Laboratory Evaluation The key laboratory study for the newborn is karyotyping.

Identi fication of the SRY sequence is performed using FISH and other cytogenetic test ; this is important if the infant is to be raised as a female. Other genes and gene mutation s can similarly be identifi ed for the purposes of genetic coun eling. Further investigations wi ll depend on the infant's phenotype: absence of palpable gonads make it imperative to test for CAH, e pec ially given the potential for adrenal in sufficiency and life-threatening sa lt-wasti ng. Serum 17-hydroxyprogesterone hould therefore be measured on all such newborn s, and electrolytes should be monitored. If maternal androgen exposure is suspected, maternal bl ood should be sampled for ovarian or adrenal tumours, and other steroid precursors as appropriate. For the infant with palpabl e gonads, whi ch suggests, irre pective of external genitalia , a diagnosis of an underv irilized male, it is neces ary to mea ure serum testosterone, dihydrate tosterone, and erum AMH . In vivo hCH stimul ation can test the integrity of the testo terone bi o yothes is path way.

Radiologic Evaluation Imaging in patients with di sorders of sex differenti ati on should not be used make the diagnosi s, but rather to document the anatomy of the child 's genitourinary tract 12. Pelvic ultra onography and flu oroscopy are the most commonly used modalities, however there is an evo lving role for magnetic resonance imagi ng (MRJ).

Pelvic ultrasonography is often the primary imagi ng modality. Thi s exam is best done during the neonata l period, when the influence of maternal hormones emphasizes the phys iology of the ovaries and Mullerian structures. Testes and ovaries can be visualized in e ither normal or abnormal posit ion, and ovote tes can frequently be di stingui shed fro m testes 12. In addition , the anato-

48

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my of the renal tract should be examined and the adrenals should be assessed for hypertrophy.

Micturating cystourethreography and genitography are fluoroscopic studies that can accurately delineate the anatomy of the vagina and the configuration of the urethra, and are therefore important for planning surgery1 2.

MRJ is limited in the pediatric population, largely by practical considerations. It is useful , how~ver, in characterizing ectopic gonads, streak gonads, and neoplastic features . It is also used to differentiate between a penis and a hypertroprued clitoris by demonstrating the bulbospongiosus muscle and transversus perinei muscle, wruch are present in the penis but not the clitoris . 12, 13

MANAGEMENT Until recently, managing intersex has followed a model descri bed by John Money in the 1970 's. He argued that, for a child to properly develop a gender identity, they require unambiguous genitalia and corresponding gender assignment at an early age 14. Management has therefore focused on early medical and surgica l intervention to establish the child as male or female , followed by rigid rearing of the child to conform with this sex assignment, without allowing for the possibility of intersex.

Lately, however, tru s model has gathered criticism from both physicians and patient advocacy groups, and the management of intersex is being rethought 15, 16, 17 .

Communication The first step in managing an infant with intersex occurs at birth, when the family should be informed that the sex of their child is indeterminate. Any language that implies gender should be avoided, and the parents should be encouraged to wait before naming their child and registering the birth 18. During trus time, communication should be open and honest, emphasizing that the child is till normal, if omewhat atypical. As well as explaining why sex assignment needs to be postponed, the family should be allowed to examine the infant's genitalia and view any available imaging for themselves J.

Assigning Sex Until all investigations have been made, sex assignment hould be deferred. The American Academy of Pediatric recommend that the dec ision be based on fertility potential, the anticipated capac ity for normal sexual function endocrine function, ri sk of malignant change in the gonads, and testosterone imprinting 18. Full consideration should be given to anticipated changes at puberty and sex of rearing should correlate to the patient's expected postpubertal sexuality 17. Special care should be taken when assigning female sex to an XY individual. A review of documented cases of sex reassignment noted that more female assigned XY patients decided to reassign their gender than did male assigned XY patients 19. The decision about sex assignment should not be made by an individual, but rather by a team including an endocrinologist, geneticist, surgeon, and the patient 's family.

Surgical considerations Surgical techniques are employed to reduce malignant potential , to improve exual and reproductive function and to feminize or masculinize the patient, in keeping with sex assignment.

Feminizing urgery includes reductive surgery of the clitoris and

vaginoplasty, or construction of the vagina using co lonic tissue or skin flaps . The goals of vaginop lasty are adequate sexua l function and optimising fertility to the extent that this is possible 20.

Masculinizing surgery ranges from hypospadias repair to penile construction with a urinary conduit and transposition of the labia to create a scrotum. Male patients with persistent Mullerian structures may also undergo laparotomy to remove these structures. Bilateral orchiectomy is employed for those with cryptorchidism at ri sk of deve loping testicular malignancies.

Early surgery for cosmetic purposes is no longer recom mended, and deci sions about surgery should be postponed until after puberty in the absence of medical indications 15, 17. In cases where sex assignment is female and feminizing surgery involves clitoral reduction , the patient may ultimately note decreased sexual and erotic function 17. Furthem1ore, the majority of patients undergoing early vaginoplasty require further interventi on for function and cosmesis 20. 21_

Long Term Outlook When a decision has been made to assign sex, it should be understood that this is the most appropriate decision given the information at the time. This does not, however, preclude reconsidering a patient 's sex assignment in the future . Indeed, there may be cases where sex reassignment is appropriate.

Developmental disturbances in gender identity cannot always be predicted 19, 22. The sex that physicians give the patient must be compatible with the social sex the patient can live with.

Puberty is a confusing time for any adolescent, and those with intersex need special attention. A physician should be prepared to answer questions about medical and surgical options, and how they may affect the patient's sexuality. The lifelong impact of intersex on the individual can be minimized by open and honest communication from the start, followed by ongoing reassessment by both the individual, their family, and the medical team . While western culture does not yet recognize intersex as a gender identity, it is a reality for some people. They should expect to find understanding and acceptance within the medical community, even if medical form s do not have a box for them to tick in just yet.

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Th e Journal of Clinical Endocrinology and Metabolism 85 (8): 26642669. 2000.

Catlin EA . Lee MM. "Disorders of Genita l Ambiguity." Oski :S Pediatrics: Principles and Practice. Chapter 60. Lippincott Williams and Wilkins, 1999.

Anhalt H. Neely EK. Hint:: RL. ''A mbiguous gen italia.'' Pediatrics in Review. 17(6):213-20. 1996 Jun .

Wright NB. Smith C. Rickwood AMK. Carty, HM. "Imaging children with ambiguous genitalia and intersex states". Clinical Radiology. 50: 823-829, 1995 Cohen, HL, Bober SE, Bow SN "Imaging the pediatric pelvis: The normal and abnormal genital tract and simulators of its diseases." Urologic Radiology 14.· 273-283, 1992.

Mon ey J. Ehrhardt AA . ''Man and woman. boy and girl. Differentiation and dimorphism of gender identity from conception to maturity" Baltimore: Johns Hopkins University Press, 1972. -pp 11 7-1 25.

Creighton SM. Minto CL. "Managing in tersex." BMJ. 323 (7324): 1264-1 265. 2001 Dec. Melton L. "New perspectives on th e management of intersex." The Lancet. 357: 2110, 2001 Jun .

Diamond M, Sigmundson K. "Management of intersexuality: Guidelin es for dealing with persons with ambiguous genitalia."

Archives of Pediatric Adolescent Medicine. 151 : 1046-1050, 1997 Oct. American Academy of Pediatrics. Committee on Genetics. "Evaluation of th e newborn with developmental anomalies of the external genitalia."

Pediatrics. 106 (1): 138-142. 2000 Jul. Meyer-Bah/burg HFL. "Gender assignment and reassignment in 46, XY pseudohermaphroditism and related conditions." Journal of Clinical Endocrinology and Metabolism. 84 (10) : 3455-3458.. 1999 Oct. Gra::iano. K. Teitelbaum DH. Hirsch/ RB. Coran AG. .. Vaginal reconstruction for ambiguous genitalia and congenital absence of the vagina: a 27-year e:~.p erien ce." Journal of Pediatric Surgery 37 {7): 955-960.

2002 Jul. Creighton SM. Minto CL. Steele SJ. "Objective cosmetic and anatomical outcomes at adole cence offemini::ing surge1y for ambiguous genitalia done in childhood." Th e Lancet. 358: 124-125. 2001 Jul. Dittmann. RW ''A mbiguous gen italia. gender-identity problems. and sex reassign ment." Journal of Sex and Marital Therapy 24:255-271, 1998.

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Speroff L, Glass RH. Kase NG. "The Ovm y - Embryology and Development." Clinical Gy necologic Endocrinology and Infertility.

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Speroff L, Glass RH, Kase NG. "Normal and Abnormal Sexual Development." Clin ical Gynecologic Endocrinology and Infertility.

Chapter 10. Williams and Wilkins. 1994.

Warn e GL, Zaja c JD. "Disorders of sexual di.fferentitation ."

Endocrinology and Metabolism Clinics of North America. 27(4) :945967, 1998 Dec. Wilson JD, Griffin JE. "Disorders of Sexual Differentiation." Harrisons Principles of Internal Medicine. Chapter 338. McGraw-Hill. 2001.

Pfaf!DW "Hormones, genes, and behavior. " Proc. Nat/. Acad. Sci. USA 94 (26): 14213-14216, 1997 Dec Hines M, Kaufman FR. "Androgen and th e development of human sextypical behaviour: rough-and-tumble playand sex of preferred p lay mates in children with congenital adrenal hype1plasia (CA H). Child Development 65 {4) : 1042-53, 1994.

McClamrock, HD, Adashi, EY. "Gestational hyperandrogenism. " Fertility and Sterility. 1992; 57 (2): 257-274, 1992 Feb. Walsh PC, Madden JD, Harrod MJ, Goldstein JL, Ma cDonald PC.

UWOMJ 72(2) 2003 49

Fetus-in-Fetu: A Diagnostic Challange

Eve Fried. Meds 2003

Fetus-in-fetu (FIF) is an extremely rare condition in which a malformed monozygotic, monochorionic diamniotic par asitic twin becomes enclosed within the body of its normally developing twin. T he condition usually presents in infancy as a rapidly growi ng abdominal mass. Imaging plays an important role in diagnosis although diagnosis is usually made intra-operatively. Two theories of this pathological embryogenesis are debated and will be discussed.

The fo llowing case was recently reported by Federici et al in Pediatric Surgery International I .

An 8 month old boy, who was born at term by normal vagina l delivery, presented with a fast-growi ng abdom inal mass, weight loss, and pall or. Repeated prenatal ultrasounds showed no congenital abnormalities. On physical examination a firm , bu lky, pai nl ess ovo id mass was found in the lower abdomen. Laboratory findings showed a mi crocytic anemia. Other values were normal.

An ultrasound showed a tumour with a mi xed cystic and solid structure; several marked ly calci fied areas were seen inside the tumour. A plain abdominal X-ray showed four well -developed bony structures. Both bl adder and bowel appeared compressed and were di spl aced superiorly. Transverse supra-umbi lica l laparotomy was performed to excise the tumour which was comp letely covered by a mooth , yellow-gray capsule. Its blood supply came fro m small vessels near the ili ac bifurcation. On pathologic examin ation, the spec imen measured 14x9x9 em and weighed 65 0 g.

"A th ick cap ul e resembling an amni oti c sac and containing a sma ll amount of clear yell ow fluid, enve loped the mass . On opening the sac, a well-developed fe tiform structure expanded to a length of 18 em. It was completely covered by intact slcin and had a cephali c extremity 7 em in di ameter covered by hair, a trunk, and upper and lower limbs with fin gers, toes and fin gernails. In the pelvic reg ion, male external genitali a were seen. Angiography performed through the umbilica l cord showed a symmetri c, well developed arteri al system. On sectioning the head, two cystic cavities were fo und with out any defi nite brain tissue. A vertebral column could be recogn ized on opening the tru nk. No structured liver, lung, or lcidney tissue could be identi f ied on hi sto logy. The postoperati ve course was uneventful and the patient was di s50

UWOMJ 72(2) 2003

charged from the hospital I 0 days after surgery in good condition.

Eight years after removal of the tumour, there is no evidence of recurrence and he is in good health ."

WH AT IS FETUS-IN-FETU? FIF is a rare condition that wa first described by Meckel in the 1800s7. To date, on ly 79 ca e have been reported in the literature9. A lthough there are orne variations in definition, it is generally accepted that FIF refers to the pre ence of a vertebral body with limbs organi zed around it growing in the body of its ho t' 2,s. It is nearly always anencephalic and the lower limbs are usually more deve loped than the upper limbs4, as can be seen in fi gure I. Anatomical locations of the FIF vary, but retroperitoneal

Figure 1: FIF specimen wit h under developed upper limbs and longer lower limbs. (Co urtesy of Pediatric Radiology)

is the predominant location, with 80% of cases occurring here4.7.

However, there are reports ofFIF in the scrotum, sacrum , ovaries, mouth and cranial cavityt .9, tO,tt ,t2. While usually occurri ng singly 7, cases of multipl e FIF have been documented4,7. FIF has a 2:1 male predominance. It usually presents in the first year of life 4·7•9 although there are some reports where it first appeared in later ch.ildhood/early adulthoodtD. Since it is usually retroperitoneal, tt usually presents a an abdomina l mass. ~IF is thought to result from " uneq ual division of the totipotent tnner mas of the deve loping blastocyst"9. Further, there is an anastomosis of the vitelline circulation tO which leads to a small cell mass becoming enclosed w ithin its maturing sister embryo9 Typically, the FIF is enclosed within a sac, not unlike the amniotic sac 2·4, and it contains some fluid, analogous to amni oti c fluidS. The FIF is suspended by a cordS. Although exceptions exist, there are usually no major vascular connections to the host twin4. FIF is usually an asymptomatic 10 mass. When symptoms do develop, they are due to the extrinsic compression on various organ systems4.7·9 and, as size increases, local mass effect and hemorrhage can result.

There has been considerable debate in the literature as to whether this condition represents a true fetiform structure or a highly organized teratoma. Those who believe that thi s condition represents a twin pregnancy in which one embryo becomes encapsulated within its twin, argue that several key features distinguish this entity from a teratoma. Willi s emphasized that the presence of a vertebral column indicates a diagnosi s of FIF rather than teratoma4 since this signifies a more advanced stage of fetal development. To develop a vertebral column, the mass must have passed through the primitive streak stage of fetal deve lopment2·8·10. Teratomas represent neoplasms which have the potential of malignant degeneration5,8,9. FIF, on the other hand, represents an aborted monozygotic twin 8 which generally does not become malignant 5,8,9 - only one such case has been reported3,4.

As a further point of differentiation, FIF is most commonly found to occur in the upper retroperitoneum. Teratomas, in contrast, occur predominantly in the lower abdomen , as well as in the ovaries and sacrococcygeal areas5,8,9.

Teratomas represent a disorganized congregation of pluripotent cells which originate from all three primitive ti ssue layers s.

As they differentiate into various tissue types, they can become highly organized with several well-formed organss. Nonetheless they lack a true vertebral arrangement, craniocaudal and lateral differentiation, body coelom or systemic organogenesis5. Those who support the notion of this mass being a teratoma believe that an original germinal cell may develop into a well-differentiated stage referred to as "fetiform teratoma"2. This, they arg ue, would be sufficient to explain this pathologyz. Further, they believe FIF should be regarded as potentially malignant since teratomas which have been malignant have co-occurred in individuals with this condition2.

THE ROLE OF IMAGING IN DIAGNOSIS Imaging plays a vital role in the diagnosis of FIF and several imaging modalities are useful in obtaining the diagnosis pre-operatively. The identification of vertebrae or long bones is essential for making the diagnosis prospectively 9.

Figure 2: Abdomen radiograph demonstrating displaced colon with linear opacities. (Courtesy of Pediatric Radiology) Prenatal ultrasound is recommended as the initial investigation . In the case of FIF, one could expect to see an amniotic sac within the developing fetus as well as areas of calcification within thi s sac 4. Plain fi lms would confirm the presence of we llformed bones in the retroperitoneum, 4 and can be seen from figure 2.

In an infant or child where the diagnosis ofFIF is be ing considered, ultrasound, plain X-Ray, CT and MRI have been used to a id in establishing a diagnosis . On ultrasound, an echogenic mass surrounded by fluid can be seen. Bony structures of fetal appearance, such as vertebrae, long bones and skull, can be visualized as well 2,5, tO Plain radiographs will reveal areas of calcifications where the fetal bones are located2.tO. Luzzatto et al suggested that once an abdominal mass is identified, an ultrasound should be used as a preliminary step to confirm the presence of the mass and to define its internal structure, to determine whether it is solid, liquid or mixed, and whether or not it possesses areas of calcifications. Also, its origin (retroperitoneal or otherwise) may be determined7 Luzzatto et a! recommended follow-up abdominal radiographs to more clearly visualize the mass' morphology if calcifications are identified within the mass7. After performing an ultrasound and plain film, a CT may be useful to provide further information 7. On CT, FIF will appear as a round or tubular collection of very low density fat surrounding a central bony structure4·8·9. While MRI will show the characteristics of the surrounding bony structures, its ability to show bony structures is inferior to that of ultrasound or plain film to. MRI can, however also define the origin of the tumour's vascular elements2. '

UWOMJ 72(2) 2003 51

MANAGEMENT Despite its generally benign nature, FIF can represent a serious di ease because of its potential to grow rapidly, which can lead to increasing pressure on organs ifleft untreated ' 路 Therefore, surgical exc ision of the fetiform structure is the treatment for Flf l,2,9. Clinical and radiological follow-up is recommended to ensure that there is no recurrence or malignant degeneration1 ,2,9.

The prognosis is generally excellent as this is a benign condition.

Patients tend to be released from ho pital within a few days of their surgery and have no further complication 1,2,9.

CONCLUSION The greatest diagnostic challenge of FIF is physician lack of knowledge of the condition as it is so rare7. Despite the presence of radiographi c findings , FIF continues to be a diagnosis that, for the most part, is made only after pathological examination of the excised mass2.8. By increasing awareness ofFIF, not only will we learn about a fasci nating condition , but we will all ow for a more timely diagnosis of this rare condition.

REFERENCES Federici S et al. Fetus in f etu: report of an additional. well-developed case. Pediatr Surg. 200I; I 7: 483-485.

2.

Hanquinet S et al. Association of a f etus in f etu and two teratomas: US and MRI. Pediatr Radio/. I 997; 27: 336-338.

3. Hopkins K et a/. Fetus-in-Fetu With Malignan t Recurrence. Journ Pediatr Surg. I99 7: IO: I4 70-I479.

4. lyer K eta/. Mu ltip le Fetuses in Fetu: Imaging Findings. 200 I .

5.

Jeanty P. de Andrade Goncalves Land SilvaS. Fetus-in-fe tu. www.thefetus.net. Sept. 2000.

6. Knox A and Webb A. Th e Clinical Features and Treatm ent of Fetus in Fetu: Two Case Reports and a Review of the Literature. Joum Pediatr Surg. I 975: IO: 483-490.

7. Luzzallo C et a/. Double f etus in f etu: diagnostic imaging. Pediatr Radio/. I994: 24: 602-603.

8. Nocera R et a/. Fetus-in-Fetu. AJR. I 982: I38: 762- 764.

9.

Patankar T et a/. Fetus in Fetu: CT Appearance - Report of Two Cases.

Radiology. 2000; 2I 4: 735-737.

I 0. Shin J et a/. Fetus-in-fe tu in the Scrotal Sac of a Newborn infant: imaging, surgical and pathological findin gs. European Radiology. I 999: 9: 945-947.

II . Thakral C and Sajwani M. Fetus-in-Fetu : A Case Report and Review of the Literature. Journ Pediatr Surg. I998: 33: I 432- I 434.

I2. Yang S and Leow S. Intracranial Fetus-in Fetu: CT Diagnosis. American Journal of Neuroradiology. I 992: I3: 1326-I 329.

I

52

UWOMJ 72(2) 2003

Turning up the heat in the OR: Brief Notes on Malignant Hyperthermia

Joseph Kim. Meds 2003

Malignant hyperthermia is a rare genetic syndrome triggered by exposure to certain anaesthetic drugs and characterized by an abnormality in the regulation of calcium flu x from the sarcoplasmic reticulum. The result is a widespread, sustained and intense muscle rigidity. Clinically, the patient presents with tachycardia, acidosis, a rise in end-tidal C02, oxygen demand and body temperature. Furthermore, muscle damage leads to myoglobin release and several electrolyte imbalances.

Treatment involves recognition of a malignant hyperthermia crisis and discontinuation of all offending agents. Immediate administration of intravenous Dantrolene should be supplemented by efforts to cool the patient. In addition, acidosis and hyperkalemia should be managed accordingly.

Although malignant hyperthermia is clinically rare, it is important for all anaesthesiologists and OR staff to be aware of this condition. With vigilance and education there is no reason why any malignant hyperthermia crisis cannot be resolved.

INTRODUCTION The story of malignant hyperthermia began on April 14, 1960 in Australia.' A 21 -year-old student run over by a car suffered compound fractures to his right tibia and fibula. He was transported to Royal Melbourne Hospital where it was discovered his concerns did not lie with his leg. Instead, the concern was focused on the prospect of receiving a general anaesthetic ...

WHAT IS MALIGNANT HYPERTHERMIA? Malignant hyperthermia is a rare pharmacogenetic abnormality of calcium metabolism resulting in a hypermetabolic state of skeletal muscle. Although the exact incidence of MH is unknown, it has been estimated to range from 1 in 15,000 to I in 50,000.2 Malignant hyperthermia is inherited in an autosomal dominant fashion but is subj ect to variable expression. Research has linked malignant hyperthermia to a mutation on chromosome 19q responsible for the ryanodine receptor gene (RYR1).3 This gene encodes a skeletal muscle calcium channel responsible for calcium release from the sarcoplasmic reticulum. When exposed to certain anaesthetic triggering agents, muscle membranes destabilize and susceptible patients undergo intense, persistent and widespread muscular rigidity or contractures. These contractures are the result of the sarcoplasmic reticulum being unable to rese-

quester calcium from the sarcoplasm. Consequently, myofibrils are activated, ATP and creatine phosphate are depleted and glycogenolysis is activated. The end result is a hypermetabolic state with muscle rigidity, muscle damage with consequent electrolyte abnormalities, and heat production.

The 21 year old student presented in the introduction had malignant hyperthermia and belonged to a family in which the incidence of malignant hyperthermia was significant. Ten of his relatives had died either during or after anaesthesia. The day of his accident the young man was induced with halothane and suffered an acute malignant hyperthermia episode. The anaesthetic was stopped, the patient was cooled down with ice-packs and he recovered without incident.

WHY IS IT CALLED "MALIGNANT HYPERTHERMIA"?

In addition to its neoplastic reference, the term malignant means "occurring in severe form , and frequently fatal ".4 When the syndrome was first described by Denborough and Lovell in 1960 as a familial hypersensitivity to general anaesthesia, little was known about the condition and how to treat it.5 Consequently, the mortality rate for malignant hyperthermia was approximately 80%. This figure has decreased to less than 10% with the introduction of Dantrolene and increased vigilance and awareness.6 UWOMJ 72(2) 2003 53

Hyperthermia means increased temperature and although it tends to declare it elf later on in an epi sode, hyperthermia associated with malignant hyperthermia is typically quite dramatic with temperature of 44째C being ob erved.7

WHAT ARE THE CLINICAL MANIFESTATIONS OF MALIGNANT HYPERTHERMIA? The clinical manifestation of ma lignant hyperthermia are : arrhythmias, cyanosis, decreased arterial 0 2 saturation, diaphoresis, genera lized muscle rigidity, increased 0 2 consumption, maseter mu cle pasm/rigidity (leading to difficulty intubating), rapid rise in core temperature, ri se in end-tidal C02 , tachycard ia (typically the f irst sign), and tachypnea.

WHAT ARE THE LABORATORY ABNORMALITIES ASSOCIATED WITH MALIGNANT HYPERTHERMIA? The laboratory abnormalitie as ociated with malignant hyperthermia are: elevated creatin e kina e, elevated lactate, hypercalcemia, hyperkal emia , hyperphosphatemia, metabolic aci dosis, myoglobinemia, myoglobinuria (which can lead to acute renal failure) , and respiratory acidos i .

HOW IS MALIGNANT HYPERTHERMIA DIAGNOSED?

c. Monitor closely since over-vigorous treatment may lead to hypothermia.

5. Dysrhythmias will usually respond to treatment of acidosis and hyperkalemia. Persistent dysrhythmias may be treated as per ACLS protocol, with the exception of calcium channel blocker (calcium channel bl ockers in these patients may result in hyperka lemi a and cardi ovascular collapse).

6. Determine and monitor end-tidal C0 2, arterial , central or femoral venous blood gases, serum potassium , calcium, clotting stud ies and urine output.

7. Hyperkalemia is common and should be treated with hyperventilation , bicarbonate, intravenous glucose and insulin (I 0 units regular insulin in 50 m.L 50% g lucose titrated to potassium level). Life-threatening hyperka lemia may also be treated with calcium admini stration (e.g. 2-5 mg/kg of CaCb).

8. Ensure urine output of greater than 2 m.L/kglhr. Consider central venous or PA monitoring because of fluid shifts and hemodynamic instability that may occur.

WHAT IS DANTROLENE AND HOW DOES IT WORK? Dantrolene wa fir t synthesized as a possible antibiotic.

Today it is used as a skeleta l muscle relaxant in the treatment of chronic mu cle spasticity associated with upper motor neuron di eases such a stroke, cerebral pal y, and sp inal cord injury. It works by blocking the relea e of calc ium from the sarcoplasmic reticulum. Con equently, excitation-contraction coupling is inhibited, mu cle contracture cea e and homeostasis can be achieved.

The current gold standard of diagno is is a mu scle biopsy test known as the caffei ne-halothane contracture test, or CHCT.S Muscle sampl es from malignant hyperthermia patients exJ1ibit an increased sensitivity to caffe ine and halothane. When exposed to th ese agents ke letal musc le fascicle s contract with a greater force than norma l and at a lower thre hold . The strip of muscle to be tested is typica lly taken from the patient 's quadricep (vastus laterali s or medi us). However, ections of rectus abdominus have been used .

In Ca nada, the mu cle biopsy is usually performed on an outpatient basis in one of three centres aero s Canada, including the University of Toronto, Toronto General Ho pita! , the Ottawa Hospital, Civ ic Site and the Winnipeg Chi ldren 's Ho pita!.

Fortunately for pati ents, the CHCT is both highly sen iti ve (I 00%) and spec ifi c (85-90%) .9 However, the test i inva ive requiring surg ical interv611tion . Resea rch is current ly underway to find a less invasive a nd le expensive te t that is equa lly sensiti ve and spec ific.

Volatile anaesthetic agents (e.g. halothane, enflurane, isoflurane, sevoflurane, de tlurane etc.), depolarizing muscle relaxants (e.g. uccinylcholine) all can trigger malignant hyperthermia .

HOW SHOULD AN ACUTE CASE OF MALIGNANT HYPERTHERMIA BE TREATED?I O

WHAT ARE SOME PRE-OPERATIVE SCREENING QUESTIONS FOR MALIGNANT HYPERTHERMIA?I O

I . Immediate ly di continue volatile anaesthetic agent and succ inylcholine. Hyperventi late w ith I 00% oxygen at hi gh flow rates (> I OL!min).

2. Admin ister dantro lene sodium 2-3 mg/kg initial bo lus, up to 10 mg/kg.

3. Administer bicarbonate to correct metabolic ac idosis as guided by blood gas analysi . (In the absence of blood gas ana lyis, 1-2 mg/kg shou ld be admini tered .)

4. At the ame time in stitute cooling measures for the hyperthermic patient, (goal = 38째C). Administer iced aline 15 mL/kg IV q 15 minute x 3. a. Lavage stomach, bl adder, rectum and open cav ities with iced saline as appropri ate. b. S urface coo l with ice and hypothermia blanket.

I . I there a family hi story of malignant hyperthermia?

2. Have there been any unexpected deaths or complications ari ing from anaesthe ia in any member of your immediate family?

3. I there a per onal hi story of dark or co la-coloured urine fo ll owing anaesthesia? (myoglobinuria) 4. I there a personal hi tory of unexp lained high fever follow ing urgery?

54

UWOMJ 72(2) 2003

WHAT DRUGS CAN TRIGGER A MALIGNANT HYPERTHERMIA EPISODE?

WHAT AGENTS ARE SAFE TO ADMINISTER TO MALIGNANT HYPERTHERMIA PATIENTS? Drugs that are safe to admini ter to someone at risk of develop ing malignant hyperthem1ia include: barbiturates, benzodiazep ines, loca l anaesthetics, narcotics, nitrou oxide, non-depolari zing mu cle relaxants (rocuronium , pa ncuronium , mivacurium , etc.), ketamine, and propofol.

SUMMARY Malignant hyperthem1ia is a rare geneti c syndrome triggered by expo ure to certain anaesthetic drugs and characterized by an abnorma lity in the regulation of calcium flux from the sarcoplasmi c reticulum . The result i a w idespread, su tained and intense

II

muscle rigidi ty. C lini ca lly, the patient presents with tachycardia, ac idosis, a ri e in end-tidal C02 , oxygen demand and body temperature. Furthermore, musc le damage leads to myoglobin release and several electrolyte imbalances.

Treatment invo lves recognition of a malignant hyperthermi a cri sis and di scontinuation of all offend ing agents. Immediate admini stration of intravenous Dantrolene should be suppl emented by efforts to coo l the pati ent. In addition, acidosis and hyperkalemia should be managed accordingly.

Although malignant hyperthermi a is clinica lly rare, it is important for all anaesthesiologists and OR staff to be aware of this conditi on. With vigilance and education a mali gnant hyperthermi a cri sis might be reso lved, or better yet avo ided.

ACKNOWLEDGEMENTS The author would li ke to th ank Dr. Ri chard Cherry, Department of Anaesthesiology, St. Joseph 's Hea lth Centre, for hi s time, knowledge and expertise in reviewing this arti cle. The author would also like to thank Haren Treasurer, Meds 2003, fo r hi s encouragement in writing this article.

REFERENCES Denborough MA . Ma lignant hyperthermia. Lancet 1998:352:11 3111 36.

2. Krivosic-Horber RM, Adnet PJ. L'Hyperthermie maligne anaesthetique: un syndrome don 't le taux de mortalite est inacceptable. La revue du Practicien. Med Genet 1992; 188:50-8.

3. Fill M, Coronado R, Mickelson JR. et a/. Abnormal1y anodine receptor channels in malignant hyperthermia. Biophys J 1009:50:4 71-4 75.

4. Stedman medical diction01y 1995:105 7.

5. Denborough MA . Lovell RRH. Anaesthetic deaths in a family. Lancet 1960;2:45-55.

6.

Gro ner/ GA . Schulman SR. Moll J. Ma lignan t hyperthermia.

Anaesthesia 1990:935-956.

7.

DonnellyAJ. Maligna nt hyperthermia : Epidemiology. pathophysiology, treatment. AORN J 1994;59:393-405.

8.

Britt BA. Ma lignant hyperthermia. Ca n Anaesth Soc J 1985:32:666-77.

9. Lorah MG. Should we use muscle biopsy to diagnose malignant hypertherm ia susceptibility ? Anaesthesiology 1993 :79:1-4.

10. Ma lignant hyperthermia Association of the Un ited States. Westport. CT. USA . 1993.

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UWOMJ 72(2) 2003 55

New developments in the Management of Osteoporosis

Eli::abeth Elliott

Osteoporosis is a complex endocrine disorder of bone and mineral metabolism resulting in loss of bone mass and bone tissue. Optimal management of this disease has always been controversial, but new research developments have led to shifts in optimal therapeutics. Until recently, estrogen replacement has been the modality of choice for prevention and treatment of osteoporosis in postmenopausal women. This guideline has been reconsidered due to the recently released results of the Women's Health Initiative Randomized Controlled Trial, which indicate that the health risks of combined ovarian hormone replacement outweigh possible therapeutic benefits. Furthermore, directives regarding Vitamin D dosing are also being challenged, as several studies have suggested current recommendations are grossly under target. While osteoporosis may be a well established medical condition, knowledge with respect to its management is still an evolving field.

DEFINITION OF OSTEOPOROSIS Osteoporos is is described by the World Health Organization as a systemic skeletal disease characteri zed by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragi lity and susceptibility to fractures .'

Diagnostically, osteoporosis is confirmed by a bon e mineral densitometry (BMD) assessment of more than 2.5 standard deviations below the sex-adjusted mean for normal young adu lts at peak bone mass (Table I ).2 Each dec line of bone mas by one standard deviation from the young adu lt mean doubles ri sk of fracture ) Loss of bone mineral density is sil ent until fracture occurs. The most common sites of fracture are the thorac ic vertebrae, lumbar vertebrae, hip , and di stal radius (Co lle's fracture).

Vertebra l collapse due to osteoporos is results in a lo s of height and the characteristic kyp hotic appearance of Dowager's hump .

EPIDEMIOLOGY AND IMPACT OF DISEASE Osteoporos is is very prevalent in North American soc iety, affecting one in four women and one in eight men over age 50 .4 The Osteoporosis Society of Canada estimates that 1.4 million Canadians have osteoporosis, and that the economi c impact of its combined acute and long term costs are $ 1.3 billion per annum. s Approxi mately 70% of hip fractures are directly related to osteoporosis, and one-year mortality rates post-fracture are 20% for women and 34% for men .6.7 It is wide ly anti cipated that hip fracture rates will exponenti ally rise within the next 40 years as inci-

56

UWOMJ 72(2) 2003

dence of osteoporosis increases in the aging population.8 Genetic factors are the primary determinant of peak bone mass, and other biological and environmental risk factors contribute to the development of osteoporosis. Biologic risk factors include estrogen deficiency (early menopause, bilateral oophrectomy, prolonged amenorrhea), low body weight (<57.8 kg), family history of pathologica l fractures , Caucasian or Asian race, female gender, glucocorticoid use, and comorbidity. Lifestyle risk factor are comprised of cigarette smoking, low calcium intake, alcohol abuse, excess caffei ne, and inadequate physical activity.9 Modifi cation of ri sk factors, where applicable, is essential for prevention and management of o teoporosis .

EVALUATION Once osteoporosis i diagnosed through risk factor assessment, physical examination and BMD, secondary osteoporosis (i.e. Cushing's disease, hyperparathyroidi sm, etc.) should be ruled out through a screening laboratory assessment of CBC, serum calcium, alkaline phosphatase, creatinine, and serum protein electrophoresis. 10 Further investigations should be pursued if these investigations yield any abnom1alities.

NUTRITIONAL SUPPLEMENTATION Appropriate intake of ca lci um and Vitamin D is crucial for en uring bone health. Calcium, a component of bone tissue inhibits parathyroid hormone release and curbs bone resorption .

Supplementation of ca lci um has been shown to moderately

Table 1: Bone densitometry standard deviations and related risk WHO Guidelines for BMD Interpretation

ll D· ~

C·

D·

:e.

SK

:e, ;.9 or

:s· i~

~

BMD T-Score (SD)

Change in Fracture Risk

WHO Category

> -1 -1 to 2.5 <2.5 <2.5 + low energy fracture

4-fold Increase 3-fold Increase 20-fold Increase

Normal Osteopenia Osteoporosis Established Osteoporosis

increase BMD and has demonstrated a modest reduction in fracture risk. 11 Current recommendations range between I 000 mg (most adults) and 1500 mg (postmenopausal women) of elemental calcium per day.t2 Vitamin D assists in calcium absorption, and its insufficiency increases the risk of osteoporotic fractures.t3 Vitamin D replacement in the elderly has been shown to reduce nonvertebral fracture rate.I 4 Vitamin D is orally absorbed as well as synthesized in the skin through sunlight exposure. Several studies have indicated that vitamin D insufficiency is more prevalent than assumed in healthy populations.t5,l6 This finding supports more aggressive supplementation of vitamin D than the present directives of 200 IU/day for adults (600 IU/day for those over age 70).1 5, 17 Toxicity is of concern when increasing vitamin D dosing, as calcium can potentially be fatally deposited into non-bony tissues. Toxicity is extremely rare, and most often results from chronic consumption of massive doses of Vitamin D in the magnitude of 40,000 IU/day.t s Several experts now recommend dietary supplementation of 1000 IU/day ofVitamin D in all populations as safe method of averting vitamin D insufficiency, and thus offsetting osteoporosis. I?

ESTROGEN REPLACEMENT THERAPY Until very recently, first line therapy for post-menopausal women at risk for osteoporosis has been Hormone Replacement Therapy (HRT) consisting of conjugated estrogen and a progestin in women with an intact uterus.t8 Estrogen inhibits bone metabolism, affording an overall increase in bone mass. The results of the Women's Health Initiative (WHI) randomized control trial released in July of 2002 have brought into question the use of HRT as primary management for osteoporosis. The WHI clinical trial was prematurely terminated after demonstrating that the health risks of combined oral HRT outweigh possible health benefits.t9 It should be noted that the WHI results only pertain to

women using combined oral estrogen and progestin, and that released results do not pertain to use of oral estrogen alone or hormone patches and creams. With respect to osteoporosis, the WHI was the first trial to demonstrate that HRT prevents hip fractures in the magnitude of an absolute risk reduction of 5 fewer hip fractures per 10,000 treated individuals (NNR = 2000). The study also confirmed HRT's ability to reduce incidence of vertebral and other osteoporotic fractures. While HRT's efficacy as a powerful anti-osteoporosis agent has been clearly established, its practical use is limited by the other health risks associated with HRT (heart disease, thromboembolic events, breast cancer - Table 2). Many experts argue that in light of the WHI evidence, HRT use in women should be avoided with rare exception .20 As a therapeutic strategy for treatment of osteoporosis, women must individually weigh their risk of osteoporosis against the risks of other diseases before embarking on hormone replacement therapy.

BISPHOSPHONATE THERAPY In the aftermath of the WHI, bisphosphonate therapy has become increasingly attractive. Bisphosphonates are pyrophosphate analogues that inhibit osteoclast activity by binding permanently to mineralized bone surfaces, minimizing bone resorption in the process of bone remodeling and affording an overall increase in bone mass. There are two classes of these drugs, namely non-nitrogen containing bisphosphonates such as cyclic etidronate (Didrocal) and nitrogen containing bisphosphonates like alendronate (Fosamax).

Cyclic etidronate is inexpensive and well-tolerated, with infrequent side effects of gastrointestinal distress and bone pain .

Two small randomized control trials (RCT) have shown that etidronate increases bone density and results in a 50% reduction in vertebral fracture rates.2t,22 No non-vertebral fracture assessment RCTs with etidronate has been performed, but a large matched cohort study has suggested that etidronate is also effec-

Table 2 Absolute Excess Risks per 10,000 after 1 year of HRT

111

C·

5I

or e, j.

Adverse Results

Advantageous Results

A. 7 more coronary heart disease events

A. 6 fewer colorectal cancers

B. 8 more strokes

B. 5 fewer hip fractures

C. 8 more pulmonary embolisms

D. 8 more invasive breast cancers UWOMJ 72(2) 2003 57

tive in reducing periphera l frac tures_23 Alendronate, a nitrogen containing bi sphosphonate, is poorly absorbed ora lly, and m ust be taken on an empty stomach with water whj le the patient re mains upri ght for 30 minutes after ingestion. Studies have shown few side effects with alendronate, but cli rucal practice suggests many users have difficulties with heartbum, indigestion, substernal discomfort and odynophagia. These symptoms are likely due to nonadherence with dosing instructions.24 Despite Alendronate 's practical diffi culties, the evidence supporting its efficacy as an anti frac ture agent at both vertebral and non-vertebra l sites has been conf inned through multipl e RCTs25.26,27 Rjsedro nate (Actonel), another nitrogen containing bi sphosphonate, has similar dosing di fficulties as Alendronate and equal quality of evidence supporting its use.28, 29, 30

OTHER THERAPEUTIC OPTIONS Ca lcito nin a nd Se lective Estroge n Reuptake Inhibito rs (SERMs) are two other medicati on classes approved for osteoporos is management. Both are effecti ve in increas ing BMD, but show a lesser effect o n fracture ri sk reduction. As such, these opti ons are usually pursued as therapeutic adjuncts or when use of more efficac ious optio ns are contraindicated.

Calcitonin is a thyro id hormone that inhibits osteoclast activity. Pharmacokjneti cally, ca lcitonin exhibits poor ora l absorption and subcutaneous delivery is limited by a hi gh incidence of side effects. As such, calci tonin is best delivered as a nasal spray, and limited side effects include rhiniti s and occas ional epi staxis. Thi s delivery method has been shown to decrease new vertebral fractures in postmenopausal women and increase bone density.3 ' U nfortunately, calcitonin 's non- vertebral fracture effects have not been assessed.

SERMs act on estrogen receptors to se lectively produce vari able estrogeni c effects on responsive ti ssues. Raloxifene (Evi sta) is one such SERM that has been approved fo r postmenopausal preventi on of osteoporosis. It exhibits agoni sti c effect on bone and lipoprote in productio n, but antagonizes breast ti ssue whi le having a neutral effect on uterine mucosa. Thus, in addition to its anti-osteoporoti c effects, Ralox ifene has been shown to improve lipid profil es and decrease the incidence of breast cancer.32, 33 Ralox ife ne sig ni f icantly reduces incidence of vertebral fractures, but has no effect on non-vertebral fractures34. Side effects of Raloxife ne include increased ri sk of veno us thromboembolic di sease, as we ll as hot fl ashes, leg cramps, and peripheral edema.

CONCLUSION Recent deve lopm ents in osteoporosis research have shifted therapeuti c foc us. Studi es indi cate that Vitamin D insuffi ciency is more preva lent than ori gina lly anti cipated, and that recommended daily a ll owances of thi s nutri ent should be increased from 400 IU/day to I 000 IU/day. Estrogen has classica lly been the therape uti c opti on of choice for preventi on and treatment of postmenopa usa l osteoporosis. G iven the hea lth ri sks associated with HRT, bisphosphonates are becoming an increasingly popu lar therapeuti c opti on. In select populations, ca lcitonin and SERM s may also fu ncti on as an adj unct or alternative treatment.

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UWOMJ 72(2) 2003

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World Health Organization. Assessment offra cture risk and its applic ation to screening fo r postmenopausal osteoporosis. No 843 ofTechmcal Reports series. Geneva: Th e Organization, 1994.

Consensus Devlep men t Confe rence. Prophy laxis and treatment of osteoporosis. Am J Med 1991;90: 10 7-1 0.

Ka nis JA , Melton U !II, Christiansen C. et al. The diagnosis of osteoporosis. J Bone Miner Res 1994;9: JJ 37-41.

Melton U Ill, Chrischilles EA , Lane A W. Riggs BL. How many women have osteoporosis ? J Bone Min er Res 1992;9:1005-1 0.

Goeree R. 0 'Brien B. Petitti DB, et at. A n assessm ent of the burden of illness du e to osteoporosis in Canada. J Soc Obstet Gy naecol Can 1996; J8(July suppi) : 15-24.

Cummings SR, Kelsey JL . Nevitt M C, 0 'Dowed KJ. Epidemiology of osteoporosis and osteop orotic fractures. Epidemiol R ev 1985; 7:178208.

Sernbo I, Johnell 0. Consequences of hip fracture: a prosp ective study of 1 yea~~ Osteoporos l nt 1993:3:148-53.

Papadimitrop oulos EA . Coyle P C. Josse R G, Greenwood CE. Current and proj ected rates of hip fra cture in Ca nada. CMAJ 199 7; 15 7(10) : 1357-63.

Kin Yuen C. Kendler D. Khan A . Brown J. Fortier M . Canadian Con ensus on Menopause and Os teop orosis: Section F Os teoporosis. J Soc Obstet Gy naecol Can 2001 ; 10 (October s upp1) :31-41.

Scientific Advisory Board, Os teoporosis Society of Canada. Clinica l practice g uidelines fo r the diag nosis and management of osteoporosis.

CMAJ 1996: 155 (8) : 1 ll 3-29.

Nordin BE C. Ca lcium and osteoporosis. N utrition 199 7;1 3:664-86.

South-Pau l JE. Os teop orosis: Part JJ - No npharmacologic and Pharmacologic Treatment. A m Fam Physician 2001 ;63 (6) : 11 21-28.

Capuy M C. A riot ME. Duboeuf F. Brun J. Crou::et B, Arnaud S, et a!.

Vi tamin D3 and calcium to prevent hip Fa ctures in elderly women. N Eng! J Med 1992: 327:163 7-42.

Reid JR . Th e role of calcium and vitamin D in th e prevention of o teoporosis. Endocrinol Metab Clin No rth Am 1998:27:389-98.

Rucker D. A llan JA. Fick GH. Hanley DA . Vitamin D insufficiency in a pop ulation of healthy western Canadians. CMAJ 2002:166{12) :151 724.

Chapuy MC, Pre::io i P, Maamer M. A rnaud S, Galan P, Hercberg S, et at. Prevalence of vitamin D insuffic iency in an adult normal population.

Osteop orosis 1nt 1997:7:43 9-43.

Vieth R, Fraser D. Vitamin D ins ufficiency: no recommended dieta~y allowance exists fo r this nutrient. CMAJ 2002; 166(12): 1541-42.

Writing Group fo r the Ontario Program fo r Optimal Th erapeutics.

On tario guidelin es fo r the prevention and treatment of osteoporosis.

Queens Printer of Ontario. Fa ll 2000.

Writing Group fo r the Women Health In itiative In ves tigators. Risks and benefi ts of Estrogen Plus Progestin in Healthy Postmenopausal Wo men. JAMA 2002: 3:32 1-3 1.

Yusuf S, Anand S. Hormone rep lacement therapy : a tim e for a pause.

CMAJ 2002; 16 7{4):35 7-59.

Watts NB, Harris ST, Genant HK. Wasnich RD, Miller PD, Jackson RD. et at. lnterm illent cyclical etidronate treatment of p ostmenopau at osteoporosis. N Eng! J Med 1990:323:73-9.

Storm T, Th amsborg G, Steiniche T, Genant HK. Sorenson OH. Effect of intermittent cyclical etidronate th erapy on bone mass and fra cture rate in women with pos tm enopausa l osteoporosis. N Eng J M ed 1990;322:1265- 71.

Craney A. Guy a/1 G. Krolic/..:i N. Welch V. Griffith L, Adachi JD. et at. A meta-a nalysis of etidronate f or th e treatment of pos tm enopausal osteoporosis. Osteoporos Int 2001;Jl 2:140-5 J. Baker D E. A lendronate and risedronate: what you need to know about their upper gastrointestinal tract toxicity. Rev Gastroenterol Disord 2002;2 (1) :20-33 .

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Cummings SR, Black DM, Thompson DE. Applegate WB, BarrellConnor E. Mus liner TA , et a/. Effect of alendronate on risk offracture in women with low bone density but without vertebral fractures. JAMA 1998;280:2077-82.

Liberman UA, Weiss SR, Broil J. Minne HW, Quan H, Bell NH. et a/.

Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteop orosis. N Eng/ J Med 1995;333: 143 7-43.

Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE. Nevitt MC, et a/. Randomised trial of effect of alendronate on risk offrac ture in women with existing vertebra/fractures. Lancet 1996;348:1535-41 .

McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG. Roux C. et a/. Effect of risedronate on hip fra cture risk in elderly wom en. N Eng/ J Med 2001;344:333-40.

Harris ST. Watts NB, Genant HK, McKeever CD. Hanga rtner T, Keller M, eta/. Effec ts ofrisedronate treatment on vertebral and nonvertebral fractures in wo men with postmenopausal osteopo rosis. JAMA 1999;282(14): 1344-52.

Reginster JY, Minne HW, Sorenson OH, Hooper M, Roux C. Brandi ML, et a/. Randomized trial of th e effects of risedronate on vertebral fra ctures in wo men with established postm enopausal osteopo rosis.

Osteoporosis Int 2000; II :83-91 .

Chesnut CH III, Silverman S, Andriano Ke. eta/ (PROOF Study Group) .

A randomized trial of nasal spray salmon calcitonin in p ostmenopausal women with established osteop orosis: the Prevent Recurrence of Osteoporortic Fractures Study. Am J Med. 2000;109:267-276.

Cummings SR, Eckert S, Krueger KA, et a/. Th e effect of raloxifene on risk of breast cancer in postmenopausal women: results from th e MORE randomized trial; Multiple Outcomes of Raloxifene Evaluation. JAMA .

1999;281:2189-97.

Delmas PD, Bjarnason NH, Mitlak BH, et a/. Effects of raloxifene on bone mineral density, sentm cholesterol concentrations, and uterine endometrium in p ostmenopausal women. N Eng J Med. 1997;337: 164147.

Ettinger B, Black DM, Mitlak BH, et a/ (Multiple Outcomes of Raloxife ne Evaluation [MORE] Investigators). Reduction of vertebral fractures risk in p ostmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA. 1999;282:637-45.

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UWOMJ 72(2) 2003 59

Pheochromocytomas in Von Hippei-Lindau (VHL) disease

Jill Shields, Chair, Canadian VHL Family Alliance

T he Ca nadia n Von H ippei-Lindau Family Alliance is a non-profit charity " dedicated to improvi ng diagnosis, treatme nt a nd q uality of life for people and families affected by Von Rippel-Lind a u disease." Ma ny medical personnel are still unfa miliar with the manifestation s of this unu sual disease. T he following a rticle by Dr. Pierre Jaco met sheds some light on this disease, both in term s of its medical impact a nd t he toll it takes on those it strikes. If only one medical trainee remembers this article and, in heightened awareness, someday cor rectly diagnoses a patient with VHL, then this article has served its purpose. T his issue is dedicated to E ndocrinology a nd Metabolism, and thu s is a very suitable forum for this a rticle, origin ally published in VHL Fa mily For um 9: 1 (Ma rch 2001 ; used with permission). For more informa tion on VHL, please visit our website www. vhl.or g.

UNCHARTED TERRITORY

By Pierre Ja come/, Chile

The experiences in my own fami ly with pheochromocytomas have led me to orne conc lusions that are on ly hinted at in the literature, but which I feel it is important for famil ies and physicians to hear. We have all read the warn ings in the VHL Handbook and in previou arti cles in the VHL Family Forum about the potentia l dangers of untreated pheo , and the need for testing. In fami lies that are aware that they are at ri sk for pheo , and who are carefu l about screenin g, the worst repercussions of pheos wi ll like ly never occur. But there are fami ly members who are " hiding out" from VHL, who do not want to get tested, or who may be unaware that they are at ri sk for VHL. It is for them that I am writing .

Of the 16 people in my family who have had pheo , on ly three have been diagnosed in time to prevent thei r deaths. The rest were diagnosed after their deaths, during the autopsy. They were not diagnosed because their symptoms were misunderstood . I did not understand how thi s cou ld happen until l learned a great dea l more about pheos. Let me ex pl ain.

Pheochromocytomas! (pheos for short) are re lative ly rare,

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VWOMJ 72(2) 2003

u ua lly benign tumor . Mo t arise from the adrenal medulla (90%) and the organ of Zuckerkand l (8%). They occur rarely in extra-adrena l ites (outside the adrenal glands) in the abdomen, che t (less than 2%) and neck (les than 0. 1%). A number of pheo in or around the heart have been reported ; these are usually located in the left atrial reg ion . In the general population, pheos occur at all ages w ith a peak of incidence in the third and fo urth decade . In adu lt , the tumor occurs with equal frequency in both exes, whereas 60% of the affected children are ma le. Mu ltiple tumors (adrena l and extra-adrenal) are more common in children (35 % of the case ) than in adu lts (8%). Approximately 10% are fami lial and more than 70% are bi lateral. Less than 10% are ma .lignant. The e are more often outs ide the adrena l 0oJands and act1vely secreting a hormone called dopamine .

Pheos are not exclusively assoc iated with VHL. Some otherwi e hea lthy fami ly groups may present with them as an isolated occurrence. Other fami lies present w ith them in as ociation w ith Multiple Endocrine Neop lasia (MEN type II and III) , and von Recklinghausen disease (Neurofibromatosi ). But a number of VHL families do develop pheos, adrenal or extra-adrenal. Most pheos secrete a number of hormone : epinephrine, norepi neph-

rine, dopamine, VMA (vanylmande lic acid) , and metanephrine .

Rarely they have been found to contain other hormones .2 The diverse symptoms produced by release of the e drugs can confuse

the diagnosis.

It is a known fact that no disease entity can cause more diverse manifestations than pheo. Some of these manifestations are associated with an increase in catecholamine levels.

Exclusion of most of these conditions can be done by combining clinical and biochemical tests . The addition of plasma metanephrine assay gives us one more tool , but it is still a complex process of confirming the existence of the pheo and then locating where it is hiding in the body. CT and MIBG can be used to locate the pheo.

As there is no prevention for pheo, all patients with severe or episodic high blood pres ure and associated symptoms should be screened, especially if they do not respond to treatment. Other indications for screening include: All hypertensive children All individuals with VHL, MEN II, or MEN III and their first-degree relatives even if they have normal blood pressure and no particularly suspicious symptoms. Cases of low blood pressure and pheos have been reported in our family. It is especially important to test people with VHL prior to any surgery, or before or during pregnancy, or before labor and delivery.

Individuals having episodes of high blood pressure during labor, exercise, anesthesia or radiologica l procedures.

Medical texts and articles stress the need to distinguish pheo symptoms from those of other conditions, a process called differential diagnosis. Among others, the following conditions can present similar symptoms. Pheochomocytomas might be misdiagnosed as any of these conditions: I. Anxiety, tension states, psychoneurosis, psychosis, or

erectile dysfun ction in males 2.

3.

4.

5.

6.

7.

8.

Hypoglycemia Menopause Vasodilating headaches, ophthalmic migraines and cluster headaches Suspected drug abuse: amphetamines, cocaine, LSD, phenylpropanolamine, caffeine Known drug effects : interaction of monoamine oxidase inhibitors with certain food and beverages (beer, wine, cheese), clonidine withdrawal symptoms, atropine administration, nasal decongestants, tricyclic antidepressants4 Lesions of the nervous system: trauma, tumor, stroke, focal arterial insufficiency, autonomic hyperreflexia , diencephalic seizure and syndrome

Dysfunctions of the central and peripheral nervous system:

cardiogenic hypertensive reflex in angina pectoris; exaggerated response to hypovolemia or infection, paroxysmal tachycardia, familial dysautonomia.

In our family, all too often the pheo presented psychotic symptoms. The patient was then sent to a psychiatrist or psychoanalyst and treated with no success, the cause of his or her condition being physical. This is dangerous and sometimes fatal, a pheos can be highly lethal tumors.

In order for a person to evolve through life it requires a cer-

tain stability, a ense of e lf. Pheos, with their abu ndant secretion of unexpected drug , alter the ba lance. In so do ing, they alter mental functions , producing attacks of pani c, angui sh, anx iety, rage, and ometimes, erectil e dysfun cti on in males.

In our famil y group, pheos have been respon ibl e fo r a number of deaths at ages that vary from 14 to 54. Mo t of them happened in males aged 30. They invariably presented the same symptoms: anxiety, angui sh, rage, drug u e, a lcoholi sm, poor decision making capabilities and extended peri od of sexual impotence. All were treated unsuccessfull y with p ychotherapeutic methods before dying. Their pheos were detected po t mortem. This state of affairs is serious because it neglects a phy ical, organic cause of a supposed neurosis. In our family group only three pheos have been detected and removed. The patients, although labelled neurotics prior to surgery, after a period of adjustment were able to lead normal lives. Two of them were alcoholics before surgery. Pheo remova l ended the alcohol abuse without need of special therapies for that particular symptom .

Based on my experience, I feel that there can be a direct relationship between pheos and psychiatric condition . This is not to say that all psychiatric patients have pheos, nor that all people with pheos display psychotic behaviours. Rather, I suggest that patients with pheos can present symptoms akin to neurotic or psychotic states. This may sound exaggerated. But we all know that drugs we take (alcohol, cocaine, and so forth) do alter consciousness. Why should it be different with chemicals produced in error by our own bodies?

This seems to be uncharted territory. Because there often is not a great deal of communication between a patient's physicians and psychologists, the relationship may go undetected. In my opinion, this state of affairs is dangerous . VHL families need to be vigilant and remember to test for pheos when any of these misleading symptoms appear in the family.

REFERENCES 1. See: Denise A. Morris and Jam es R. Sowers. ''Ph eochromocytoma: An Update" in Manual of Endocrinology and Metabolism. Norman Lavin , ed .. Little Brown & Co. New York.

2. Hormones reported associated with pheos include vasoactive intestinal peptide, serotonin, ACTH. somatostatin . opioid peptides, alpha-MSH. calcitonin (particularly in MEN II and III). parathyroid-like hormone, and neuropeptide Y (a potent vasoconstrictor).

3. Bahemuka, M. "Carre pondence: Ph eochromocytoma with schizophreniform psychosis." British Journal of Psychiatry 142(1983) 422429.

"Tricyclic antidepressants (which block neuronal uptake of norepineph4. rin e) represent another drug categ01y with effects that can either mimic pheochromocytoma or can provoke an attack in patients with a pheoin addition th ese drugs complicate differential diagnosis since in addition to blood pressure disturbances they can cause fa lse-positive biochemical test results. They are more commonly used than MA O inhibitors. In particulm; there are a lot ofVHL patients who are on these drugs."- Graeme Eisenhofer, Ph.D., NIH. Manger & Gifford, "Ph eochromocytoma", Blac/o-ve/1-Science, 1996 Owen eta/, "Increased dopamine-receptor sensitivity in schi:::ophrenia" Lancet (1978) ii. 223-5 Schildkraut, J.J. "The catecholamine hypothesis of affective disorders: a review of supporting evidence." American Journal of Psychiatry, 122(1965) 509-22.

UWOMJ 72(2) 2003 61

Polycystic ovary syndrome and the phenomenon of insulin resistance

Shoba Sujana Kumar. Meds 2003

Polycystic ovary syndrome is a common cause of both anovu lation and infertility in North American women.

Its pathogenesis is linked to ovarian steroidogenesis and insulin function, and there is an increasing understanding of the intertwining of the two. This a rticle wiU explore the role of insulin resistance and hyperinsulinemia in the pathogenesis of an d treatment options for the synd rome.

INTRODUCTION Polycystic ovary syndrome (PCOS) is the most common cause of infertility in North American women today, affecting approximately six percent of the female population.I-3 It is classically defined in the literature as a constellation of hyperandrogenism and ovulatory dysfunction , exclusive of specific disorders such as congenital adrenal hyperplasia, hyperprolactinemia or androgen-secreting tumours .4.5 At present, an odd aspect of clinical practice is that the practical diagnosis of PCOS actually does not depend upon the presence or number of ovarian cysts.

However, the accepted standard for ovarian pathology used in PCOS research protocol s is that women have eight or more cysts less than I 0 em in di ameter and increased ovarian troma .3-5 Women affected with PCOS exh ibit a range of signs and symptoms that include hirsuti sm, acne, anovulation and accompanying menstrual cycle dysfunction- oligomenorrhea or amenorrhea. Many are also hypertensive and obese and most are hyperinsulinemic and insulin resistant.' . 6-8 This combination of signs and symptoms has led to the popular comparison of PCOS to the metabolic Syndrome X. What is increasingly recognized, however, is that insulin resistance is not only associated with the manifestations of the syndrome, but also may actually be central to its pathogenesis, especially in obese women. Research in thi s area therefore has profound implications for the management ofPCOS and of infertility.

PATHOGENESIS OF PCOS It has been known for some time that at least one fundamental abnormality in PCOS is that of androgen excess, which produces the common morphology that includes hirsuti sm and acne.

In the course of steroi dogenesis in the normal individual, proges-

62

UWOMJ 72(2) 2003

terone is converted to 17-a-hydroxyprogesterone and androstenedione by 17-a-hydroxylase and 17,20-lyase in the theca cells of the ovary. Subsequently, these intermediates are further converted to testosterone in the theca cells and then estradiol in the ovarian granulosa cells due to the effects of a granulosa cell aromatase.3,6 This shift to an estrogenic environment due to aromatase activity is u ually followed by ovulation. Excess androgens, in contrast, interfere with the emergence of a dominant follicle , and therefore also with ovulation.9 In PCOS, increa ed activity of both 17-a-hydroxylase and 17,20-lyase produce an increase in testosterone production compared to normal. The excess testosterone acts both locally to cau e follicular atresia, and systemically to create the characteristic signs of androgen excess.6 This creates the vicious cycle of PCOS, because follicular atresia itself results in a decrease in estrogen and progesterone production, but not androgen production .10 Increased androgen production leads to more follicular atre ia, and the cycle goes on. Two hormones are implied in this process; one is luteinizing hormone (LH) and the other is insulin.

Their effects on androgen production and function in the woman I with PCOS are synergistic.

In normal steroidogenesis, the secretion of LH causes stromal .and thecal cell growth and thereby facilitates androgen pro- I duct10n . However, this process is carefully regulated, and ovarian thecal cells increase steroid production in response to an LH surge, but stop responding when LH levels rise above a certain p.oint.9 T~i s .process involves down-regulation of LH receptor Sites which mvolves down-regulation of androgen biosynthesis by factors produced by the granulosa cells. In essence, granulosa c~lls pro~uce factors that down-regulate thecal androgen syntheSIS (steroids) and upregulate it (inhibin and insulin-like growth factor, IGF-1 ). IGF-1 and its receptor are remarkably similar to

insulin and its receptor, and when present in high amounts , insulin can mimic the action of IGF-1 .4 The theory is therefore that in PCOS, due to the pre ence of insulin in its excess amounts, the thecal cells are able to e cape from this regulatory process and secrete exce androgens .9 This effect i replicated when normal thecal cell are incubated with IGF-1 or in ulin while stimulated with LH. In ulin has a further effect on androgen function , by its uppression of ex hormone binding globulin (SHBG). The ultimate result is more freely available testosterone.l 0-1 2 This testosterone is therefore available to act in ways previously de cribed.

There are therefore two a pects of the pathogenicity of PCOS : the increase in enzyme production, and the effects of increased serum insulin, which acts to upregulate LH and steroidogenesis. 13 The latter is increasingly being studied. Women with PCOS and anovulation have a demonstrated decreased senitivity to in ulin in muscle and adipose tissue, producing hyperglycemia and problems of glucose control, as well as hyperinsulinemia. Hyperinsulinemia, in this ca e, is likely due to both increased basal insulin secretion and decreased hepatic clearance.4 Postulated mechani m for the insulin resistance and hyperglycemia include aberrant insulin tyrosine kinase activity, reduced binding of insulin to its receptor, decreased efficacy of insulin in facilitating glucose transport, and decreased expression of the peripheral glucose transporter, GLUT-4 .4,14 It is thought that these effects are amplified in obese PCOS women. IS The problem with the elevated insulin level in women with PCOS is therefore not only that it creates the known problems of glucose metabolism, but also that it interferes with steroid function. As we have already seen, insulin acts to increase the amount of freely available testosterone. Why insulin causes the ovarian stimulation seen in PCOS but not in women without PCOS is the subject of much speculation. One hypothesis is that a defect in P450cl7 a activity itself is responsible for making the enzymes more re pon ive to insulin effects.J-5 Insulin is known to retain its mitogenic and anabolic effects in PCOS,9 and to enhance LHmediated responses in thecal cells to a greater degree in PCOS than in normal women. IS Insulin excess can in itself also lead to low sex-hormone binding globulin leve ls, independently of effects on androgens. II

INSULIN RESISTANCE AND THE ANOVULATION LINK Therefore, women with PCOS have been found to have a greater frequency of hyperin sulinemia and insulin resistance than women without PCOS . While this finding is greater in obese women than thin womenl s, it has been demonstrated in both .2路4 However, this phenomenon is not universal in PCOS- women with normal ovulation exhibit normal serum insulin and insulin sensitivity. It is only the anovulatory women that display insulin resistance. I It is therefore likely that the mechanism of anovulation involves insulin resistance: in other words, insulin resistance in PCOS produces anovulation, but anovulation does not produce insulin resistance.1 ,4,5 This implies that insulin resistance is a critical factor in the process leading to anovulation .

IMPLICATIONS If insulin resistance and hyperinsulinemia are linked to the

hyperandrogeni sm and anovulation of PCOS, then cou ld method to decrease insulin resistance reverse the ovu latory dysfunction ?

Several studies have shown that thi s is a c lini ca lly relevant theory. Two studies performed in Venezue la1 6,17 among other , show that decrea ing in sulin levels is correlated with a decrease in androgen leve ls and an increase in SHBG leve l in women with PCOS, through the direct suppression of in ulin secretion. 6 This has been achieved by nonpharmacological methods such a diet and exerci e8, or with medications which inhibit in ulin secretion such as omatostatin and diazox ide.6. 1s Thi s correlation of decreased serum in sulin leve ls and decreased serum androgen level i al o een with agents uch as metformin and the thi azo lidenediones, which erve to increa e peripheral insulin sensitivity_2.18 Metformin specifically, has multiple beneficial effects in the management of PCOS- it reduces weight, in sulin resistance and secretion, decreases P450c 17 a activity and LH secretion, and increases SHBG concentration s.12 These data therefore have great implications, not only for the management of the syndrome, but also for the enhancement of fertility in PCOS women who wish to conceive.

The work done to date on insulin resistance in PCOS also challenges standard treatments for the syndrome. Oral contraceptives have long been used to manage menstrual irregularities and hyperandrogenism , but as a side effect, they may produce and enhance insulin resistance .4,19 Clomiphene citrate, an antiestrogen which has traditionally been used to induce ovulation in PCOS women , is often less effective in obese PCOS women .2 One theory to explain this ha been that obesity is correlated with greater degrees of hyperinsulinemia, which in tum, as previously described, has been linked to defects in folliculogenesi s and ovulation. Accordingly, it has been shown that metformin can be used in these women to enhance the response to clomiphene, re tore cyclicity and induce spontaneous ovulation .2,20 Comfort with this approach is increasing, as there is evidence mounting that there is no associated teratogenicity with metformin, nor are there any adverse effects on pregnancy outcome .2 PCOS is therefore a common condition which illustrates uncommon roles for androgen and insulin in the female reproductive system. As such, it has fascinating implications for the health and fertility of the women it affects. New information learned about thi s syndrome continues to enrich our knowledge about the interaction of physiology and pharmaco logy in the arena of womens' health .

For the present time, th e detail s of the pathophysiology of PCOS remain somewhat elusive, as much remains to be investigated-the mechanisms for insulin action in PCOS, for example, have yet to be fully elucidated. Perhaps further work in this area will clarify the pathogenesis and lead to newer and more effective treatment and prevention strategies in the yndrome.

ACKNOWLEDGEMENT The author would like to thank Dr. Ruth McManus for reviewing this article in detail prior to submi ssion, and providing welcome help and advice.

REFERENCES I. Legro RS, Kunselman AR, Dodson WC. Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose toler-

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ance in polycystic ovmy syndrome: A prospective. controlled study in 254 affected women. Journal of Clinica l Endocrinology and Metabolism 1999; 84(1): 165-1 69 Nestler JE, Jakubo wic:: DJ. Evans WS. Pasqua/i R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. New England Journal of Medicine 1998 Jun 25; 338(26) .路 1876-1880 Hunter MH. Sterrel/ JJ. Polycystic ovmy syndrome: It s not just infertility. American Family Physician 2000 Sep 01 ;62: 1079-1088. 1090 Dunaif A. insulin resistance and th e polycystic ovary syndrome: Mechanism and implications fo r pathogenesis. Endocrin e Reviews 1997: 18(6) : 774-800 Franks S. Polycystic ovary syndrome. New England Journal ofMedicine 1995 Sep 28; 333(13): 853-861 Utige1; RD. Insulin and th e polycystic ovary syndrome. Th e New England Journal of Medicine 1996 Aug 29; 335: 657-658.

Pa qua/i R, Gambin eri A, Anconetani B. Vice1mati V. Co litta D. Caram el/i E et a/. Th e natural history of the metabolic syndrome in young women with th e polycystic ovary syndrome and the effect of longterm oestrogen-progestogen treatment. Clinical Endocrinology 1999;50:5 17-527 Huber-Buchholz M-M. Carey DGP. No rman RJ. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: Role of insulin sensitivity and luteinizing hormone. Th e Journal of Endocrinology & Metabolism 1999; 84(4): 14 70- 1474 Rosenfield RL. Polycystic ovary syndrome and insulin-resistant hyperinsu/inemia. Journal of th e America/ Academy of Dermatology 2001 Sep; 45 (3) Poretsky L. On the paradox of insulin-induced hyperandrogenism in insulin-resistant states. Endocrine Reviews 1991; 12(I): 3- 9 Nestler JE. A direct effect of hyperinsulinemia on serum sex hormonebinding globulin levels in obese women with the polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 1991 Jan OJ ; 72(1):83-89 Nestler JE, Jal.:ubowicz DJ. Decreases in ovarian cytochrome P450cl ?a activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. New England Journal of Medicine 1996; 335: 617-623.

Ehrmann DA. Barnes RB, Rosenfield RL, Cavaghan MK. imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovG/y syndrome. Diabetes Care 1999 Jan 01 : 22(1): 141- 146 Tritos NA , Mantzoros CS. Syndromes of severe insulin resistance.

Journal of Clinical Endocrinology and Metabolism 1998; 83(9) : 30253030 Morales AJ. Laughlin GA. Butzow T. Mah eshwari H. Baumann G. Yen sse. insulin. somatotropic and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: Common and distinct featu res. Journal of Clinical Endocrinology and Metabolism 1996: 81(8) : 2854-2864 Velazq uez EM. Mendoza S. Ham er T. Sosa F; Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsu/inemia, insulin resistance, hyperandrogenemia, and systolic blood pressure. while facilitating normal menses and pregnancy. Metabolism 1994; 43: 647-654 Velazquez EM, Mendoza SG. Wang P. Glueck CJ. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor}, lipoprotein (a). and immunoreactive insulin levels in patients with the polycystic ovG/y syndrome. Metabolism 1997; 46: 454-457 Morin-Papun en LC. Koivunen RM, Tomas C. Ruokonen A. Martikain en HK. Decrea ed serum leptin concentrations during metformin therapy in obese women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 1998: 83(7) :2566-2568 K01y tkowski MT. Mokan M, Horwitz MJ. Berga SL. Metabolic effects of oral contraceptives in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 1995; 80(1 1) : 3327-3334 Velazquez E. Acosta A. Mendoza SG. Menstrual cyclicity after metformi n th erapy in polycystic ovary syndrome. Obstetrics and Gy necology 1997 Sep; 90(3): 392-395

UWOMJ 72(2) 2003

MCMASTER UNIVERSITY Faculty of Health Sciences Department of Psychiatry and Behavioural Neurosciences We are a multidisciplinary department consisting of 51 full-time and 145 part-time MD and non-MD faculty working within a unique regional network of psychiatric services that integrates two general hospitals, a 24hour psychiatric emergency service, a primary care mental health program, a community of psychiatric agencies, and outreach services for children, adults and the elderly. This rich array of resources has allowed us to develop and maintain a vigorous and integrated academic environment that spans multiple clinical teaching sites.

Areas of academic excellence within the Department include mood, anxiety and women's health (Regional Mood Disorders Program, Anxiety Treatment and Research Centre, Depression Information & Resource Education Centre (DIRECT) , Women's Health Concerns Clinic, BrainBody Institute) child psychiatry, epidemiology and population mental health (Canadian Centre for Studies of Children at Risk), evidence-based psychotherapy training, and innovative models of mental health care delivery.

The Department is committed to achieving and maintaining excellence in teaching and innovative educational program development, excellence in research and, through collaboration with our Hospital partners, creative models of clinical service delive ry.

Phone (905) 522-1155 extension 3498

Fax (905) 540-6533

Subclinical Hypothyroidism - Should We Treat?

Rania Rabie, Meds 2003

Suclinical hypothyroidism is the entity composed of elevations in serum thyroid-stimulating hormone and normal th~r.oid hon~one levels in the presence or absence of symptoms of an underactive thyroid gland.

Although It IS a relatively common condition, affecting up to 20% of elderly women, its management has yet to be agreed upon. Proponents of thyroid hormone replacement for these patients cite several potential advantages of treatment. The most well studied include a halt in the progression to overt hypothyroidism and its associated morbidity; a lowering of serum cholesterol; and a favourable effect on both physical and emotional ~ell.-bei~g. Evidence both for and against treatment is mounting and today, with the majority of clinical gUidelines m favour of treatment. Although the evidence is at times inconsistent, the importance of individualizing treatment is unanimously agreed upon. This article hopes to provide an overview of both the clinical dilemma faced in subclinical hypothyroidism and the recommendations emerging from it.

INTRODUCTION Diseases of the thyroid gland comprise a significant part of both the endocrinologists and the family physician's practice.

Hypothyroidism, a result of undersecretion of thyroid hormone from the thyroid gland, makes up a large proportion of thyroidrelated disorders and is perhaps the most well known of these amongst the general public. There is a broad clinical spectrum of hypothyroidism and the question of how and when to treat is not always an easy one. Cases of overt hypothyroidism, in otherwise well patients, are relatively straightforward to manage and treatment almost always involves some sort of thyroid hormone supplementation. On the other hand, thyroid hormone replacement in the entity known as subclinical hypothyroidism (SH) remains controversial. I

DEFINITION Overt hypothyroidism can be thought of as a triad of the classical signs and symptoms of an underactive gland, elevated thyroid stimulating hormone (TSH) levels and subnormal levels of thyroxine (T4) or triiodothyronine (T3) .2 In contrast, the patient with SH is defined as having an elevated TSH and normal levels of thyroid hormones in the setting of absent or few symptoms of thyroid underactivity.3 The term "mild" hypothyroidism is perhaps more accurate than "subclinical" as upon close questioning often patients do disclose mild, nonspecific symptoms.4 A com-

mon scenario involves a patient presenting to their family practitioner's office with fatigue, weight gain, unexplained depression or irregular menses and subsequently having their thyroid function screened with a serum TSH assay. Alternatively, a patient at increased risk of thyroid dysfunction such as a post-menopausal woman may be identified on routine screening to have an abnormal elevation of her TSH. In either of these settings, the term SH wou ld be app li ed if on further testing, free thyroxine (FT4) and free triiodothyronine (FT3) were found to be within the normal range. These clinical situations arise because of the sensitivity of the TSH assay to failing thyroid function, resulting in a rise in TSH before either the FT4 or FT3 decrease below the normal range.4

PREVALENCE Overt hypothyroidism is a relatively common condition with a prevalence in the general North American population of 1. "dence mcreases .

2o/ :ro. 2â&#x20AC;˘5 Th e mc1 with age and women are more common ly affected with a female-to-male ratio of 8:1.2 The prevalence of SH is estimated to be 1-10% with the elderly and women being at increased risk. Amongst women greater than 60 years old the prevalence rates approach 20% in some reports .6,7 Other groups at increased risk of both overt and SH include those with treated ~~~rthyroidism , a history of neck irradiation, postpartum t.hyr01ditis, and certain autoimmune disorders, especially type 1 diabetes mellitus.4 UWOMJ 72(2) 2003 65

ETIOLOGY Primary thyroid di sease i overwhelm ingly more common than secondary (pituitary) or tertiary (hypothalamic) causes of hypothyroidism ) In developed countries, the number one cause of both overt and subclinical thyroid fai lure is autoimmune destruction of the thyroid gland, a condition known by some as Hashimoto 's thyroiditis (chronic lymphocytic thyroiditis) .S As such, measurement of anti-thyroid antibodi es (anti-thyroperoxidase or anti-TPO) is often undertaken once hypoactive thyroid function is discovered . Among patients with SH, 50-80% have positive antibody tests.4 Other causes include iatrogenica lly induced hypothyroidism following treatment of Grave's di sease, the hypothyroid phase of ubacute (deQuervain 's) or po t-partum thyroiditis drugs or goitrogens, and iodine deficiency. Secondary and tertiary causes with resultant pituitary insufficiency of TSH or hypothalami c insufficiency of thyrotropin-releasing honnone (TRH) respectively, are rare.9

POTENTIAL BENEFITS OF TREATMENT OF SUBCLINICAL HYPOTHYROIDISM Prevention of Progression to Overt Hypothyroidism Several studies have looked at the rate of progression from subclinical to overt hypothyroidism in an effort to predict the natural hi story of the disease and the utility of treatment of the subclinical fonn . A large population-based study with a long follow up period began in 1972. The Whickham survey involved almost 2800 randomly selected adults in whom thyroid function was assessed between 1972 and 1974. 6 The participants were followed for 20 years and the rate of conversion to overt hypothyroidism was assessed in those who had initial SH (i ncreased TSH , normal T4 and T3) . Al though the transition from subclinical to overt disease did not prove to be inevitable, an overa ll conversion rate of 5-8% annually was discovered . Those at the highest risk of conversion were women who had SH and anti-thyroid anti bodies at baseline. This group was found to have a 38-fold increase in risk over women who had nonnal serum TSH leve ls and no anti-thyroid antibodies at the start of the study period. The presence of an elevated TSH or anti -thyroid antibodies alone also conferred an increase in risk. IO The sign if icance of these results can best be appreciated clinica lly by looking at the number needed to treat to prevent one case of overt hypothyro idi sm which has been calculated as 4.3-14.3.1 1

Favourable effect on serum cholesterol In overt hypothyroidi m the pia rna chole terol (total and low-density lipoprotein or LDL) and tri g lyceride leve l increa e.

These effects are in part exp lained by decreased hepat ic ynthe i of LDL receptors and decreased lipop rotein lipase activity, re pectively. The effect of SH on serum lipid leve ls ha remained controversial for some time but a recent meta-analys is looking at the effect of thyroid hormone replacement in SH demonstrates a favourab le effect on cho lesterol leve ls. Specifica lly, LDL cholestero l level s were lowered by 0.26 mmol per liter. 12 The issue of whether this reduction is clin ically relevant is still under debate .

After a 20-year fo ll ow up of the Whickham cohort, rates of death from all causes and death from cardiovascu lar disease were no higher in the gro up that exhibited SH at baseline when compared 66

UWOMJ 72(2) 2003

to the euthyroid group . 14 Another more recent study has challenged this finding wi th evidence that middle-aged women with SH were twice as likely to have atherosclerosi s and a hi story of myocardial infarction than the ir euthyroid counterparts. 15 Uncertainty remains in those with only minimally elevated serum TSH levels (5 -1 0 mU per liter) and some small studies have suggested that thi s sub-group does not benefit from thyroxine replacement. 1路13

Favourable effects on Physical and Mental Health Several studi es have examined the physica l and psychological effects of treatment of subclinical hypothyroid individuals.

Two randomized controlled trials (RCT) regarding the efficacy of early treatment of SH in women have shown that up to 28% of patients benefited from treatment as their level of well-being, assessed by various quality of life questionnaires, increased. On the basis of these trial s four women would need to be treated for one to benefit symptomati ca lly. I 6, I 7 It should be noted that these results may reflect an overestimate of the benefits of treatment since one study was conducted only on women who had been previously treated for hyperthyroidi sm and the likelihood that these women would have developed overt hypothyroidism in the future may have been greater than the usual asymptomatic population. I 6 Additionally two more recent RCT's found thyroxine replacement in subclinical cases to confer no benefit on symptoms. I . I 8 When studi es have been limited to improvements in cognitive function and memory, results have been more consistent with four small studies showing modest improvements in treated groups. I 7-20 The relationship between hypothyroictism and mood, specifically depression, has been recognized since the publication of the Clini ca l Society of London 's " Report on Myxoedema" in 1888.21 Today it is common practice to screen for and treat thyroid dysfunction when a patient presents with signs or symptoms of depression . In some cases, nonnalization of thyroid failure can all eviate the symptom of depress ion. The psychological effects of SH are unfortunately not as clearly defined, although there have been reports linking higher depression and anxiety scores to SH. 19,22 The results however have been inconsistent and some studi es have in fact reported a worsening of anx iety with treatment of SH. l,20,23 Adding to the controversy is the debate over which thyroid agent should be used for replacement in the context of depression . The standard preparation used in almost all other cases of hypothyroi di sm is T4 or levothyroxine but recent evi dence in the psych iatric literature suggests an advantageous role for T3 in the setting of depress ion.24,25

ARGUMENTS AGAINST TREATMENT OF SUBCLINICAL HYPOTHYROIDISM The arguments agai nst treatment are largely intuitive. The individual and societa l co t of potentially unnecessary treatment and the likelihood that orne or even most patients w ill not benefit have been cited by ome. 26 More importantly, the ri sks of overtreatment leading to iatrogenic hyperthyroidism and it associated ~orbidity (increa ed ri sk of atrial fibrillation, osteoporo is, angma) may be more seri ous than leaving the SH untreated.3,4

CONCLUSIONS AND RECOMMENDATIONS At this time there is no universally accepted answer to the

que tion po ed in the title. However, given the re lative ly high rate of conversion to overt hypothyroidism, the m ajority of professional organizations do advocate treatment in pati ents with SH, especially if they have circulating anti-thyroid antibodies .27,28,29 Potential exceptions include the elderly and cardiac patie nts w ith only slight elevations in serum TSH. The deci sion to treat must be individualized with careful analysis of the pote ntial risks and benefits of thyroid replace ment. Each patient should be eva luated for symptoms, the presence of a goiter, serum cholesterol leve ls and cardiac status.JOIt should be mentioned that pregnant women and women with ovulatory dysfunction should be treated regardless of symptoms, antibody levels or chol estero l. 4 It is the hope that careful evaluation of each patient coupl ed with appropriate tests and monitoring will produce the g reatest benefit for pati ents with SH.

16.

17.

18.

19.

20.

ACKNOWLEDGEMENT The author would like to sincerely thank Dr. Tom M cDonald for hi s time and valuable contributions to thi s article. Dr. McDonald is an endocrinologist with a spec ial interest in the management of thyroid diseases.

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Kong WM, Sheikh MH, Lumb PJ. Freedman DB, Crook M. Dore CJ, Fin er N A 6-month randomized trial of thy roxine treatm ent in women with mild subclinical hypothy roidism. Am J Med 2002; 11 2:348-54.

Day an CM. Interpretation of thy roid fu nction tests. Lancer 200 1: 35 7: 619-24.

Wilson JD Foster DW Williams Textbook of Endocrinology. 8th ed.

Philadelphia: WB. Saunders Company: 1992. p .357-48 7.

Coop er DS. Subclinical Hypothy roidism. N Eng ! J Med 2001: 345:260265.

Mandel SJ. Brent GA, Larsen PR. Levothy roxin e therapy in pa rienrs wirh thy roid disease. Ann Intern Med 1993 : 11 9:492-502.

Turn bridge WMG. Evered DC. Ha ll R. et a!. Th e spectrum of thy roid disease in a community: th e Whickham survey. Clin Endocrinol (Oxf) 19 77; 7: 48 i-93.

Canaris GJ. Mano witz NR. May or GM. Ridgeway EC. Th e Colorado thy roid disease prevalence study. Arch intern Med 2000: 160:526-34.

Staub J-J, Althaus B U. Engler H, eta/. Spectrum of subclinical and overt hypothy roidism : effect on thy rotropin. prolactin , and thy roid reserve, and metabolic impact on periph eral target tissues. Am J Med 1992: 92:63 1-42.

McPhee SJ, Lingappa VR. Ganong WF. Lange JD. Pathophysiology of Disease. 3rd ed. New York: McGraw-Hill; 2000. p.48 J-99.

Vanderp ump MP. Turnbridge WM. French JM, er al. Th e incidence of thyroid disorders in the community: a twenty-year fo llow-up ofr he Whickham survey. Clin Endocrinol (Oxf) 1995: 43 :55-68.

Helfand M, Redfern CC. Screening fo r thy roid disease: an update. Ann intern Med i998; 129: i44-58.

Danese MD, Ladenson PW. Meinert CL. Powe NR. Effec t of thy rox ine therapy on serum lipoproteins in patients with mild thy roid fai lure: a quantitative review of the literature. J Clin Endocrinol Metab 2000: 85:2993-3001.

Dickman T. Lansberg PJ. Kastelein JJ, Wiersinga WM. Prevalence and correction of hypothy roidism in a large cohort of patients referred fo r dyslipidemia. Arch Intern Med i 995; i55:1490-95.

Vanderp ump MP. Turnbridge WMG, French JM, eta!. Th e development of isch emic heart disease in relation to autoimmune thy roid disease in a 20-y ear fo llow up study of an English community. Thy roid i996; 6:i55-60.

Hak AE, Pols HAP. Visser TJ. Drexhage HA, Hofman A, Witteman J C.

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Cooper DS, Halpern R. Wood LC. Levin AA . Ridgeway EC. L-thyroxine therapy in subclinical hypothy roidism: a double-blind placebo-conrrolled trial. Ann intern Med 1984; 10 1:18-24.

Nystrom E. Caidah/ K. Fager G. Wikkelso C. Lundberg P-A. Linds redr G. A double-blind cross-over 12-monrh study of L-rhy roxine rreatm enr of women with 路路subclinical " hypothy roidism. Clin Endocrinol (Oxf) 1988; 29:63- 75.

Ja eschke R. Guyall G. Gersrein H. er a!. Does treatm ent with L-rhy roxin e influence health status of middle-aged and older adults with subclinical hypothy roidism? J Gen Intern Med 1996: 11 :744-9.

Monzani R. Del Guerra P. Carracio N er a!. Subclinical hypothy roidism: neurobehavioral feat ures and beneficial effect of L-thy roxine treatment. Clin Jn vestig 1993; 71:367- 71.

Baldini 1M. Vita A. Mauri MC. et a/. Psychopathological and cognitive f eatures in subclinical hypothy roidism. Prog Neuropsychopharmacol Bioi. Psychiany 199 7; 21:925-35.

1888 Report on myxoedema. Transact Clin Soc Lon 21 (Suppl) .

Man cier G. Dartig ues JF. Decamps A, eta/. Th e PAQUJD survey and correlates of subclinical hypothy roidism in elderly community residents in th e southwest of France. Age Aging 1995: 24:235-41.

Lindeman RD. Schade DS, LaRue A. er a/. Subclinical Hypothy roidism in a biethn ic. urban community. J Am Geriatr Soc 1999: 47:703-9.

Joffe RT. Sokolov RT. Thy roid hormone treannent of primwy unipolar depression: a review. In! J Neuropsychophannacol 2000: 3: 143-7.

Rack SK. Makela EH. Hypothy roidism and depression: a th erapeutic challenge. Ann Phannaco rher 2000: 34:1142-5.

Braverman LE, Utiger RD. Wern er & lngbar :S Th e Thy roid: A Fundam ental and Clinical Text. 8th ed. Philadelphia: Lippinco rr Williams & Wilkin s: 2000. p . 1002-6.

Clinical practice guidelin es fo r the evaluation and treatm enr of hyperthy roidism and hypothy ro idism. Ja cksonville. Fla .: Am erican Association of Clinical Endocrinologists, 1996.

Va nderpump MP. Ahlquist JA . Frankly n JA. Clayton RN Consensus statement f or good practice and audit measures in the management of hypothy roidism and hyperthy roidism. BMJ 1996: 313: 539-44.

Singer PA, Cooper DS. Levy EG. eta!. Treatment g uidelin es fo r patients with hyperthy roidism and hypothy roidism. JAMA 1995: 273:808-12.

McDermoll MT. Ridg way EC. Subclinical Hyp othy roidism is Mild Thy roid Failure and Should be Treated. J Clin Endocrin ol Metab 2001 ; 86.4585-90.

UWOMJ 72(2) 2003 67

The male andropause: a valid clinical entity?

Matei Andreoiu, Meds 2003

The term andropause has been around since the 1950's, when it was first used to describe a cluster of physiologic and behavioural changes occurring in some men entering the middle stage of their life. However, it has gained increasing popularity of usage, especially amongst the lay public and the media, over the last decade.

This has coincided with an increasing focus on age-related health changes affecting the large baby-boomer generation. Increasingly, demands for some remedy have been made from men believing they are experiencing midlife changes akin to those of menopausal women. This increased focus has paved the way for greater research in the area of age-related male endocrinology, but has also created substantial controversy among the urological community regarding the need for testosterone supplementation in men with hypogonadal or low-normal androgen levels complaining of a subjectively poorer quality of life. The purpose of this article is to present a brief look at the existing evidence for andropause as a real clinical phenomenon and the appropriateness of androgen supplementation in certain men.

INTRODUCTION The term andropause itself is not entirely accurate, as it ca nnot be considered equi va lent to the fe male menopau e, whi ch invo lves compl ete ovari an fa ilure and degeneration with a concomitant drastic drop in estrogen levels over a relati ve ly short peri od of time in all women. A more clini ca lly appropri ate term has been advanced recently, androgen dec line in the aging male (ADAM). Thi s more appropriately describes the milder, more progress ive phys ica l and emoti onal changes that take place in many, but not all males, that may be parti ally or large ly attributed to changing hormonal leve ls. A clini ca l di agnos is ca n be based on the criteri a outlined in Figure I .

THE PHYSIOLOGY OF AGE-RELATED ANDROGEN CHANGES IN THE MALE The prim ary sites of testosterone producti on are the Leydi g cell s of the testes, whi ch use pregnenolone as a precursor.

Secretion is irregul ar and pul satil e and occurs in a diurnal pattern , with an early morn ing peak and an evening tro ugh. Release is tri ggered by gonadotro pins (LH, FSH) released by pituitary, itse lf in turn stimul ated by GnRH secreted by the hypothalamus.

Androgens produced by the testes can feed back to negative ly inhibit secreti on at the pi tuitary and hypothalami c levels. Aging is

68

UWOMJ 72(2) 2003

as ociated with di sturbed secretion of GnRH and a blunted response of Leydi g cell to LH to hCG I. 2. 3. The pituitary alone seems to be pared, with constant LH release upon stimulation by GnRH in older men 4â&#x20AC;˘ 7 . Older men also seem to lose the circadian rhythm for testo terone leve ls in young men, who have the highe t leve ls in the early morning s.

Testosterone is present in the body in three main form s: 2% the total circulating amount is free testosterone, 30% is tightly bound to sex -hormone-binding g lobulin (SHBG) and the remaining 68% is bound to a lbumin and other proteins. Only the testosterone th at is free or bound to albumin is bioavailable to exert its action, which invol ves binding to a high affinity intra-cellular receptor protein. The hormone receptor complex can then bind to appropri ate steroid-responsive genomic elements and cause its bi o logica l effect by influencing the cellular protein production profile .

Testosterone leve ls typically are high at birth and decline abruptly in infancy, beginning to ri se only during secondary sexual maturati on at puberty. Level s eventually plateau only to g radually decline after age 30. Several longitudinal studies have clearly demonstrated this pattern 9, I0. 11 . In these studies, the rate of dec line ranged from 0.5 to 1.0% per year. Importantly, thi s dec line was independent of the effects of chronic illness or medicati ons (including alcohol and tobacco). The exception wa beta-

agonists, which were associated with higher serum free and total testosterone levels. Concomitant with this decline, men also experience decreases in strength, bone density, muscle mass, body hair, as well as diminished sexual desire and erectile quality, altered mood with increased depression and frustration , reduced energy levels and decreased motivation.

It should be mentioned that more recent research has shown that although testosterone is the most well-known and investigated male hormone, other hormones are likely to play a role in the age-related effects traditionally attributed to testosterone. Most prominent are growth hormone and IGF-1 , which apparently decrease together. Declining levels of these factors have been associated with decreased lean muscle mass, bone density, hair distribution, and obesity 12, 13. Subsequent administration of GH reversed some of these trends, the reversal being more pronounced in eugonadal than hypogonadal ment 4. However, GH supplementation in GH-deficient men has not shown positive effects in improving mood and feelings of well-being ts.

Additionally, a few studies have shown that men with low testosterone levels and symptoms frequently responded to GH administration alone 16, 17, 18. Although declining testosterone levels may very well have the greatest impact on the associated symptoms appearing in mid-life and resembling those of men with medical hypogonadism, there is likely some degree of hormonal interdependence with drops in other endogenous substances contributing to some of the clinical manifestations previously attributed solely to testosterone deficiency.

Various physiological developments in the elderly men have been linked to diminishing bioavailable testosterone. However, a definite causal relationship has been difficult to establish . For example, men have been shown to experience the most rapid rate of muscle Joss between 41 and 60 years of age, with body fat doubling from 18% to 36% in aging men 20, 21. The evidence that declining androgen levels is the cause of this decrease is tenuous and is speculative.

Several studies have also shown a correlation between decreasing serum testosterone levels and bone mineral density in older men 22, 23, 24 while others have not shown this linkage 25, 26, 27, 28.

The proposed association and its potential importance to the development of osteoporosis in older men remains a controversial and hotly debated topic. Even more tenuous is the relationship between declining testosterone levels and diminished mood and sexual function. Although an epidemiologic study seemed to demonstrate higher rates of depression in men with low testosterone levels 29, no strong evidence exists to support blunted sexual function in such men.

as well as the mode and schedule of testosterone admini stration.

Nevertheless, the preponderance of data, although not definitive, seems to indicate a cautious role for such therapy in a carefull y selected population of men.

Short term studies have shown decreases in fat mass, increases in lean body rna s, and increases in upper or lower extremity strength in response to exogenous testosterone supplementation in men with low or low-normal levels 30-33 . A longer range tudy seems to show that these beneficial effects persist and do not wear off. In a 3-year study by Tenover and others, intramuscular testosterone produced significant increases in lean body mass and handgrip strength in older men with low testosterone levels less than 3.5 ng/ml 34 Furthermore, a study by Snyder and coworkers using testosterone transdermal patches over 3 years in men over 65 years of age with low total testosterone levels showed a significant decrease in fat mass and increase in lean mass in the group receiving the hormone versus the placebo group3S. With regards to bone mineral density, the two above-mentioned long-term studies also evaluated any changes in this variable 34, 36. Tenover 's study found a significant increase in BMD in the testosterone-treated group, while in the study by Snyder, the difference was found to be non-significant. However, there are several factors which may have played a part in decreasing the size of the effect in the Snyder study, including higher baseline total testosterone levels, concomitant supplementation with Vitamin D and calcium, and the route of testosterone administration (patch vs. intramuscular in Tenover 's study). Nevertheless, both studies did show an increase in BMD in older men with low testosterone levels. Ultimately, what is needed are long-term prospective randomized studies to assess if the favorable changes in BMD and body muscle composition and strength translate into improved functional outcomes such as improved independent living and decreased fracture rates .

What about men with low testosterone levels who complain of psychological symptoms such as depression, anger, anxiety or simply decreased general well-being? Recent reports seem to indicate a marked improvement in such symptoms in men given testosterone 37-39. The Tenover study also showed an improved sense of general well-being in those men on testosterone supplementation 34. Mood also seems to become more stable 29, 41 ,42 .

Furthermore, although sexual function seems not to have a strong association to testosterone levels, libido is usually much diminished in hypogonadal men and improves substantially with exogenous androgen administration40.

POSSIBLE BENEFITS OF TESTOSTERONE SUPPLEMENTATION

There are two main concerns with attempting testosterone supplementation. First, for a long time it was thought that testosterone would raise LDL cholesterol levels, increase triglycerides, and lower HDL levels, thereby potentially worsening coronary artery disease and predisposing men with the disease to fatal heart attacks. A harmful impact on blood lipid levels was indeed shown by studies usmg 17-alkylated steroids (eg .

Methyltestosterone) 46. However, more recent studies indicate that testosterone itself may not negatively impact on blood lipid levels but rather may induce an improvement in the lipid profile.

Although androgen boosts are clearly indicated and have shown beneficial effects in hypogonadal men, given such mixed findings in relatively healthy older men with low-normal androgen levels, what is the evidence for the beneficial effects of testosterone supplementation in this population ?

Generally, the weight of the evidence rests on a relatively small number of trials that never extended beyond three years in duration. They also vary in their inclusion and exclusion criteria,

ARE THERE DRAWBACKS TO TESTOSTERONE SUPPLEMENTATION ?

UWOMJ 72(2) 2003 69

Testosterone is in fact an aromati zable androgen, unlike the 17alkylated counterparts, and as such can be converted into estrogens. Testosterone itself has in fac t been shown to decrease both triglyceride and total and LDL cholesterol leve ls 32. Furthermore, some evidence shows no short-term changes in HDL levels after testosterone therapy 43.44,45, while some studies have shown either a sli ght decrease 47 or even HDL increases in hypogonadal men 48.

Popul ation studies revealed men with hi gh testosterone levels to have higher HDL and lower triglyceride levels 49 while men with more severe coronary artery disease tended to have lower androgen levels compared to those wi th milder disease so. Additionally, type 2 diabetics with dyslipidemia have been found to have lower androgen levels 51. On the other hand, testosterone decreased liposynthesis and increased lipolysis in abdominal fat 52 On the balance, testosterone in fact seems to have a positi ve effect on coronary disease and to be cardia-protective. A likely mechani sm for action may involve the documented increase in fibrinolytic activity by endogenous testosterone whi ch seems to stimulate the production and activation of ti ssue pl asminogen activator 53 .

These various benefits have come out of short-term studies and it remains to be seen if these effects persist over the duration of longer studies.

The main contraindi cation to testosterone suppl ementation in men with low testosterone leve ls is a current or past hi story of prostatic carcinoma. The reason is the proven association between the presence of androgens and the benign enlargement of the prostate and/or the development of prostatic carcinoma. Given hypogonadal men rarely get prostate cancer and that one of the most effective treatments for prostate cancer is orchidectomy or anti androgens, androgens have been implicated as a possible inciting agent. As the cancer tends to manifest in elderly men in whi ch testosterone levels have been gradually decreasing for some time, li fe long exposure to normal or high testosterone levels in the body seem to have a cumulati ve effect. As of yet, no fi rm evidence has been brought forward to suggest exogenous testosterone triggers mali gnant changes or speeds up the process.

Several studies, in whi ch men receiving testosterone therapy were investigated for an increased incidence of prostate cancer, showed no significant difference in the inci dence of the di sease compared to men not receiving androgens 54 . However, one study found no change in prostate size but elevated PSA after three month s on

testosterone treatment. Given that testosterone clearly p lays an important role in the eventual development of prostate cancer, the short duration of the testosterone therapy trial studi es so far carried out can not exclude the very real possibility that exogenous testosterone, although unlikely to initiate the process in older men, may speed it up in men with subclinical malignant changes.

Some other documented side effects to androgen supplementation exist. Gynecomastia occurs in some men because of the increased available substrate for aromatization, leading to abnormally high male levels of estrogens. Testosterone has also been shown to have an erythropoietin-stimulating effect, sometimes rai sing hemoglobin concentration to excessively high levels ss.

There is also evidence that testosterone can worsen sleep apnea 56. Table I gives a quick reference for the advantages and disadvantages of testosterone therapy.

TREATING TESTOSTERONE DEFICIENCY The two main forms of testosterone supplementation in Canada must be given intramuscularly. They are testosterone cypionate (Depo-Testosterone) which comes in a 100 mg/ml concentration and testosterone enanthate (Delatestry l) at a 200 mg/ml concentration. These medications are long acting , resulting in a maximum concentration at 72 hours post-inj ection, with diminishing levels over the next 10-14 days. Injections of 200 mg are therefore given every two weeks or so. An oral preparation also exists, testosterone undecanoate (Andriol) but its efficacy is variable as it depends on intestinal absorption . With a lack of hepatotoxicity and a dosing schedule that allows for more consistent physio logi c levels of androgen (intramuscular treatments usually lead to low levels pre-injection and supra-physiologic levels postinj ection), Androil has some advantages. More recently, a transdermal testosterone patch has become avai lable. This approach tends to produce more physiologic levels of testosterone during the day by allowing application at bed time, thereby reproducing the normal diurnal pattern of testosterone leve ls with higher levels in the early morning. The patch is more expensive than the other preparations. Table 2 demontrates the available testosterone preparations li sted above.

During testosterone therapy, changes in the size of the prostate gland must be monitored, whi ch could be reflected in the onset or worsening of obstructive voiding ymptoms. Patients

Table 1. Risks and benefits of testosterone therapy

Benefits

Risks

Increase muscle mass

Fluid retention

Preserve or improve bone mass and prevent fractures

Prec ipitation or worsening of sleep apnea (not proven)

Increase strength , stamina and physica l function

Development of gynecomastia

Improve we ll-being and mood

Induction of polycythemia

Decrease ca rdi ovascul ar risk

Increase cardiovascular ri sk

Improve libido and erecti le dysfunction

May hasten onset of clinically signifi cant benign or malignant pro tate di sease Liver toxicity (only alkylated testosterone)

70

UWOMJ 72(2) 2003

Table 2. Available testosterone preparations Generic Name

Trade Name

Dose

Testosterone cypionate

Depo-testo terone cypionate

200-400 mg every 3-4 weeks

Testosterone enanthate

Delatestryl

200-400 mg every 4 weeks

Oral

Testosterone undecanoate

Andriol

120-1 60 mg daily

Trans dermal

Testosterone patch

Androdem1 Testoderm

2.5-5 gms daily 10-15 mg daily

Testosterone gel

Androge l

2.5-5 mg daily

Injectable

must also be evaluated annually or biannually for signs of prostatism. Doses can be reduced, or the medication discontinued. A digital rectal examination should be carried out and hemoglobin and PSA levels checked several times in the first year of treatment and annually after that.

Declaring declining testosterone levels in the aging male a valid phenomenon requiring therapy remains a controversial topic. Increasing evidence points to a clinically significant deficiency that may prove symptomatic in some men, leading to decreased mood, libido, energy, bone density and muscle mass.

An increasing number of studies are showing improvements in these symptoms among men treated with exogenous testosterone.

Nevertheless, most of these studies have been relatively short in duration and have had small test subject populations. More prospective, randomized, placebo-controlled multi-centre studies will be needed to arrive at a definitive conclusion. Until then , physicians will be left to rely on their own discretion and level of expertise in dealing with such complaints from men.

REFERENCES

Figure LOne approach to the diagnosis of Testosterone Deficiency

6.

The St. Louis ADAM (Androgen Deficiency in the Aging Male) questionnaire asks for the following symptoms:

1.

2.

3.

4.

5.

7.

8.

1. Decrease in sex drive.

2. Lack of energy.

3. Decrease in strength and/or endurance.

4. Lost height.

5. Decreased "enjoyment of life."

6. Sad and/or grumpy.

7. Erections less strong.

8. Deterioration in sports ability.

9. Falling asleep after dinner.

9.

10.

11 .

12.

1O.Decreased work performance.

Men experiencing problems 1, 7, or a combination of any four or more might be candidates for replacement therapy.

13.

Harman SM, Tsitouras PD. Reproductive hormones in aging men: 1.

Measurement ofsex steroids. basal luteinizing hormone and Leydig cell response to human chorionic gonadotropin. J C/in Endocrinol Metab 1980: 51 :35.

Mulligan T, Kuno H. Clore J, et a/. Pulsatile infusions of recombinant human LH in leuprolide-down-regulated older vs. young men unmask an impoverish ed Leydig cell secretory response in aging to mid-physiological LH stimuli. Proceedings of the 82nd Annual Meeting of Th e Endocrine Society, Toronto, Canada. 2000.

Ve/dhuis JD. Zwart A, Mulligan T, et al. Muting of androgen negative f eedback unveils impoverished gonadotropin-releasing horm one/luteinizing hormone secretory reactivity in healthy older men.

J Clin Endocrinol Metab 2001; 86:529.

Harman SM, Tsitouras PD, Costa PT, et al. Reproductive hormon es in aging men: II. Basal pituitary gonadotropins and gonadotropin responses to luteinizing hormone-releasing hormone. J C/in Endocrino/ Metab 1982; 54:547.

Mulligan T, Iranmanesh A. Ker:ner R. et a/. Two-week pulsatile gonadotropin releasing hormone infusion unmasks dual (hypotha lamic and Leydig cell) defects in the healthy aging male gonadotropic axis.

EurJ Endocrino/1999; 141 :257.

Snyder PJ. Reitano JF. Utiger RD. Serum LH and FSH responses to synth etic gonado tropin releasing hormone in normal men. J Clin Endocrinol Metab 1975; 41 :938.

Veldlwis JD. Recent insights into neuroendocrine mechanisms of aging of the human male hypothalamo-pituitary-gonadal axis. J Andro/ 1999; 20: 1.

Bremner WJ, Prinz PN. A loss of circadian rhy thmicity in blood testosterone levels with aging in normal adult males. J Clin Endocrinol Metab 1983; 56:1278.

Harman SM. Metter EJ. Tobin JD. eta/. Longitudinal effects of aging on serum total and free testosterone levels in healthy men: Baltimore Longitudinal Study ofAging. J C/in Endocrinol Metab 2001 ; 86:724.

Morley JE, Perry HM. Kaiser FE. eta/. Longitudinal changes in testosterone. luteinizing hormone. and follicle-stimulating hormone in healthy older men. Metabolism 1997; 46:410.

Zmuda JM, Cauley JA. Kriska A. eta/. Longitudinal relation between endogenous testosteron e and cardiovascular disease risk factors in middle-aged men : a 13-year fo llow-up of former Multiple Risk Factor Intervention Trial participants. Am J Epidemiol 1997; 146:609.

Holmes SJ, Economou G, Whitehouse RW. et a/. Reduced bone mineral density in patients with adult onset growth hormone deficiency. J Clin Endocrinol Metab 1994; 78: 669.

Block GJ, de Boer H. Go01路en UG, va n der Veen EA . Growth hormone substitution in adult growth-hormon e deficient men augments androgen effect on the skin. Clin Endocrino/19 97: 47:29.

UWOMJ 72(2) 2003 71

i4. Baum HB, Biller BMK. Finkelstein JS. el a/. Effects of physiologic growth hormone therapy on bone density and body composition in patients with adult-onset growth hormone deficiency. A randomized placebo controlled trial. Ann in/ Med i 996; i25:883. i 5. Bawn HBA . Katznelso L. Sherman JC. et a/. Effects of physiological growth hormone (GH) therapy in cognition and quality oflife in patients with adult-onset GH deficiency. J Clin Endocrinol Metab i998: 83: 3i 84. i 6. Rosenfalck AM. Maghsoudi S. Fisker S. et a/. The effects of30 months replacement th erapy with recombinant human GH on insulin and c-peptide kinetics and body composition in GH-deficient adults. J Clin Endocrinol Metab 2000: 85:4i 73. i 7. Fern holm R. Bramnert M. Hagg E. Growth hormone replacement therapy improves body composition and increases bone metabolism in elderly patients with pituitary disease. J Clin Endocrinol Metab 2000: 85:4i04. i 8. Janssen YJH. Doornbos J. Roelfsma F. Changes in muscle volume. strength. and bioenergetics during recombinant GH therapy in adults with GH deficiency. J Clin Endocrinol Metab 2000: 84:279. i 9. Vermeulen A. Dehydroepiandrosterone sulfate and aging Ann NY A cad Sci i995; 774: i 2i .

20. Bross R, Ja vanbakht M, Bhasin S. Anabolic interventions for agingassociated sarcopenia. J Clin Endocrinol Metab i999; 84:3420.

2 i . Novak LP. Aging. total body potassium .fat fi'ee-mass, and cell mass in males and f emales between ages i 8-85 years. J Gerontal i972 ; 27:438.

22. Center JR . Nguyen Tv. Sambrook PN. e/ a/. Hormonal and biochemical parameters in th e determination of osteoporosis in elderly men. J Clin Endocrinol Metab i999; 84:3626.

23. Foresta C, Ruzza G, Mioni R, eta /. Osteoporosis and decline ofgonadal fun ction in the elderly male. Horm Res i 984; i 9: i 8.

24. Greendale GA. Edelstein S, Barrell-Connor E. Endogenous sex steroids and bone mineral density in older women and men: Th e Rancho Bernardo Study. J Bone Miner Res i99 7; i 2:i 833.

25. A min S, Yuqing Z, Sawin CT. et al. Association of hypogonadism and estradiol levels with bone mineral density in elderly men from the Framingham study. Ann intern Med 2000; i33 :951 .

26. Drinka PJ. Olson J. Bauwens S. et a/. Lack of association between fi'ee testosterone and bone den ity separate from age in elderly males. Calcif Tissue int i993: 52:67.

27. Rapado A, Hawlc'ins F, Sobrinho L. e/ a/. Bone mineral density and androgen levels in elderly males. Calcif Tissue lnt 1999: 65: 4i 7.

28. S/emenda CW Longcope C. Zhou L. el a/. Sex steroids and bone mass in older men: positive associations with serum estrogens and negative associations with androgens. J Clin in vest i99 7: iOO: 1755.

29. Sarrett-Connor E. Voo Muhlen DC. Kritz-Silverstein D. Bioavai/able testosterone and depressed mood in older men: The Rancho Bernardo Study. J Clin Endocrino/ Metab i999; 84: 573.

30. Bakshi V, Elliott M. Gentili A. eta/. Testosterone improves rehabilitation outcomes in ill older men. JAm Geriatr Soc 2000: 48:550.

Ji . Morley JE. Perry HM. Kaiser FE, eta/. Effects of testosterone replacement therapy in old hypogonada/ males: a preliminQ/y study. JAm Geriatr Soc i993: 4i :i49.

32. Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab i 992; 75 :i092.

33. Urban RJ. Bodenburg YJ-1, Gilkison. eta/. Testosterone administration to elderly men increases skeletal mu cle strength and protein synthesis. Am J Physio/1995; 269:E820.

34. Tenover JL. Testosterone for all? Proceedings of th e 80th Meeting of the Endocrine Society, New Orleans, i998.

35. Snyder PJ. Peachey H. Hann oush P. et a/. Effect of testosteron e treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab i999; 84:2647.

36. Snyder PJ. Peachey H. Hann ou h P. et a/. Effect of testosteron e treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab i999; 84:i 966.

37. Bhasin S, Bagatell CJ, Bremner WJ, Plymale SR, Tenover JL, Korenman SG, et a/. issues in testosterone replacement in older men. J Clin

72

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Endocrinol Metab i998; 83: 3435.

38. Tenover JL. Testosterone and the aging male. J Andro/1997: i8:i03.

39. Sih R, Morley JE, Kaiser FE, et a/. Testosterone replacement in older hypogonadal men: a i 2-month randomized control study. J Clin Endocrinol Metab i997; 82: i661 .

40. Franchi F, Luisi M. Kicovic PM. Long term study of oral testosterone undecanoate in hypogonadal men. lnt J Androl i978; i :270.

4i . Wang C. Alexander G, Berman N. et al. Testosterone replacement therapy improves mood in hypogonada/ men-a clinical research center study. J Clin Endocrino/ Metab 1995; 8i: 3578.

42. Barrell-Connor E. Von Muh/en DC. Kritz-Silverstein D. Bioavailable testosterone and depressed mood in older men : the Rancho Bernardo study. J Clin Endocrinol Metab 1999; 84:573.

43. Tenover JL. Effects of testosterone supplementation in the aging male. J Clin Endocrino/ Metab 1992; 75: i092.

44. Friedl KE. Hannan CJ. Jones RE, Ply male SR. High-density lipoprotein cholesterol is not decreased if an aromatizable androgen is administered. Metabolism i990: 39:69.

45. Morley JE, Pen y HM, Kaiser FE. eta/. Effects of testosterone replacement therapy in old hypogonada/ males: a pre/iminGiy study. JAm GeriatrSoc i993: 4i:l49.

46. Bardin CW Swerd/off RS, San ten RJ. Androgens: risks and benefits. J Clin Endocrinol Metab i99i ; 73 :4.

47. Katzne/son L. Finkelstein JS, Schoenfeld DA , et a/. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J C/in Endocrinol Metab i996: 81 : 4358.

48. Sorva R, Kuusi T. Tas/..:inen MR, et a/. Testosterone substitution increases the activity of lipoprotein lipase and hepatic lipase in hypogonadal males. Atherosclerosis 1988: 69:191 .

49. Haffn er SM. My kkanen L, Valdez RA. Katz MS. Relationship of sex hormones to lipids and lipoproteins in non-diabetic men. J Clin Endocrinol Metab i993: 77: i6i0.

50. Phillips GB. Pinkemell BH. Jing T-Y. The association of hypotestosteronemia with coronary artery disease in men. Arterioscler Thromb , 1994: i4:70i .

51. Barrell-Connor E. Lower endogenous androgen levels and dyslipidemia in men with non-insulin-dependent diabetes mellitus. Ann Intern Med 1992; i 17:807.

52. Marin P. Holmang S. Jonsson L. eta/. Th e effects of testosterone treatment on body composition and metabolism in middle-aged obese men. int J Obesity i 992: 16:99i .

53. Glueck CJ. Glueck HI, Stroop D. eta/. Endogenous testosterone. fibrinolysis. and corona1y heart disease in hyperlipidemic men. J Lab C/in Med 1993: 122(4):4i 2.

54. Nomura A. Heilbrun LK. Stemmermann GN, Judd HL. Prediagnostic serum hormone and the risk of prostate cance1: Cancer Res i988; 48:35i5.

55. Hajjar RR. Kaiser FE. Morley JE. Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J Clin Endocrinol Metab i997: 82: 3793.

56. Matsumoto AM. Sandblom RE. Schoene RB. eta/. Testosterone replacement in hypogonadal men: effects on obstructive sleep apnea. respiratory drives. and sleep. C/in Endocrino/ i985; 22:713.

The Atkins' Regime: A Critical Look at the 'Ketogenic' Approach to Weight Loss

Ms. Preet Virdee, BSc (Hans) McGill Un iversity, Faculty of Medicine, Department of Physiology M1~ Vikas Agarwal, BSc (Hans) University of Western Ontario, Faculty of Medicine, Class of 2004 Mr. Rishi Narine, BSc (Hans) University of Western Ontario, Faculty of Medicine, Class of 2004

Canadians have become infatuated with dieting and weight loss. The landmark 1994-95 National Population Health Survey (NPHS), conducted by Statistics Canada, indicated that 68% of 1 Canadians over the age of 12 are concerned with the amount of fat in their diet. I Furthermore, of those concerned, 89% of women ' and 83% of men reported taking actions to lower their dietary fat intake.! This survey also indicated that, besides avoiding fat, Canadians have also been diligent in attempting to increase dietary starch and fiber in accordance with the directives outlined in Canada 's Guidelines for Healthy Eating. I Interestingly, despite this wide-spread concern with minimiz1 ing fat intake, Canada is currently facing an unprecedented obesity epidemic. If defined as a body mass index (BMI)* greater ;. than 27, obesity currently affects 35% of Canadian men and 27% ' of Canadian women.2 Even when the definition of obesity is e restricted to a BMI over 30, the prevalence rate among Canadian 1 adults is 14.8%, a more than two-fold increase from 1985.3 As a result, the direct medical cost associated with Canadian adult obe.. sity in 1997 was a shocking 1.8 billion dollars, or 2.4% of total I路 direct healthcare costs.J-5 The paradoxical increase in obesity and obesity-related morbidity, in the face of increased compliance with the recommended low-fat diet, has caused many frustrated individuals to re-examine the current nutritional guidelines.

Health Canada has evolved its approach to diet and nutrition from a philosophy which generally encourages the consumption of a variety of food types. 6 As outlined in Table I, the Canadian * BMI is calculated by dividing body mass (in kilograms) by the square of the patient's height (in meters). The normal range is from 18.5-24.9. Generally, patients between 25 and 29.5 are considered to be overweight, while patients scoring over 30 are classified as obese.

Guideline for Healthy Eating further emphasizes foods like cereals, breads and other grain products .6 Basic to this paradigm is the classic idea of the food ' pyramid '. At the apex of the pyramid are high-fat, high-calorie foods , for which reduced consumption is recommended. High-carbohydrate foods are positioned towards the base, comprising the bulk of the recommended food intake.

Essentially, thi s approach views all calories as being equivalent, regardless of their source. Therefore, si nce fats are the nutritional macromolecules highest in calories, reducing the fat concentration in the diet should logically reduce both caloric intake and body fat storage.? This outlook has gathered support from numerous studies indicating that the safest and most successful treatment for long-term weight loss includes "a controlled diet with an intake of 500 - 1000 kcal (2 100 - 4200 kJ) per day, with reduced dietary fat intake of less than 30% of total energy intake."8 In light of such studies supporting a diet based in moderate calorie consumption, it is surprisi ng to find that this approach has shown such disappointing results among the Canadian population. The increase in corpulence throughout Canada, almost seeming to occur in tandem with the development and propaga-

Table 1: The 5 Healthy Eating Recommendations from Health Canada 1997 Enjoy a variety of foods Emphasize cereals, breads, other grain products, vegetables and fruits Choose lower-fat dairy products, leaner meats and foods prepared with little or no fat Achieve and maintain a healthy body weight by enjoying regular physical activity and healthy eating.

Limit salt, alcohol and caffeine

UWOMJ 72(2) 2003 73

tion of the recommended low-fat doctrine, has caused critics to question the validity of the low-calori e approach to d ieting.I0-13 The rising frustration with this unsatisfactory outcome has also contributed to the willingness of Canadians to experiment w ith diets radica lly different than the current guidelines.

The Atkins program is the prototype of these diets. First described by New York cardiologist Dr. Robert C. Atki ns in his controversial 1972 book "Diet Revo lution", the Atkins ap proach is the ultimate manifestation of a ' ketogenic ' diet. This program abandons conventiona l medical recommendations and instead promote the controversial message of a low-carbohydrate, highfat diet.II.I2 Although di smi ssed by authorities as a ' fad diet', the popularity of thi s program has persisted for nearly 30 years . In fact, the significance of thi controversy was highlighted by the 1992 release of a modified program, entit led Dr. Atkins' ew Diet Revo lution , as well as numerous recent citations in the popular press, including the September 2nd, 2002 cover ofTime magazine.I ODubbed the "alternative hypothesis", this philosophy has galvanized many nutritional experts into two intransigent camps, staunchly divided on the fat-versus-carbohydrate debate.IO The physiology underlying the Atkins program begins with the severe restriction of di etary carbohydrates (as low as 20 grams per day), while encouraging the patient to eat protein and fat ad libitum .ll ,l2 The rationale used to expl ain this paradoxical program is the metabolic process of ketogenesis. Ketoacid (ketone) generation is the body 's response to prolonged carbohydrate deficit. As a result of glycogen depletion, adipose becomes the body 's primary source of energy, producing ketones from the incomplete oxidation of fatty aci ds. I4 Described as a protei n-sparing modified fast, the ketone bodies (acetoacetate, beta-hydroxybutyrate and acetone) are eventually filtered at the kidney and excreted via the urine.11 .12 There are four phases to the Atkin s approach : (1 ) Induction, (2) Ongoing Weight Loss Di et, (3) Pre-maintenance and (4) Maintenance. During the Induction stage, di eters severely limit their carbohydrate intake to 20 grams per day by avo iding all fruit, bread, grains, starchy vegetables and most dairy products.

Thi s process largely dep letes the body's g lycogen stores and stimulates the initial production of ketoacids. Thi s initial stage lasts for 14 days and is marked by drastic weight lo s. While the subsequent stages in the Atkin ' program all ow a modest increase in carbohydrate intake, th e total amount is maintained below 90 grams per day (far less th an the 55% or 138 grams per I 000 Kca l in Hea lth anada 's RNI va lues).6 Patients are enco uraged to gauge compliance to the diet with urine dipsticks to indicate ketone production. Table 2 demon strates the food that can be eaten on the Atkin s di et for induction, weight loss and maintenance.

Atkins claims that thi s program safely and efficiently optimizes the release of energy stored in body fat, resulting in fast, effective weight loss. Hi s organization cites a recent New York study in whi ch 40 obese patients were di vided into a low-fat, lowcalorie ( 1 I 00 callday) group and a low-carbohydrate, hi gher-calorie group ( 1830 callday) . Over a 6 month period, the low-carbohydrate group lost nearly twice as much weight, as the low-fat, lowcal group . IS Additionally, a study from Pediatrics describes 6 morbidly obese adolescents who lost an average of 15.4 kg(+/- 1.4 kg) 74

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over 8 weeks on a ketogenic program.I6 Another investigation divided 104 chi ldren into a low-carbohydrate group and a low-fat group and found that, over an 8 week period, the low-carbohydrate group experienced significantly more weight Joss than the low-fat group. ' 7 Critic of these ketogenic programs have several major concerns with low-carbohydrate diets. The most serious condemnation is that these diets are unsafe . They high li ght the fact that the weight loss experienced early in the Atkins' program is largely a result of massive water loss econdary to glycogenolysis. IS Thi s acute diuresis can result in serious complications such as orthostatic hypotension and electro lyte depletion, with altered sympathetic nervous system activity and symptoms of fluid and electrolyte imbalances.I4, 18 Furthermore, these diets also involve high-protein intake, which increases the potential for kidney damage, espec ially in individual s with impaired renal function , parti cularly those with diabetes or hypertension . 14 .25 The American Medica l Association Council on Food and Nutrition has issued a warni ng that " the unlimited intake of saturated fats under Atkins ' food plan can increase the dieter's risk of heart di sease."20-22 They cited a study of24 obese individuals following the Atkins ' diet for 3 months, who demonstrated a significant increase in cardiovascular disease risk factors , such as increased LDL levels.I6 Finally, critics point out that all studies supporting Atkins ' work have focused on short-term weight-loss and have not offered any information on its long term success. A 2002 study at the University of Oklahoma comparing subjects following either the Atkins' or conventional diets over 12 weeks found equivocal we ight loss, but significantly increased attrition rates in the Atkins' subj ects.I 9 It was also pointed out that whi le Dr. Atkins has been treating hi s patient with this prog ram for over thirty years, his organization has not published a single longitudinal study demonstrati ng the long-term efficacy of hi s program. IS It becomes apparent that while the current management approach of obesity in Canada has been inadequate, the dangers of ketogenic programs must preclude thei r endorsement by responsible authoriti es. Additionally, the paucity of long-term ev idence supportin g the efficacy of the low-carbohydrate ap proach to dieting questions the validity of programs based in thi s paradi gm. However, if the low-fat approach has not worked and the low-carbohydrate ap proach is not hea lthy, what recourse is there for people interested in achieving or maintaining a hea lthy body weight? What novel soluti on will be uncovered to create a Canada devoi d of fatne s?

Perhaps, instead of seeking a radical shift away from current guidelines, Ca nadian s could focu on amending the existing paradigm. For in stance, the deve lopment of the Glycemic Index (GI) , has called into question some of the recommendations in the current guidelines. The GI i a measure of the postprandial blood g lucose and overall postprandi al blood g lucose response, during the first two hour after consumption of specific foods .27 GI meaurement indi cate that some of the carbohydrates currently endorsed by the guidelines (i.e. pasta, potatoes, etc.) might be prohibitive to weight loss.2 7 It is felt that the body 's hormonal re ponse to these hi gh-GI foods may optimize fatty acid uptake by adipocytes, hence increasing body fat. 28 However, there are a number of low-GI, carbohydrate-rich foods that do not have this

Table 2: A Typical Daily Menu for Thee Phases of the Atkins' Diet:

Breakfast

Lunch

Induction

On Going Weight Loss

Maintenaince

Sugarless Sausage Bacon or Ham Eggs Tea & Coffee

Inducti on Items

Inducti on and Ongo ing Weight Loss Items

Bacon Cheeseburger without bun Salad Seltzer Water

Plus Omelette Crisp bread Tomato Juice

Plus

Induction Items

Induction and Ongoing Weight Loss Items

Fruit

Plus Plus Ham & Cheese Sandwich, Mayonnaise Herbal Tea

Dinner

Shrimp Cocktail Mayonnaise Steak Roast Pork Chops Fish or Poultry Salad Whipped Cream

Induction Items

Roast Chicken Salad Vegetables Dressings Induction and Ongoing Weight Loss Items

Plus Plus Seafood Salad Salmon Vegetables from a specified List Strawberries

proposed ' insulinogenic ' effect and should therefore be emphasized in responsible nutritional guidelines.28 A separate, but related concept is the Glycemic Load (GL).

Whereas the GI compares equal quantities of different carbohydrates, the GL is an estimate of the glycemic effect of a specific portion of various foods .27 This measure incorporates the different serving sizes of various carbohydrates, as they are realistically prepared and consumed, in order to compare their glycemic effect. A diet rich in high-GL foods (controlling for total energy) has been associated with increased risk of diabetes and coronary heart disease.28 Hence, both the qualitative and quantitative aspect of different carbohydrates may influence the effect of diet on the body. Both these features of nutritional physiology are being considered as potential tools in unraveling the proliferation of obesity within the recommended low-fat model.

Despite the numerous pitfalls of the Atkins approach, the dramatic public interest in this program can serve as a measure of the dissatisfaction with the current nutritional guidelines. The fact that ketogenic programs are unsafe and current recommendations are ineffective illustrates that further research, with subsequent amendment of the existing nutritional guidelines, is clearly required. Although still controversial, concepts such as the GI and GL may someday allow us to conclusively offer Canadians dietary recommendations conducive to a healthy body weight.

Soup Vegetables Potato Fruit Wine

These tool s may eventually provide further insights into carbohydrate metabolism and the paradoxical co-occurrence of widespread low-fat dieting with an increased preva lence of obesity.

Ideally, these concepts would buttress the current low-calorie paradigm to create effective nutritional guidelines without the dangers inherent to programs such as Atkins '.

ACKNOWLEDGEMENT: We would like to thank our Faculty Supervisor, Dr. Ruth McManus, MD, FRCP(C) of the University of Western Ontario, Faculty of Medic ine, Department of Endocrinology for her advice and contributions.

REFERENCES: 1.

2.

3.

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Canadians and Healthy Eating: how are we doing? Health Ca nada: 1997 Ca talogue Number: H49- 107/1997E Douketis, JD, Feighmer. JW, Attia, J, Feldman, W Periodic Health Examination, 1999 update: 1. Detection, prevention and treatment of obesity. CMAJ (Ca nadian Medical Association Journal) . 1999; 160 (4):5 13-525 Katzmar::yk PT. Th e Canadian obesity epidemic, 1985-1 998. CMAJ (Ca nadian Medica l Association Journal) . 2002; 166 (8): 1039-40.

Kat:::marzyk. PT, Gledhill. N. Shephard, RJ. Th e economic burden of physical inactivity in Canada. CMAJ (Ca nadian Medical Association Journal). 2000: 163 (Jl) 1435-1440.

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5.

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7.

8.

9.

10.

11 .

12.

I3 .

14.

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16.

17.

18.

19.

20.

2I .

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Tremblay MS. Kat::mar:::yk PT. Willms JD. Temporal trends in overweight and obesity in Canada, 1981-I996. International Journal of Obesity & Related Metabolic Disorders. 2002; 26 (4): 538-43.

Canada s Food Guide to Hea lthy Eating. Health Canada; I992 Cata logue Nu mber: H39-252/ 1992E. Birmingham CL. Jones PJ. Clinical nutrition : 5. Ho w much should Canadians eat? CMAJ (Canadian Medical Association Journal) . 2002; 166 (6): 767-70.

Lau DC. Call for action : preventing and managing the expansive and expensive obesity epidemic. CMAJ (Canadian Medical Association Journal). 1999; 160 (4):503 -6.

Tremblay MS. Willms JD. Secular trends in the body mass index of Canadian children. CMAJ (Ca nadian Medical Association Journal) .

2000: I63 (JJ): I429-33.

Taubles. G. What if It sAil Been a Big Fat Lie? Th e New York Tim es 200 1 July 7 Atkins RC: D1: At/..'ins 路 New Diet Revolution. New York (NY): Avon Books. I992 Atkins RC, Herwood RW Dr. At/..'ins 路Diet Revolution . New York (NY): Bantam Books. 1972 Sharman MJ. Kraemer WJ. Love DM et al. A ketogenic diet favorably affects serum biomarkers for cardiovascular disease in normal-weight men. Journal of Nutrition . 2002; I32 (7) : 1879-85.

Gumbiner, B. Obesity. Phi/edelphia (Pennsylvania) : American College of Physicians, 2001 Sondike 2002 Willi SM. Oexmann MJ. Wright NM eta/. Th e effects of a high-protein, low-fat, ketogenic diet on adolescents with morbid obesity: body composition. blood chemistries, and sleep abnormalities. Pediatrics. I998; 1OJ (1 Pt 1): 61- 7.

Pena. L, Pena, M, Gonzalez J. Claro, A. A comparative study of two diets in the treatement of primary exogenous obesity in children. Acta Paediatr Acad Sci Hung; 20(1) :99-103 Riley RE. Popular weight loss diets. Health and exercise implications.

Clinics in Sports Medicine. 1999: I 8 (3) :69 I -70 I, ix.

Landers P. Wolfe MM, Glore Set a/. Effect of weig ht loss plans on body composition and diet duration. Journal - Oklahoma Slate Medical Association. 2002: 95 (5) :329-3I .

While PL. A crilique of low-carbohydrale kelogenic weight reduction regim ens: A review of D1: Atkin :S diet revolution . JAMA 1973 (224) :1415-I4I9 Miller BV eta/. Effe cts of /ow carbohydrale, hig h protein diet on renal fun ction . Obesity Research 8 (supplement I) :82S, 2000 Lyznicki JM, Young DC, Riggs JA eta/. Obesity: assessment and management in primary !!are. American Family Physician. 2001: 63 (11):2 I 85-96.

Poston WS. 2nd, Foreyt JP. Successful management of the obese patienl.

American Family Physician. 2000: 6 I (! 2):36I 5-22.

Berke EM, Morden NE. Medical managemenl of obesity. American Family Physician. 2000; 62 (2):4 I9-26.

St. Jeor ST. Howard BV. Prewi/1 TE et a/. DieiCIIy Prolein and Weight Reduction : A Statement for Healthcare Professionals From the Nutrition Committee of th e Council on Nulrition. Phys ical Activity. and Metabolism of th e American Heart Association. Circulation 2001; I 04 (I5) :1869-74.

Eating Disorders and Obesity: A Comprehensive Handbook. 2nd Edilion ed. C Fariburn; K Brownell. editors. New York (NY) : Th e Guildord Press; 2002. 633 p . (C Fariburn ; K Brownell editors).

Foster-Powell. K, Holt. SH. Brand-Mille1; JC. i nternational Table of glycemic index and glycemic load values: 2002. American Journal of Clinical Nutrition 2002: 76(5):5-56 Ludwig, D. Dietwy Glycemic Index and Obesity. American Society for Nu tritional Services 2000; Supplement 280-3

UWOMJ 72(2) 2003

Renal Hormones and Hypertension

Ali Namazie, Meds 2005

Arterial hypertension has been implicated in causing a vast number of cardiovascular complications, including strokes, heart attacks, heart failures , heart rhythm irregularities, and kidney failure. Although the major cause of hypertension is idiopathic, endocrine disorders can play a significant role in the development of hypertension. This article will present a brief examination of the renal origins of hypertension.

INTRODUCTION Hypertension is a major public health issue in industrialized nations, affecting approximately 20% of adults' ¡ The close associations of hypertension with atherosclerosis, coronary and cerebrovascular disease, diabetes, and end-stage renal disease make it a major contributor to the most common causes of morbidity and mortality in adult populations. Hypertension can be caused by a number of factors , including renal and endocrine effects, vascular consequences, medications, and idiopathic etiologies. This artic le will focus solely on the renal origin of hypertension.

THE RENIN-ANGIOTENSIN SYSTEM Pioneer studies by Page and Helmer and Braun-Menendez in the 1930s demonstrated that renin enzymatically c leaves angiotensinogen to form angiotensin I, which is subsequently cleaved by angiotensin-converting enzyme (ACE) to form angiotensin II, a peptide with powerful vasoconstrictor effects 2â&#x20AC;˘3 .

During this same period, Goldblatt noted that reducing the flow of blood to the kidney in experimental animals was followed by an increase in blood pressure4. It was later found that these two observations were related; reducing blood flow to the kidney stimulates the renin-angiotensin system, resulting in an increase in blood pressure.

Renin Renin is produced and secreted by the juxtaglo~erular cells of the afferent arteriole as it enters the glomerulus. It IS controlled by three major effectors:

(1) baroreceptors in the wall of the afferent arteriole that are stimulated by decreases in renal arteriolar pressure, perhaps mediated by local production of prostaglandins; (2) cardi ac and systemic arterial receptors that activate the sympathetic nervous system, resulting in increased circulating catecholamines and increased direct neural stimulation of juxtaglomerular cells via 13,-adrenergic receptors; (3) cells of the macula densa that appear to be stimulated by a reduction in Na+ or cr ion concentrations in the tubular fluid delivered to this site.

Angiotensinogen Angiotensinogen is secreted by the liver, and its production is increased by glucocorticoids and by estrogen. It is usually present in the plasma at a concentration of 1 mmoVL. Although plasma renin concentration primarily determines angiotensin II concentration, since the concentration of angiotensinogen is below the Vmax for the reaction, an increase in angiotensinogen concentration can produce an increase in angiotensin I levels even when plasma renin concentrations are unchanged.

Increased levels of angiotensinogen have been noted in patients with essentia l (idi opathic) hypertension and there appears to be a linkage between a variant allele for the angiotensinogen gene and the presence of essential hypertension in selected populationss.

Angiotensin-Converting Enzyme ACE is a glycoprotein that cleaves dipeptides from a number of substrates. In addition to angiotensin I, these include

UWOMJ 72(2) 2003 77

bradykinin , enkephalins, and substance P. Inhibitors of ACE are wide ly used to prevent the formation of angiotensin II in the circu lation and thus block its biologic effects. However, a serine protease known as chymase has been shown to convert angiotensi n I to angiotensin II. This enzyme has been identified in various tissues, most notably the cardiac ventric les, and therefore, there appears to be an ACE-independent pathway for the production of angiotensin 116. The concentration of ACE is greatest in the lung, but is also loca lized in the luminal membrane of vascular endothelial cells, the glomerulus, the brain, and other organs.

Angiotensin ll Angiotensin II causes vasoconstricti on of peripheral arterioles, thereby increasing total peripheral resistance. It may also increase the rate and strength of cardiac contraction.

Angiotensin II also acts directly on the adrenal cortex to stimulate aldosterone secretion , whi ch promotes retention of sodium and excretion of potassium. For example, when Na + levels are low, extracellular fluid vo lume is decreased, stimulating the renin-angiotensi n system to: {I ) constrict blood vessels to help maintain blood pressure, and (2) stimulate aldosterone secretion, and thus Na + retention to allow vo lume to be conserved.

Blockage of angi otensin II is usefu l therapeutica lly. For example, in low-output congestive heart failure , plasma leve ls of angiotensin II are hi gh, thereby constri cting arteri oles, and promoting salt and water retenti on, thereby raising peripheral vascular resistance and increas ing cardiac afterload. Treatment with ACE inhibitors results in peripheral vasodilati on, thereby improving ti ssue perfusion and cardiac performance as well as aiding rena l elimination of sa lt and water.

RENAL CAUSES OF HYPERTENSION Essential Hypertension Blood pressure is a product of cardi ac output and peripheral vascul ar resi stance. Essential hypertension is caused by an elevation in peri phera l vascul ar resistance, although the specific factors that underli e the pathogenes is of essenti al hypertension remain to be determined . As menti oned earli er, Na + loading increa es renal bl ood fl ow and reduces renal reabsorpti on ofNa +, thereby faci litating the excretion of the Na + load. It has been observed that about one-half of patients with essenti al hypertension with normal or hi gh pl asma renin level may not modulate their adrenal and vascular re ponsiveness to a Na ' load7. These " non-modulators" do not increase their renal blood fl ow in response to a hi gh-sa lt diet nor do they increa e aldo terone secretion in response to a low sa lt diet, and are therefore unable to excrete a Na load, leading to elevation in blood pressure. It is suggested that there is an abnorma li ty related either to loca l angiotensin II production or the angiotensin receptor such that target tissue responsiveness is not modified when Na + intake is altered. Adrenal and vascul ar responsiveness can be restored in these patients by reducing angiotensin II using ACE inhibitors.

Renovascular Hypertension Renovascul ar hypertension is defined as the presence of lesions in the renal artery causing hypertension . It is the most common cause of renin-dependent hypertension, (present in 1-4% of patients with hypertension)8, and is the most common correctable 78

UWOMJ 72(2) 2003

cause of secondary hypertension. Renovascular hypertension is usually due either to atherosclerosis or to fibromuscular hyperplasia of the renal arteries, which results in decreased perfusion of the renal segment di stal to the obstructed vessel. The decreased blood flow of the di stal artery stimulates renin release and angiotensi n II production, which acts to elevate blood pressure.

The resulting increase in blood pressure and angiotensin II levels suppress renin release from the contralateral kidney, and therefore, total plasma renin may be only slightly elevated or even normal.

Anatomic correction, especially transluminal angioplasty, is the preferred therapy for renovascular hypertension when it is possibl e and the patient is considered able to tolerate the procedure.

Renin-Secreting Thmors Renin-secreting tumors are extremely rare, and are usually hemangiopericytomas containing elements of the juxtaglomerular cells. They can be located by CT scan and the presence confirmed by measurement of renin in the venous effluent.

Accelerated Hypertension Accelerated hypertension is characterized by marked elevations of diastolic blood pressure that can be abrupt in onset. It is associated with progressive arteriosc lerosis, and the plasma levels of renin and aldosterone may be extremely high . It is believed that the vasospastic events that occur and the excessive renal cortical nephrosclerosis lead to hyperreninemia, which accelerates the hypertensive processs. Antihypertensive therapy usually results in a reduction in the vasospasti c process and an amelioration of hyperreninemia with time.

Estrogen Therapy As mentioned earlier, ang iotensinogen production may be increased during treatment with replacement estrogen therapy or oral co ntraceptives . This causes a presumed increase in angiotensin II levels, which further causes a secondary increase in aldosterone levels. However, hypokalemia rarely occurs during estrogen admini strati on.

CONCLUSION The hormones presented above compri se the reninangiotensin system and provide rena l control of blood pressure.

Other hormones not di scussed, but which also play a role in the regulati on of blood pressure are insulin, natriuretic peptides, endothellum-den ved relax ing factor, endothelin, kinin, and the sympathetic nervous sy tern . It is only through a thorough understanding of all these systems and hormones that effective treatment .for hyperte ~ s ion can be developed. Since hypertension has been 1~1pllcated 111 the progression of strokes, heart attacks, kidney failure , hemorrhages of the retina of the eye, and generalized ather~sc l ero~ I S, effective control of thi s disease is critical to reducmg pati ent morbidity and mortality.

REFERENCES 1. Norwood, Victoria F : Hyp ertension.: Pediatrics in Review: 23(6). 2002 2. Broun-Menendez E, Fasciola JC, Leloir LF. Munoz JM: Th e substan ce caus111g renal hypertension. J Physiol 98: 283-298, 1940 3. ~age 1H, ~elmer OM: A crystallin e pressor substance (a ngiotonin) 1esult111g fiom th e react1 on between renin and renin-activator. J E . :xp Med 71: 29-42. 1940 .

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Goldblatt H, Lynch J. Hanzal RF. Summerville WW Studies on experimental hypertension: The production of persistent elevation of systolic blood pressure by means of renal ischemia. J Exp Med 59: 347-379, 1934 Pirola CJ :Molecular genetics of essential hypertension. Susceptibility and resistance genes. Medicina (B Aires) 60(1): 59-66. 2000 Miya:::aki M: Local angiotensin if-generating system in vascular tissue : th e roles ofchymase. Hypertens Res 24(3): 189-93, 2001 van Paassen P: Renin inhibition improves pressure natriuresis in essential hypertension. JAm Soc Nep hrolll (10): 1813-8. 2000 Don. Burl R. and Schambelan, Morris: Basic and Clinical Endocrinology 6th edition ; Endocrine Hypertension. Lange Medical Books: 2001: pp. 3 77-397

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UWOMJ 72(2) 2003 79

The Effect of Protein Intake upon Osteoporosis

Kristine L. Roth. BS . (Food and Nutrition) and YoussefAlmalh, Meds 2004

Osteoporosis is a devastating metabolic bone disease. 11 % of bone loss at age 70 has been attributed to menopause and 18% due to age. This has lead to research into other factors affecting bone loss. Protein intake has been proposed as being both promoting and protective against bone loss. Several studies have also raised controversy as to which type of protein source, vegetable or animal, is protective. This article sheds light on the pertinent studies regarding protein intake and its affect upon bone health.

Osteoporosis is a devastating metabolic bone disease that results from an imbalance between bone resorption and bone formation.' The World Health Organization recognizes osteoporosis as major public health problem with an estim ated lifetime risk of fracture >40% for women and 13% for men .2 It has been estimated that 70% of fractures in those over the age of 45 result from osteoporosis ) The china glass appearance of osteoporotic bone on radiographs can be seen in the areas most affected by osteoporosis, which are the hip, vertebrae, proximal humerus, pelvis and wrist.' Hip fracture , for examp le, resu lt in a 12-20% increase in mortality in the first year after a fracture .4.5,6 Of those that survive, on ly 25-50% maintain mobility and the abi lity to sustain their activities of daily living_7.8 Osteoporosis has been traditiona lly associated with elderly, postmenopausal , Caucasian fema les; yet, Nordin et al attributed on ly II % of bone loss at age 70 to menopause and 18% due to age.9 Findings such as Nordin 's lead researchers to explore the different factors that effect bone metabolism. The focus of thi s review is to shed light upon the field of research concerned with dietary protein intake and its relation to osteoporosis.

Although research evidence suggests that dietary protein has an important influence on bone health , the nature of its role has been controversial. The controversy stems from the endogenous acid hypothesis coined in 1968, whi ch states that diets rich in protein wi ll increase bone loss because calc ium wi ll leave the skeleton in order to buffer the elevated acidity caused by protein catabolism.' o Some studies have supported this hypothesis by demonstrating that the urinary calcium level will increase with increased protein intake.ll-14 Another study found that increased protein 80

UWOMJ 72(2) 2003

intake leads to both a net increase in calcium absorption and uri- .. nary calcium concentration. IS Spencer eta! found that commonly consumed proteins do not cause calciun1 loss, which was postulated to be due to the high phosphorus content of most protein- 1.: rich foods .16 These findings have lead some researchers to view ;;1 protein intake as a negative or positive ri sk factor for osteoporoSIS .

The recommended daily allowance (RDA) of protei n is 46- ful 50g and 58-63g for women and men, respectively.! ? The WHO li recommends that protein intake be no more than double the upper ÂŤI RDA ; yet, the average protein intake in the population is I 06 1ii, g/day.I7 Diets like the Dr. Atkins' low-carbohydrate high-protein ~ diet, re ult in acid-base disturbances because of the extremely lint high acidity resulting from protein catabolism.18 Reddy et a! to:! examined the effects of diets like Dr. Atkins' on acid-base balance ~~ and calci um metabolism. IS Subjects who were on the low-carbo- i\1 hydrate high-protein diet were found to have decreased urine pH, 1f1 increased net acid excretion, a twofold increase in net urinary sat- -~ uration of undissociated uric acid, and increased urinary calcium The increased urinary calcium levels were not counteracted by aro increase in fractional intestinal ca lcium absorption resulting in a l~ decrease in estimated calcium balance.1 8 Reddy et a! concluded ~: that eati ng a diet low in carbohydrates and high in protein for . lill weeks delivered a marked acid load to the kidney, increased th risk for stone formation, decreased estimated calcium balance ~ and hence may increase the risk of bone loss.

1, Feskanich et a! followed participants from the Nurses Healt, 1~ Study and foun~ a 21% increase in forearm fractures over a 1:; year follow-up m women aged 35-59 years who consumed mor 111<

than 95g of both total and animal protein per day compared to those who consumed less than 68 g per day.I9 The study also found that women who con umed five or more servings of red meat per week al o had signi ficantly increased risk of foreann fracture compared with women who ate red meat less than once per week. A number of studies have linked the type of protein intake, namely animal protein, to increased amounts of calcium in the urine. 18-2I It ha been stated that ani ma l protein provi des mainly acid precur ors that are metabolized to sulfuri c ac id, whereas vegetable protei n conta ins amino acids with substantial amounts of base precursors such as potass ium bicarbonate.22 The base precursors help to neutrali ze the acid and pare the ca lci um in bones. The vegetables al o upply ub trates, such as carbonate, for bone formation . It has al o been found that under experimental , in vitro, metaboli c acidosi directly stimul ates osteoclastic activity and inhibits o teoblastic act ivity.23 A prospective tudy conducted by Sellmeyer et a l found that animal prote in wa a sociated with a higher ri sk of hip fractures in women over the age of 50 .20 Sellmeyer et al also found that the ratio of animal to vegetable protein was key to fracture ri sk, that is a high ratio of vegetable to animal protein resulted in decreased fractu re ri sk. Sellmeyer propo es that an imbalance between ani mal and vegetable protein causes a chronic net dietary acid load and may have adverse consequences on bone. A prospective study of Norwegian men and women found the ri sk of hip fracture doubled in those in the highest quartile of dietary intake of nondairy animal protein in the presence of low (<623 mg/d) dietary calcium. The study also found that women wi th a hi gh animal to vegetable protein intake had a signi f icantly hi gher rate of bone loss at the femoral neck and a greater ri sk of hip fracture than did • those with a low ratio . Also, women in the highest quintile of ani1 mal to vegetable protein intake ratio (~ 3.17) had nearly a 4-fold 1 greater risk of hip fracture compared to women with low ratios.

Countering the findings of vegetabl e protein intake and high protein intake as whole are two prospective cohort studies that followed subjects for 4 years and asse sed bone mineral density (BMD).24,25 The first is the Rancho Bernardo Study that consid0 er ered 572 postmenopausal females and 388 men over the age of ~ 55, who were part of the Rancho Bernardo Heart and Chronic m Disease Study.24 The mean protein intake was 72 g/day for the :~ entire group. The study found a stati sti ca lly significant correla~ tion between animal protein intake and BMD in women, but not cc men. For every 15 g/day increase in animal protein consumption, o- BMD increased by 0.010 g/cm2 for the total body in women H, (p=0.04). A negative association was found between vegetable ll· protein intake and BMD in both genders. The authors concluded D that animal protein has a protective effect in elderly women. lf The second study suggesting that higher animal protein intake does not affect the skeleton adversely wa the Framingham 3 ~ Osteoporosis Study.25 It was found that low percent animal pro·, ·ein intake was found related to lower femoral and spine BMD, , ·mt not radial shaft. Furthermore, the authors of the Framingham 1 r ..;tudy concluded that protein intake is important in maintaining ·1one or minimizing bone loss as it was found that e lderly persons t ·ith relatively lower protein intake had increased bone loss.

In light of the studies regarding protein intake, it may be safe state that increased protein intake is negatively associated with

ske leta l hea lth under condition oflow ca lcium intake. 26 High protein intake substan ti ally above the RDA my be negative ly a sociated with bone health in the elderly beca use of their decreased glomerular filtration rate and the kidney's abili ty to excrete a dietary acid load.27-30 Further study i wa rranted into the ro le and severity of in vivo metaboli c acido is in relati on to bone turnover.

To decrease intake below th e RDA would re ult in a catabo li c state with subsequent bone loss.20 Yet, the aforementi oned tudie quote hi gh protein intake between the RDA and doubl e the RDA , so further investigati on is required to eluc idate the exact role of protein intake with the consideration of other factors that may affect protein metaboli m in study subj ects. Although the acid hypothesis makes intuiti ve sense, th e debate over vegetable and animal protein may be reso lved by detennining the rol e of other constituents that accompany the different types of protein, such as high phosphorus contents of animal protein that may protect against calcium loss.

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Gordon M and Huang J Osteoporosis. hronic Diseases in anada 1995;16:1-35.

Kanis J and the WHO Study Group. Asses ment offractu re risk and its applications to screening f or postm enopausal osteoporosis of a WHO report. Osteoporosis lnternationa/ 1994:4:368-381. lskrant AP. Smith RW Osteoporosis in women 45 years and over related to subsequent fra cture. Public Health Rep 1969:84:33-38.

Gallagher JC, Melton LJ. Riggs BL, et a/. Epidemiology offra ctures of th e proximal f emur in Rochester Minn esota. Clin Orth o Rei Res 1980;150:163- 71 Lewinnek GE. Kelsey J. White AA . eta/. Th e significance and comparative analysis of the epidemiology of hip fra ctures. Clin Orth o Rei Res 1980:152:35-43.

Jensen JS, Tondevold E. Mortality after hip frac tures. Acta Orthop Scand 1979;50:161-167.

Jensen JS, Tondevo/d E. Sorensen PH. Cost of trea rm enr of hip f ractures. A calculation of th e consumption of th e resources ofhospirals and rehabiliration institurions. Acta Orthop Scand 1980:51:289-296.

Cooper C. Review of UK data on rheumaric diseases-6. Osteoporosis.

Brit J Rheum 1991;30:135- 137.

Nordin BE, Need AG. Chaffer/on BE, et a/. Th e relarive contributions of age and years since menopau e to posrm enopau a/ bone loss. J C/in Endorinol Metab 1990; 70:83-88.

Wa chman A. Bern tein DS. Diet and osreoporosis. Lancer 1968:1:958959.

Margen S. Chu JY. Kaufmann NA. eta/. Srudies in calcium merabo/ism I. Th e calciuretic effect of diera1 y protein. Am J Clin Nutr 1974;2:584589.

Schuelfe SA , Zemel MB. Linkswiler HM. Studies on th e mechanism of protein-induced hypercalciuria in older men and II'Omen. J Nutr 1980;1 10:30-3 15.

Heany RP. Recker RR. Effects of nitrogen. phosphorus, and caffeine on calcium balance in women. J Lab Clin Med 1982;99:46-55.

Hegsted DM. Lint..·-wiler HM. Long-term effects of/eve/ ofprotein inrake on calcium merabolism in young adult women. J Nutr 1981;111:24425 1.

Lutz J. Linkwi/er HM. Calcium metabolism in postmenopausal and osteoporotic women consuming two levels of dietary p rorein. Am J Clin Nutr 1981;34:2178-2 186.

Spencer H, Kramer L. Osis D. Do protein and phosphorus cause calcium loss? J Nutr 1988; 11 8: 65 7-660.

Frances. S. Whitn ey, E. Nutrition -Concepts and Controversies. 2000: 8th Ed. :197, 205-206.

Reddy St, Wang CY. Sakhaee K eta/. Effect of low-carbohy dra re high-

UWOMJ 72(2) 2003 81

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protein diets on acid-base balance. stone-formation, and calcium metabolism. Am J Kidney Dis 2002:40:265-74.

Feskanich D. Wille// WC. Stampfer MJ eta/. Protein consumption and bone fract ures in women. Am J Epidemiol 1996; 143:472-9.

Sellmeyer DE. Stone KL. Sebastain A et a/. A high ratio of dietCIIy animal to vegetable protein in creases the rate of bone loss and the risk of fracture in postemenopausal women. Am J Clin Nutr 2001 :73:118-22.

Abelow BJ. Holford TR. 1nsogan KL. Cross-cultural association between dietary animal protein and hip frac ture: a hypothesis. CalcifTissue 1nt 1992:50. 14-18.

Frassello LA. Todd KM. Morris RC eta/. Estimation of net endogenous noncarbonic acid production in humans fro m diet potassium and protein content. Am J Clin Nutr 1998;68:576-83 Krieger NS. sessler NE. Bushinsky DA . Acidosis inhibits osteoblastic and stimulates osteocla tic acti vity in vitro. Am J Physiol 1992:262 .F442-8.

Prom is/ow JH. Goodman- Gruen D. Slymen DJ et a/. Protein consumption and bone tnin eral density in the elderly: The Rancho Bernardo Study. Am J Epidemiol 2002: 155:636-44.

Hanna MT. Tucker KL. Dawson-Hughes B eta/. Effect of dietary protein on bone loss in elderly men and women: the Framingham

Osteoporosis Study. J Bone Miner Res 2000: 15:2504-12.

Heaney RP. Protein intake and bone health : the influence of belief systems on the conduct of nutritional science. Am J Clin Nutr 2001; 73: 5-6.

Frassetto LA . Morris RC. Sebastian A. Effect of age on blood acid-bse composition in adult humans: role of age-related renal f unctional decline. Am J Physio/1996;271:1 114-22 Adler S. Lindeman RD. Yiengst MJ eta/. Efeect of acute acid loading on urinCIIy acid excretion by the aging human /.:"idney. J Lab Clin Med 1969:72:278-89.

Agarwal BN, Cabebe FG. Renal acidificaiton in elderly subjects.

Nephron 1980:26:291 -5.

Hilton JG. Goodbody M. Kruesi OR. Th e effect of prolonged administration of ammonium chloride on th e blood acid-base equilibrium of geriatric subjects. JAm Derian· Soc 1955;3:697-703.

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UWOMJ 72(2) 2003

The debate continues: A review of current practices in the treatment of hyperthyroidism

Nabil Sultan , Meds 2004

Hyperthyroidism is common, affecting 2-5% of all females at some point in their life. Controversy and debate over the treatment of hyperthyroidism has existed for more than 60 years. The current treatment options that exist for hyperthyroidism are antithyroid drugs, radioiodine and rarely, surgery. Each treatment option has advantages and disadvantages. Practices and beliefs differ widely within and between countries; and many different factors must be considered to choose the appropriate treatment for a specific patient.

BACKGROUND Hyperthyroidism is common, affecting 2-5% of all females at some point in their life, with a sex ratio of 5:1 (f:m) and most often between the ages 20 and 40 years! . Grave 's disease, an autoimmune disease that produces thyroid stimulating antibodies, is the most common cause. Hyperthyroidism causes an excess of circulating thyroid hormones both of which modulate energy utilization, heat production and facilitate growth. Clinical manifestations include weight loss, tachycardia, diarrhea, tremor, and heat intolerance. Diagnosis is usually done using a serum TSH, which is a very sensitive and specific test fro hyperthyroidism.

Serum T3 and T4 can be subsequently measured to confirm a diagnosis.

TREATMENT It is in the treatment of hyperthyroidism where practices often differ. Classically the treatment options that exist for hyperthyroidism are antithyroid drugs, radioiodine and rarely, surgery.

There is currently no fully satisfactory treatment. Each treatment option has advantages and disadvantages, advocates and opponents, and its own traditions in the therapy of hyperthyroid individuals. Practices and beliefs differ widely within and between countries; and treatment often depends on patient preference and local expertise. In surveys of thyroidologists in the US , radioiodine was the preferred treatment for most patients2,3, with Canada following the same trend. In contrast, anti-thyroid drugs are the treatment of choice in much of the rest of the world, including

Europe, Japan , and South America2. Europe also tends to use surgery more often than other areas. Treatment modalities can be considered to be either definitive or conservative. The definitive modalities are radioiodine and subtotal thyroidectomy, these methods will control the symptoms of hyperthyroidism and produce a permanent remission of the disease in more than 90% of patients by reducing the mass of functioning thyroid tissue.

Antithyroid drugs, which block thyroid hormone production and release, are considered conservative because only a fraction of patients reach permanent remission.

Antithyroid drugs Anti-thyroid drugs have been a mainstay of treatment of patients with hyperthyroidi sm since their introduction in the mid40s4. The antithyroid drugs commonly in use throughout the world are the thiocarbamides. These drugs block thyroid hormone synthesis by inhibiting thyroid peroxidase, inhibit thyroid release, and some partially inhibit peripheral conversion of T4 to T3 . In North and South America, the two most commonly used thiocarbamides are propylthiouracil (PTU) and methimazole (MMI) , in Europe and Japan MMI is most common, and Carbimazole is more routinely prescribed in the UKS. All three drugs are very effective in controlling thyrotoxicosis and to some extent the choice between drugs is a matter of preference, although there has been evidence to show that MMI may be superior because patients treated with it become euthyroid sooner6 and it may have fewer side effects7.

UWOMJ 72(2) 2003 83

z,~.-.-~~ · atorvastatin calcium tablets

EFFICACY TO REACH TARGETS "LIPITOR• (atorvastann calcrum) t 0 mg. 20 mg. 40 mg and 80 mg tablets THERAPEUTICClASSIFICATION: Upid MetaboliSm Regulator ACTIONS AND CLINICAL PHARMACOLOGY LIPITOR (atorvastann calcium) is a synthetic liprd·lowenng agent It is a selecbve. competitive rnhrbrtor of 3- hydroxy-3-meth~ ­ glutaryl-coenzyme A (HMG-CoA) reductase This enzyme catalyzes the conversron of HMG-CoA to mevalonate. which is an early and rate-limrting step rn the brosynthesls of cholesterol LIPITOR lowers plasma cholesterol and lipoprotern levels by rnhibitlng HMG-CoA reductase and cholesterol synthesrs rn the liver and by rncreasing the number of hepabc tow Density Upoprolern (lDL) receptors on the cell-surtace for enhanced uptake and catabolism of Low Density l.Jpoprotein (LOL) UPITOR reduces LDL-Cholesterol (lDL·C) and the number of LDL particles. LIPITOR also reduces Very Low Oensrty I.Jpoprotein·Cholesterol (VLDL-C), serum triglycendes (TG) and tntenmedrate Density Upoproteins QOL), as well as the number of apotrpoprotern B (apo B) contarnrng particles, but rncreases Hrgh Oensrty LJpoprotern·Cholesterol (HDL·C) Elevated serum cholesterol due to elevated LDL-C is a maJilf nsk factor for the development of cardrovascular drsease. Low serum concentration of HDL-C IS also an rndependent nsk factllf. Elevated plasma TG is also a nsk factor for cardiovascular disease, particularly II due to rncreased IOL, Of assocrated with decreased HOL ·C or rocreased LDL -C Atorvastabn rs raprdly absorbed after oral admrnrstration, maxrmum plasma concentranons occur W1thrn 1 to 2 hours.Atorvastatrn tablets are 95% to 99% bioavaJiable compared to solutions Mean drstnbution of atorvastann rs appro~mately 381 litres Atorvastatin rs ~8% bound to plasma proteins Atorvastatin IS extensrvely metabol~ed by cytochrome P-450 3A4 to ortho· and para-hydroxylated denvanves and to vanous beta-o~dation products. Approxrmately 70% of circutanng inhrbrtory activity for HMG-CoA reductase is aftnbuted to active metabolrtes.

Atorvastann and 115 metabofrtes are eliminated by brliary excrenon. Less than 2% of a dose of atorvastann is recovered rn unne foiiDW1ng oral adminrstranon. Mean plasma elimrnatron half-lrfe ol atorvastatin rn humans is approximately 14 hours, but the hall-life of rnhrbrtory acnvity for HMG-CoA reductase IS 20 to 30 hours due to the contribution of longer-lived active metabolites INDICATIONS AND CLINICAL USE UPITOR (atorvastann calcrum) rs indrcated as an adjunct to lifestyle changes, rncluding dret, (at least equrvalent to the Adult Treatment Panel Ill (ATP 110 TLC diet], fllf the reductJOn of elevated total cholesterol, ~otai-C), LDL·C, TG and apolrpoprotein B (apo B) in hyperfrprdemrc and dyslrprdemrc condmons, when response to diet and other nonphanmacological measures alone has been rnadecuate, iocluding • Pnmary hypercholesterolemra (Type lla), • Combined (miXed) hyperfiprdemia (Type lib), rncludrng famrlial combrned hyperfrpidemra, regardless of whether cholesterol or tnglycendes are the lipid abnonmality of concem; • Oysbetalrpoproternemia (Type 110.

• Hypertnglycendemra (Type IV), • Familial hyperchofesterolem~ (homozygous and heterozygous) FOf homozygous familial hypercholesterolemia, UPITOR should be used as an adjunct to treatments such as lDL apheresis, Of as roonolherapy II SLICh treatments are not avaJiable.

UPITOR also raises HOL-cholesterol and therefore Jowers the LDL-CIHDL·C and totai-C!liDL·C ratios in patients with primary hypercholesterolemia and combined (m~ed) hyperlipidemia (Frednckson Type Ita and lib ~ipidemia) . In pooled data from 24 controlled clinical tnals, UPITOR rrused HDL·C levels 5%-7% in pnmary hypercholesterolemic (type Ita) panents and t 0%- 15% in miXed (type lib) dysliprdemrc patients. These changes in HDL -C wrth HMG-CoA reductase inhrMors should be considered as modest when compared to those observed in LDL -C and do not play a primary role in the Jowenng of LDL·OODL·C and total·OODL·C ranos In clinical trials, UPITOR (10 to 80 mg/day) srgnlficantly improved lipid profiles rn patients with a W1de variety of hyperfrprdemrc and dyslipidemic condrtions In 2 dose-response studies in mildly to moderately hyperlipidemic patients (Frednckson Types Ita and lib), UPITOR reduced the levels of total cholesterol (29-45%), LDL·C (39-60%), apo B (32-50%), TG (19-37%), and increased hrgh density lipoprotern cholesterol (HDL·C) levels (5-9%). Comparable responses were achieved rn patients with heterozygous farnrlial hypercholesterolemia, non-farnrlial fonms of hypercholesterolemia, combined hyperlipidemia, including familial combined hyperfrpidemra and panents with non-rnsulin dependent drabetes mellmus In patients with hypertriglyceridemia (Type IV), LIPITOR (10 to 80 mg dally) reduced TG (25-56%) and LDL·C levels (23·40%). UPITOR has not been studied in conditions where the major abnormality is elevation of ch~microns (TG levels > 11 mmoi/L), i.e. types I and V. In an open-label study rn panents with dysbetalipoproteinemra (Type 110. UPITOR (1 0 to 80 mg darly) reduced totai-C (40-57%), TG (40·56%) and IDL·C + VLDL·C levels (34-58%) In an open label study rn patients wrth homozygous farnrlial hypercholesterolemia (FH) UPITOR (1 0 to 80 mg daily) reduced mean LDL -C levels (22%). In a prlot study, UPITOR 80 mg/day showed a mean LDL -C lowenng of 30% for patients not on plasmapheresrs and of 31% lor patients wiho continued plasmapheresis. A mean LDL ·C lowering of 35% was observed in receptor defective pabents and ol1 9% rn receptor negative patients (see PHARMACOLOGY. Clinical Studies).

For rrae detaJis on efficacy results by pre-defirOO ctassdicaOOn and pooled data by Freciickson types,see PHARMACOLOGY, Clni:al Stucles.

Pnor to inrbating therapy with UPITOR, secondary causes should be excluded fllf elevabons in plasma lr pid levels (e.g poorly controlled drabetes mell~us, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, and alcoholism), and a lipid profile pertonmed to measure total cholesterol, LDL·C, HDL·C, andTG. Fllf patients wrth TG <4.52 mmolll (<400 mg/dl), LDL-C can be estimated using the followrng ecU!Ilon LDL·C (mmof/L) = totai·C • 1(0.37 x (TG) + HOL·C)) LDL ·C (mg/dL) = total-C • [(0 2 x (TG) + HDL -C))' For patients •nth TG levels >4.52 mmol/l. (>400 mg/dL), thrs ecuatlon Is less accurate and LDL·C concentrations should be measured directly or by ultracentrifugation.

Patients with hrgh or very high triglyceride levels, 1 e. >2.2 mmol/l. (200 mg/dL) Of >5.6 mmol/l. (500 mg/dl), respectively, may requrre tnglyceride-lowering therapy (fenofibrate, bezalrbrate or nrcotinic acid) alone Of In com~na tron with UPITOR In general, combination therapy with fibrates must be undertaken cautiously and only after risk-benefit analysis (see WARNINGS, Muscle Effects, PRECALITIONS, Pharmacokinetic Interaction Studres and Potential Drug Interactions).

Elevated serum tnglycerides are most often observed In patients with the metabolic syndrome (abdominal obesity, atherogeniC ~ipidemia [elevated triglycendes, small dense LDL particles and low HOL-cholesteroij, Insulin resistance with or wrthoul glucose intolerance, raised biOCIC pressure and prothrombrc and prolnflarnmatllfY states).

(For the treatment of specmc dyslipidemras refer to the Report of the Canadian Worf<ing Group on Hypercholesterolemia and Other Oyslipidemias or to the US NCEP Expert Panel on Detection, Evaluatlon, and Treatment of High BIOCIC Cholesterol in Adults [Adult Treatment Panelllij, under SELECTED BIBLIOGRAPHY in product monograph).

When drugs are prescnbed attention to therapeutic lifestyle changes (reduced Intake of saturated fats and cholesterol, weight reduction, increased physical activity, rngestlon of soluble fibres) should always be maintained and reinforced The Atorvastatin Versus Revascularizatlon Treatments (AVERT) study examined the effect of rnfensive lipid-lowering In patients with stable coronary aJrlery disease and LDL ·C at least 3.0 mmof/L in patients referred for percutaneous translumlnal coronary angioplasty (PTCA). Patients were randomized for 18 months to UPITOR 80 mg daily or to PTCA with usual medical care which could include lipid metabolism regulatllfs. The results of the AVERT study should be considered as exploratory since several limitations may affect its desrgn and conduct. In tha medical-treated group with UPITDR there was a trend lor a reduced rncidence of rschemic events and a delayed time to frrst Ischemic event. The results also suggest that intensive treatment to target LDL -C levels wrth UPITOR Is additive and complementary to angioplasty and would benefit patrents referred IOf this procedure (see SELECTED BIBLIOGRAPHY in product monograph).

CONTRAINOICATIONS Hypersensitivity to any component of thrs medicabon.

Pdive i'M OOea5e Of une>plained persistent elevations rl serum transarnira<;es exceeclng 31ifres the upper Umrt of nonma [see WARNINGS).

Pregnancy and lactation (see PRECALITIONS) WARNINGS Pharmacoklnetic Interactions The use of HMG·CoA reductase inhrbrtors has been associated with severe myopathy, Including rhabdomyolysis, which may be more frequent when they are co-adminrstered with drugs that inhibit the cytochrome P-450 enzyme system. Atorvastatin Is metabofrzed by ~hrome P-450 lsofonm 3A4 and as such may interact with agents that inhrbit this enzyme (See WARNINGS, Muscle Effects and PRECAUTIONS, Drug lnteracnons and ~ochrllfne P-450-medrated Interactions).

1 fne<leWald WI et aJ Ctm Chern 1972.18(6) 489·502

Heoatic Effects . .

In dinical trials, persistent increases in serum transarrinases greater tl1an three times the upper lim~ of nonmal occurred " <1% of pabents wiho received UPITOR. When the 005age of UPITOR was reduced, Of when drug treatment was interrupted Of drSOilfffin_ ued, _serum transarrinase levels retuned to pretreatment levels. The increa<;es were generaly not associated with jaurdce llf other drnical srgns llf symptoms. Moo1 patients contnued treatment with a reduced 00sa of UPITOR without dinical sequelae. .

LJver function tests should be pertonmed before the initiation of treatment and periodically thereafter. Special anentron should be pard to patients wiho develop elevated serum transaminase levels, and in these patients measurements should be repeated promptly and then pertonmed more frequently. ~increases in alanine aminotransferase (ALD or aspartate aminotransferase (ASD show evidence of progression, particularty ff they rise to greater than 3 times the upper limit of normal and are persisten~ the dosage should be reduced or the drug discontinued. .

UPITOR should be used with caution in patients who consume substantial quantities of alcohol and/or have a past hrstory of Jrver drsease Active liver disease or unexplarned transaminase elevations are contraindications to the use of UPITOR; ff such a condition should develop during therapy, the drug should be discontinued.

Muscle Effects Myopathy, defined as muscle aching or muscle weakness in conjunction with rncreases in creatinine_phosphoknase (CPK) values to greater than ten times the upper limrt of nonmal, should be consrdered rn any patient wrth drffuse myalgra, muscle tenderness or weakneiSs, and/or marf<ed elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness Of weakness, partiCularly II accompanied by malaise Of fever. UPITOR therapy should be drsconunued ff marf<edly elevated CPK Jeveis occur or myopathy is diagnosed Of suspected.

The nsk of myopathy and mabolomyolysis during treatment with HMG-CoA reductase inhrb~ors is increased with concurrent adminrstration of cyclosporin, fibnc acid derivatrves, erythromycin, clarithromycin, niacin (nicotinic acid), azole antifungals Of nefazodone As there is no experience to date with the use of LIPITOR given concurrently with these drugs, with the exceptiOn of phanmacokinenc studies conducted in heafthy sub;ects with erythromycin and clarithromycin, the benefits and risks of such combrned therapy should be carefully considered (see PRECALITIONS, Phanmacokinetic lnteracbon Studies and Potential Drug Interactions) Rhabdomyofysis has been reported rn very rare cases with UPITOR (see PRECALITIONS, Drug lnteractiOOIS).

RhaJxfomyofysrs with renal dysluocnon secondary to myoglobinuria has also been reported with HMG·CoA reductase inhibnors.

UPITOR therapy should be temporarily withheld Of drsoontlnued in any patient with an acute serious cond~n suggestive of a myopathy Of haWlQ a nsk factor predisposmg to the development of renal failure secondary to rhabdomyofysis (such as severe acute rnfection, hypotensron, ma,oor surgery, trauma, severe metabole, endocrine and electrolyte disorders, and uncontrolled seizures).

PRECAl/TIONS General The effects of atorvastatin-lnduced changes In lipoprotein levels, Including redurction of serum cholesterol on cardiovascular morbidity or mortality or total mortality have not been established.

Before instrtunng therapy with LIPITOR (atllfvastabn calcium), an attempt should be made to control elevated serum lipoprotein levels with appropriate diet. exercise, and werght reduction in overweight patients, and to treat other underlying medical problems (see INDICATIONS AND CLINICAl USE). Patients should be advised to infonm subsequent physicians of the prillf use of UPITOR Of any other liprd-lowering agents Effect on tl!e Lens Current long-tenm data from clinical trials do not indicate an adverse effect of atllfvastatin on the human lens.

Effect on Ubiquinone ICo0101 Levels Significant decreases in circulabng ubiquinone levels in patients treated with atllfvastatin and other statins have been observed.

The clinical ~gnificance of a potentiallong-tenm stann-rnduced defcrency of ubiquinone has not been established. II has been reported that a decrease in mycrcardral ubrquinone levels could lead to impaired cardiac function in patents with borderline congestive heart failure (see SEUECTED BIBLIOGRAPHY rn product monograph).

Effect on lipoprotein fal In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a coocom~t ircrease in l.p(a) lipoprotein concentrationS. Present knowiedge suggests the rll'jlOrtance of high l.p(a) leve~ as an emerging risk factllf fllf coronary heart disease. ~ is thus desirable to mruntam and rernfllfCe lffestyte changes in high risk patients placed on atorvastatin therapy (see SELECTED BIBLIOGRAPHY rn product monograph) Hypersensitivity An apparent hypersensrti~ty syndrome has been reported wrth other HMG-CoA reductase inhibitllfS which has included 1 or more ol the following features: anaphylaxis, angioedema, lupus erylhematous-like syndrome, polyrnyalgia meumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemo!ytJc anemra, positrve ANA, ESR increase, eDISnophrlia, arthntis, arthralgia, urticaria, asthenra, photosensrtrVlty, fever, chrlls, flushrng, malarse, dyspnea, toxrc epidenmal necrolysis, erylftema multifonme, including Stevens-Johnson syndrome. Although to date hypersensiti~ty syndrome has not been described as such UPITOR should be drscontinued ~ hypersensrtiVlty rs suspected ' Use in Pregnancy LIPITOR is contraindicated during pregnancy (see CONTRA!NDICATIONS).

Atherosclerosis Is a chronrc process and drsoonbnuabon of lipid-lowering drugs during pregnancy should have little impact on the outcome ollong-tenm therapy of pnmary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essentral components lor fetal development Oncluding synthesis of steroids and cell membranes). Since HMG-CoA reductase inhrbrtllfS decrease cholesterol synthesis and possibly the synthesis of other biologically actrve substaoces derived from cholesterol, they may cause hanm to the fetus when administered to pregnant women.

There are no data on the use of LIPITOR during pregnancy. UPITOR should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been infonmed of the potential hazards. nthe patient becomes pregnant while taking UPITOR, the drug should be discontinued and the patient apprised of the potential risk to the fetus.

Nursing Mothers In rats, m_rlk concentratiOns ol ato~astatin are srmilar to those in plasma. II is not knOW1n whether this drug Is excreted in human mrlk. Because of the potenUal for adverse reactrons rn nursrng rnfants women taking UPITOR should not breast-feed (see CONTRA!NOICATIONS). ' Pediatric Use Treatment experience in a pedratric pop_ulation is limited to doses ol UPITOR up to 80 mg/day for 1 year in 8 patients with hllfnDzygouSlamrlial hypercholesterolemra. No clinical or biciChemical abnormalities were reported in these patients.

Geriatric Us Treatment experience in adults 70 years or older (N=221) with doses of LIPITOR up to 80 mg/day has demonstrated that the safety and effectrveness of ato~statrn rn thrs population was similar to that of patients <70 years of age. Phanmacokinetic evaluation of atorvastatrn rn sub;ects over the age of 65 years indicates an increased AUC. As a precautionary measure the lowest dose should be administered initrally (see PHARMACOLOGY, Human Phanmacokinetics· SELECTED BIBLIOGRAPHY In product mooograph). ' Renal fnsufficlenc Plasma concentrations and LDL ·C low_ering efficacy of LIPITOR was sh0W10 to be similar in patients with moderate renal Insufficiency compared W1th _patrents wrth nonmal renal lunctron. However, since several cases of rhabdomyolysis hava been reported In patrents ~rth a hrstory of renal Insufficiency of unknown severity, as a precautionary measure and pending further experleoce I~ renal drsease, the lowest dose (10 mg/day) of LIPITOR should be used in these patients. Similar precautions a 1y rn pauents With severe renal insufficiency [creatinine clearance <30 mUmln (<0.5 mUsec)); the lowest dosage should be d and rmplemented cautiously (see WARNINGS, Muscle Effects; PRECALITJONS, Drug Interactions). se Refer also to DOSAGE AND ADMINISTRATION. E ocrine F nell n

tP

HMG-CoA reductase .inhrbttors _intertere with cholesterol synthesis and as such might thellfetlcally blunt adrenal and/or gonadal steroid prodUCtion. Clinrcal studres with atorvastatin and other HMG·CoA reductase lnhibttllfS hava suggested that these a ts do not reduce plasma cortJsof concentration llf impair adrenal reserve and do not reduce basal plasma testosterone gen .

However, the effects of HMG-CoA reductase lnhiMilfS on male fertility have not been studied in adecuate numbers oF":ntratstiThon. effects, tt any, on the p~u~ry-gonadal axis in premenopausal women are unknOWn. pa en · e Patients treated with atorvastatin wiho develop clinical evidence of erdocrine dysluoction should be evaluated dllfJiqlnately. Caution

should be exercised ~ an HMG-CoA reductase inhiMor or other agent used to lower cholesterol levels is admimstered to patients receMng olhar drugs (e.g. ketocooazole, splrooolactone or cimetid1ne) lhat may decrease lhe leve~ of endogerous steroid hormones Phannacokinetic Interaction Sill dies and Potential Drug Interactions Pharma.cokinetic Interaction stud1es c~nducted with drugs in healthy subjects may not detect the possibility of a potential drug Interaction m some patients due to differences In underl~ng diseases and use ol concomitant medications (see also Geriatric Use; Renal Insufficiency; Patients with Severe HypercholesterOlemia).

Concomitant Therapy with Other Lipid Metabolism Regulators: Combined drug therapy should be approached with caution as information from controlled studies is lim~ed .

Bile Acid Sequestrants: Patients wrth mild to rmc!erate hvoercholesterolemHJ: LDL-C reduction was greater when LIPITOR 10 mg and coiesllpoi 20 g were coadm1nistered (-45%) than when either drug was administered alone (-35% for LIPITOR and -22% for colestipoQ. Patients with seyere hyperchOlesterOlemia: LDL-C reduction was similar (-53%) when LIPITOR 40 mg and colestipoi 20 g were coadm1mstered when compared to lhat wrth LIPITOR 80 mg alone Plasma concentrallon of atorvastatin was lower (appro~mate~ 26%) when LIPITOR 40 mg plus coiestipol 20 g were coadministered compared wrth LIPITOR 40 mg alone.

However, the combination drug therapy was less effective in lowering the triglycerides than LIPITOR monotherapy in both types of hyperchOiesterolemc patients (see PHARMACOLOGY, Clinical Stud1es) When LIPITOR is used concurrently wrth colestipol or any other resin, an 1n1erval of at least 2 hours should be ma1ntained between the two drugs, since the absorption of LIPITOR may be impaired by the resin.

Fibric Acid Derivatives (Gemfibrozil, Fenofibrate, Bezafibrate) and Niacin (Nicotinic Acid): Although lhare is lim~ed expenence with the use of LIPITOR given coocurrently wrth fibric acid derivallves and niacin, lt1e benefits and risks of such combined therapy should ble careful~ considered. The risk of myopathy during treatment with other drugs in this class, Including atorvastabn, is increased with concurrent administration (see WARNINGS, Muscle Effects and SELECTED BIBUOGRAPHY in product monograph).

Coumarin Anticoagulants: LIPITOR had no clinically significant effect on prothrombin time when administered to patients recei~ng chronic wartarin therapy (see SELECTED BIBLIOGRAPHY in product monograph).

Digoxin: In healthy subjects, digoxin pharmacokinetics at steady-state were not significantly altered by coadministration of digo~n 0.25 mg and LIPITOR 10 mg daily. However, digo~n steady-state concentrations 1ncreased approximately 20% follOWing coadministration of d1go~n 0.25 mg and LIPITOR 80 mg daily (see Human Pharrnacokmetics). Patients taking d1go~n should be monitored appropriately.

Antihypertensive agents (amlodipine): In clinical studies, LIPITOR was used concomMntly with antihypertensive agents without ~dence to date of clinical~ significant adverse interactions. In healthy subjects, atorvastabn pharmacokinetics were not attered by the coadministration of LIPITOR 80 mg and amlodip1ne 10 mg at steady state (see Human Pharmacokinetics). (quinapril): In a randomized, open-lablel study in healthy subjects, steady-state quinapril dosing (80 mg OD) did not sign~icantly affect the pharmacokinetic profile of atorvastatin tablets (1 0 mg 00) (see Human Pharmacokinetics).

Oral Corrbraceptives and Honmone Replacement Therapy: Coadministration of LIPITOR with an oral contraceptive, contaimng 1mg norethindrone and 35 ~g ethinyl estradiol, increased plasma concentrations (AUC levels) of norethindrone and ethinyl estradiOl by appro~mately 30% and 20%, respectively. These increases should ble considered when selecting an oral contraceptive. In clinical studies, LIPITOR was used concomitantly with estrogen replacement therapy without evJdence to date of clincally signffcant adverse interactions.

Antacids: Administration of aluminum and magnesium based antacids, such as Maalox" TC Suspension, with LIPITOR decreased plasma concentrations of LIPITOR by appro~malely 35%. LDL-C reduction was not altered but the triglyceridelowenng effect of LIPITOR may ble affected.

Cimetidine: Administration of cimetidine with LIPITOR did not alter plasma concentrations or LDL -C lowering efficacy of LIPITOR, however, the triglyceride-lowering effect of LIPITOR was reduced from 34% to 26%.

Cytochrome P-450-mediated Interactions: Atorvastatin is metabol~ed by the cytochrome P-450 isoenzyme, CYP 3A4.

Erythromycin, a CYP 3A4 inhiMor, increased atorvastatin plasma levels by 40%. Coadministration of CYP 3A4 inhiMors, such as g rapefru~ juice, some macrOlide antibiotics Q .e. erythromycin, clarithromycin), immunosuppressants (cyclosporine), azote antifungal agents Q.e. itraconHlZOie, ketoconazOie), protease inhiMms, or the antidepressant, nefazodone, may have lt1e potential to increase plasma concentrations of HMG-CoA reductase inhibrtors, including LIPITOR (see SELECTED BIBLIOGRAPHY in product monograph).

Caution should thus ble exercised with concomMnt use of these agents (see WARNINGS, Pharrnacokinetic Interactions, Muscle Effects; PRECAUTONS, Renal Insufficiency and Enldocrine Function; DOSAGE AND ADMINISTRATION; SELECTED BIBLIOGRAPHY in product monograph).

In healthy subjects, coadministration of ~mum doses of both atorvastatin (80 mg) and tertenadine (120 mg), a CYP 3A4 substrate, was shown to produce a modest increase in tertenadine AUC. The OTc interval remained unchanged. However, since an interaction between these two drugs cannot be excluded in patients with predisposing factms for arrhythmia, (e.g. pree~sting prOlonged OT interval, severe coronary artery disease, hypokalemia), caution should be exercised when these agents are coadm1nistered (see WARNINGS, PhanrrHJcokinetic Interactions; DOSAGE AND ADMINISTRATION).

Antipyrine: Antipyrine was used as a non-specific model for drugs metabolized by the microsomal hepatic enzyme system (cytochrome P-450 system). LIPITOR had no effect on the pharmacokinetics of antipynne, thus interactions with other drugs metabOlized via the same cytochrome 1sozymes are not expected.

Macrolide Antibiotics (azithromycin, clarilllromycin, erythromycin): In healthy adults, coadministration of LIPITOR(10 mg 00) and azltllrornycin (500 mg 00) did not sign~ atter lt1e plasma concentrations of atorvastatin. However, coadministration of atorvastatin (1 0 mg 00) wrth erythromycin (500 mg OlD) or clarithrom)On (500 mg BID), whdl are both CYP 3A4 irllilm, increased plasma concentrations of atorvastatin approxi'rn~ 40% and 80%, respedively (see Wm.INGS, Muscle Effects; Human Pharmacd<inelics).

Protease Inhibitors (nelfinavir mesylate): In healthy adults, coadministration ol nelfinavir mesylate (1250 mg BID), a known CYP 3A4 mhiMor, and atorvastatin (1 0 mg OD) resulted in increased plasma concentrations of atorvastatin. AUC and C... of atorvastatin were increased by 74% and 122% respectively.

Patients with Severe Hypercholesterolemia: Higher drug dosages (80 mg/day) required for some patients w~ severe hypercholesterolemia Qncluding familial hypercholesterolemia) are associated with increased plasma levels of atorvastatin.

Caution should be exercised in such patients who are also severely renally impaired, elde~y, or are concomitantly being administered digoxin or CYP 3A4 inhibitors (see WARNINGS, Phannacokinetic Interactions, Muscle Effects; PRECAliTJONS, Drug Interactions; DOSAGE AND ADMINISTlRATIDN).

Druq/laboratorv Test Interactions LIPITOR may elevate serum transaminase and creatinine phosphokinase levels (from skeletal muscle). In the differential diagnosis of chest pain in a patient on therapy with LIPITOR, cardiac and noncardiac fractions of these enzymes should be determined.

ADVERSE REACTIONS LIPITOR is generally well-tolerated. Adverse reactions have usually been mild anld transient. In controlled clinical studies (placebo-controlled and active-controlled comparative studies w~ other lipid lowering agents) involving 2502 patients, <2% of patients were discontinued due to adverse experiences attributable to LIPITOR. Of these 2502 patients, 1721 were treated for at least 6 months and 1253 for 1 year or more.

Adverse experiences occunring at an incidence ;,1% 1n pahents participating in placebo-controlled clinical studies of LIPITOR and reported to be possibly, probably or definrtely drug related are shown in Table 1 beklw: TABLE 1. Associated Adverse Events Reported in >1% of Patients in Placebo-Controlled Clinical Trials Placebo % (n 270) LIPITOR % (n- 1122 ) GASTROINITESTINAL Constipation Diarrhea Dyspepsia Flabulence 0 Nausea NERVOUS SYSTEM Headache MISCELLANEOUS <1 Pain 1 Myalgia <1 Asthenia The fOllowing additional adverse events were reported in clinical trials; not all events listed below have bleen associated with. a causal relationship to UPITOR therapy: Muscle cramps, myos~is, myopathy, paresthesia, panpheral neuropathy, pancreatitis, hepat~is, cholestatic jaundice, anorexia, vomiting, alopecia, pruritus, rash, impotence, hyperglycemia, and hypoglycemia.

Post-marl<eting excerience: Very rare reports: severe myopathy with or without rhabdcmyOiysis (see WARNINGS, Muscle Effects; PRECAUTONS, Renal Insufficiency and Drug Interactions). IsOlated reports: thrombocylopenHJ, arthralgia and allergiC reactions including urticaria, angioneurotic edema, anaph~s and bullous rashes Qnclud1ng erytheme mullifonrre, Stevens-Johnson syndrome and to~c epidermal necrolysis). These may have no causal relationship to atorvastatin.

Ophlhalmolog1c observalions: see PAECAUTONS Laboratory Tests: Increases 1n serum transaminase levels have been noted 1n clinical lnals (see WARNINGS) SYMPTOMS AND TREATMENT OF OVERDOSAGE There 1s no specffic treatment for atorvastabn overdosage. Should an overdose occur, lt1e pabent should be treated symptomaocaJiy and supportive measures insbtuted as required Due to extensive drug b1nd1ng to plasma proteu-.s, hemodialysiS ~ not expected to ~gnrficantly enhance atorvastabn clearance DOSAGE AND ADMINISTRATION Patients should be placed on a standard cholesterol -lowenng d1et (at least eqwvalentto the Adurt Treatment Panel Ill (ATP IIQ TLC diet] blefore receiving UPITOR, and should conMue on thiS d1et dunng treatment v.th LIPITOR ~ appropnate, a program of we1ght control and physical exercise should be Implemented Prjmary Hypercholesterolemia and Combined !Mixed) Hyperfip1dem1a Including Famtlial Combmed Hyperlimdemta The recommended dose of LIPITOR is 10 mg once a day. The majority of patrents achieve and mamtam target chOlesterol levels Wlth UPITOR 10 mg/day. A sign~icant therapeutK: response is ~dent withm 2 weeks, and the max~mum response IS usual~ ach1eved within 2-4 weeks. The response is mamtamed during chrome therapy Doses can ble g~en at any bme of the day, wrth or Wlthout food, and should preferably be given 1n the evening. Doses should be 1ndMdualized according to baseline LDL -C and/or TG levels, the desired LDL -C and/or TG target (see the Detecticn and Management of Hypercholesterolemia, Working Group on lt/l)ercholesterotem1a and other Dyslipidem1as [Canada] and/or the US Nat1onal CholesterOl Education Program [NCEP Adult Treatment Panel Ill)), the goal of therapy and the patient's response. AdJustments of dosage, rt necessary, should be made at Intervals ol 4 weeks or more. The recommenlded dose range for most patients IS 10 to 40 mg/day. The max~mum dose is 80 mg/day, wh1ch may be reqwred in a m1nority of patrents (see section below) Upid levels should be monitored periodically and, ff necessary, the dose of LIPITOR adjusted based on target lipid levels recommended by guidelines.

The following reductions in total cholesterol and LDL-C levels have been observed in 2 dose-response studies, and may serve as a gu1de to treatment of patients with m1id to moderate hypercholesterOlemia· TABLE 2. Dose-Response in Patients With Mild to Moderate Hypercholesterolemia (Mean Percent Change from Baseline)' LIPfTOR Dose (mg!day) Upid Parameter 10 20 40 80 (N-20) (N-22) (N=21) (N=23) -29

-33

-37

-45

-39

-43

-50

-60

a. Results are pooled from 2 dose-response studies. b. Mean baseline values.

Severe Dyslloidemias In patients with severe dyslipJdemJas, including homozygous and heterozygous familial hypercholesterolemia and dysbletalipoproteinemia (Type IIQ, higher dosages (up to 80 mg/day) may be requlfed (see WARNINGS, Pharmacokinetic Interactions, Muscle Effects, PRECAUTIONS, Drug Interactions).

Concomitant Therapy See PRECAUTONS, Drug Interactions.

Dosage In Patients With Renal Insufficiency See PRECAUTONS. PHARMACEUTICAL INFORMATION Drug Substance Proper Name: Atorvastatin calcium Chemical Name: (R-(R",R")]-2-(4-fluorophenyi)-B, 1\-dihydroxy-5-(1 - meth~ethyQ-3-phenyl-4-((phenylamino) carbonyl)1l:!-pyrrole-1 -heptanoic acid, calcium sart (2:1) trihydrate Empirical Formula: (C33H34 FN20,)2Ca• 3H20 Molecular Weight: 1209.42 Structural Formula:

0

o-

Ca··

•3H.O

Description: Atorvastatrn calcium IS a white to off-wh1te crystalline powder thai IS practcally InsOluble 1n aqueous solutions of pH 4 and blelow. Atorvastatin calc1um is very slightly soluble in distilled water, pH 7 4 phosphate buffer and acetonmle, slightly sOluble in ethanOl, and freely soluble in melhanol.

Tablet Comoosition: Each tablet contains either 10 mg, 20 mg, 40 mg or 80 mg atorvastaM as the active ingredient. Each tablet also contains the IOIIowing non-medicinal ingredients: calcium carbonate, candelilla wax, croscarmelklse sod1um, hydroxyprop~ cellulose, lactose monohydrate, magnesium stearate, microcrystalline celluklse, hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium d1o~de, polysortJate 80 and simethicone emulsion.

Stability and Storage Recommendations: Store at contrOlled room temperature 15 to 30'C. AVAILABILITY OF DOSAGE FORMS LIPITOR (atorvastatin calcium) IS available in dosage strengths of 10 mg, 20 mg, 40 mg and 80 mg atorvastatin per tablet.

1D mg: White, elliptical, film-coated tablet, coded "10" on one ~de and "PO 155" on the other. Available 1n bottles of 90 tablets.

20 mg: WhiTe, elliptical. film-coated tablet, coded "20" on one side and "PO 156" on the other. Available in bottles of 90 tablets.

40 mg: WhiTe, elliptical, film-coaled tablet, coded "40" on one side and "PO 157" on the other. Available 1n bottles of 90 tablets.

80 mg: WhiTe, elliptical, film -coated tablet, coded on one side and "PO 158" on the other Blisters of 30 tablets (3 strips X 10).

References: 1. LIPITOR (alorvastatin calcium) Product Monograph, Pfizer Canada Inc., February 2002. 2.1MS Global Services; March 1997 - September 2002. 3. Pitt B, el a/. Aggressive lipid-lowering therapy compared w1th ang1oplasty 1n stable coronary artery disease: N Eng/ J Med 1999;341:70-76. 4. Data on F1le, Pf1zer Canada Inc. 5. S1mon Day. Dictionary for ClinicaiTrials, 1999, John Wiley & Sons Ltd. 137-38.

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For a copy of the Product Monograph or full Prescribing lnformat1on, please contact:

Lift U our Uf t's work Cl 2003

Pfizer Canada Inc. Kirkland, Quebec H91 2M5

•rM pfizer Ireland Pharmaceuticals pfizer Canada Inc., hcensee

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