Indian Journal of Clinical Practice July 2016 by IJCP

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ISSN 0971-0876

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Volume 27, Number 2

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July 2016, Pages 101â&#x20AC;&#x201C;200

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IJCP Editorial Board Obstetrics and Gynaecology Dr Alka Kriplani, Dr Thankam Verma, Dr Kamala Selvaraj Cardiology Dr Praveen Chandra, Dr SK Parashar Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses, Dr Sidhartha Das, Dr A Ramachandran, Dr Samith A Shetty, Dr Vijay Viswanathan, Dr V Mohan, Dr V Seshiah, Dr Vijayakumar ENT Dr Jasveer Singh, Dr Chanchal Pal Dentistry Dr KMK Masthan, Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar, Dr Rajiv Khosla, Dr JS Rajkumar Dermatology Dr Hasmukh J Shroff, Dr Pasricha, Dr Koushik Lahiri, Dr Jayakar Thomas Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan, Dr Vineet Suri, Dr AV Srinivasan Oncology Dr V Shanta Orthopedics Dr J Maheshwari

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Volume 27, Number 2, July 2016 FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF

105 New Bio-Medical Waste Management Rules, 2016: What Every Doctor Must Know

KK Aggarwal

AMERICAN FAMILY PHYSICIAN

109 Common Skin Rashes in Children

Amanda Allmon, Kristen Deane, Kari L. Martin

115 Practice Guidelines 118 Photo Quiz ANESTHESIOLOGY

120 A Comparative Study of Intravenous Lignocaine Hydrochloride and Dexmedetomidine in Prevention of Pain Due to Propofol Injection: A Double-blind Randomized Controlled Study

Bipin Arya, Ankesh, Atul Dixit, Sadhana Sanwatsarkar, Prachi Laad, Pooja Jain

CARDIOLOGY

124 A Rare Case of Infective Endocarditis by Mycobacterium abscessus (NTM)

Vishal Sadatia, Mayank Thakkar, Tushar Patel

DIABETOLOGY

128 SGLT2 Inhibitors: A Novel Therapy for Type 2 Diabetes Mellitus

PG Raman

ENDOCRINOLOGY

132 Insulin Resistance

Mukesh Mehra

GASTROENTEROLOGY

137 Nonalcoholic Fatty Liver Disease, Cardiovascular Risks and Therapeutic Approaches

Pragati Kapoor, Pankaj Kumar, AK Kapoor

INTERNAL MEDICINE

147 Acute Kidney Injury: A Rarity in Methemoglobinemia

R Umarani, Baburaj K, Jino Vincent, Saravanan M

OBSTETRICS AND GYNECOLOGY

153 Laparoscopic Evaluation of Endometriosis in Infertility and Chronic Pelvic Pain in a Tertiary Care Center: An Observational Study

Parmjit Kaur, Ruby Bhatia, Rajwinder Kaur, Aman Dev, Surinder Kumari

157 Comparison of Serum Anti-mullerian Hormone with Ultrasound as a Diagnostic Marker in Polycystic Ovarian Syndrome

Aneesha Awasthy, Shikha Singh, Rekha Rani

OBSTETRICS AND GYNECOLOGY

Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Ltd. and Published at E - 219, Greater Kailash, Part - 1 New Delhi - 110 048 E-mail: editorial@ijcp.com

161 Predictive Factors for Pregnancy After Controlled Ovarian Hyperstimulation and Intrauterine Insemination: A Prospective Study

Shikha Jain

167 Ectopic Pregnancy Presenting as True Gestational Epilepsy

Printed at New Edge Communications Pvt. Ltd., New Delhi E-mail: edgecommunication@gmail.com

Shyamal G, Vijayalakshmi, Sunil Kumar N, Anudeep Reddy

PEDIATRICS

170 Pierre Robin Syndrome

The copyright for all the editorial material contained in this journal, in the form of layout, content including images and design, is held by IJCP Publications Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.

Nishad Patil, Sunil Mhaske, Ramesh B Kothari, Sandip Deokate, Ram Sethi, Pavan Suryawanshi, Rahul Maski, Nivrutti Mundhe, Suraj Nair

PSYCHIATRY

175 Illness Anxiety Disorder: A Case Report

Editorial Policies

Pankhuri Aggarwal

SURGERY

The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.

177 Situs Inversus: A Preoperative Finding Not So Uncommon

Venkatesh Subbiah, S Asokan, Somasundaram

MEDILAW

179 A Known Phenomenon is not Medical Negligence CONFERENCE PROCEEDINGS

182 60th Annual Conference of the Indian Orthopaedic Association (IOACON 2015) 185 62nd Annual Conference of Cardiological Society of India (CSI 2016) 188 India Live 2016 AROUND THE GLOBE

192 News and Views LIGHTER READING

Note: Indian Journal of Clinical Practice does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature in this issue.

196 Lighter Side of Medicine

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New Bio-Medical Waste Management Rules, 2016: What Every Doctor Must Know New bio-medical waste management rules get stringent, Pune doctors unaware The New Indian Express Anuradha Mascarenhas | Pune | Updated: June 10, 2016 1:33 am Doctors will now have to set up their own websites and upload the amount of bio-medical waste that has been generated at their clinics or hospitals every month. This data will have to be sent to the Maharashtra Pollution Control Board, which in turn will forward it to the central pollution control authorities for a stricter check. With pollution becoming a significant threat, particularly by bringing down life expectancy, the Environment Ministry’s Bio-Medical Waste Management Rules, 2016 has also imposed stricter norms for incinerators that dispose bio-medical waste to ensure that emissions are below the permissible limits. The new rules have laid down various criteria, which are to be implemented soon. However, when contacted, several doctors and civic officials were unaware of them. It has been 2 months since the New Bio-Medical Waste Management Rules, 2016 were released, but there is a clear lack of awareness among doctors and even civic authorities about the rules, admits Pradeep Mulay, Director of Passco Environmental solutions, which disposes bio-medical waste daily from Pune’s hospitals and dispensaries. “In fact, the common incinerator facility operators will hold a meeting on June 10 to discuss these new rules and how to implement it in the city,” Mulay said. Here are the Points to be Known to Every Doctor The new Bio-Medical Waste Management Rules, 2016 shall apply to all persons who generate, collect, receive, store, transport, treat, dispose or handle bio-medical waste in any form including hospitals, nursing homes, clinics, dispensaries, veterinary institutions, animal houses, pathological laboratories, blood banks, Ayush hospitals, clinical establishments, research or educational institutions, health camps, medical or surgical camps, vaccination camps, blood donation camps, first aid rooms of schools, forensic laboratories and research labs.

(d) "Authorised person" means an occupier or operator authorised by the prescribed authority to generate, collect, receive, store, transport, treat, process, dispose or handle bio-medical waste in accordance with these rules and the guidelines issued by the Central Government or the Central Pollution Control Board, as the case may be; (f) "bio-medical waste" means any waste, which is generated during the diagnosis, treatment or immunisation of human beings or animals or research activities pertaining thereto or in the production or testing of biological or in health camps, including the categories mentioned in Schedule I appended to these rules;

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FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF Duties of the Occupier. - It shall be the duty of every occupier to (a) Take all necessary steps to ensure that bio-medical waste is handled without any adverse effect to human health and the environment and in accordance with these rules; (b) Make a provision within the premises for a safe, ventilated and secured location for storage of segregated biomedical waste in colored bags or containers in the manner as specified in Schedule I, to ensure that there shall be no secondary handling, pilferage of recyclables or inadvertent scattering or spillage by animals and the bio-medical waste from such place or premises shall be directly transported in the manner as prescribed in these rules to the common bio-medical waste treatment facility or for the appropriate treatment and disposal, as the case may be, in the manner as prescribed in Schedule I; (c) Pre-treat the laboratory waste, microbiological waste, blood samples and blood bags through disinfection or sterilisation on-site in the manner as prescribed by the World Health Organisation (WHO) or National AIDS Control Organisation (NACO) guidelines and then sent to the common bio-medical waste treatment facility for final disposal; (d) Phase out use of chlorinated plastic bags, gloves and blood bags within two years from the date of notification of these rules; (e) Dispose of solid waste other than bio-medical waste in accordance with the provisions of respective waste management rules made under the relevant laws and amended from time to time; (f) Not to give treated bio-medical waste with municipal solid waste; (g) Provide training to all its health care workers and others, involved in handling of bio medical waste at the time of induction and thereafter at least once every year and the details of training programmes conducted, number of personnel trained and number of personnel not undergone any training shall be provided in the Annual Report; (h) Immunise all its health care workers and others, involved in handling of bio-medical waste for protection against diseases including Hepatitis B and Tetanus that are likely to be transmitted by handling of bio-medical waste, in the manner as prescribed in the National Immunisation Policy or the guidelines of the Ministry of Health and Family Welfare issued from time to time;

(j) Ensure segregation of liquid chemical waste at source and ensure pre-treatment or neutralisation prior to mixing with other effluent generated from health care facilities; (k) Ensure treatment and disposal of liquid waste in accordance with the Water (Prevention and Control of Pollution) Act, 1974 (6 of 1974); 5 (l) Ensure occupational safety of all its health care workers and others involved in handling of bio-medical waste by providing appropriate and adequate personal protective equipments; (m) Conduct health check up at the time of induction and at least once in a year for all its health care workers and others involved in handling of bio- medical waste and maintain the records for the same; (n) Maintain and update on day-to-day basis the bio-medical waste management register and display the monthly record on its website according to the bio-medical waste generated in terms of category and colour coding as specified in Schedule I; (o) Report major accidents including accidents caused by fire hazards, blasts during handling of bio-medical waste and the remedial action taken and the records relevant thereto, (including nil report) in Form I to the prescribed authority and also along with the annual report; (p) Make available the annual report on its web-site and all the health care facilities shall make own website within two years from the date of notification of these rules; (q) Inform the prescribed authority immediately in case the operator of a facility does not collect the bio-medical waste within the intended time or as per the agreed time; (r) Establish a system to review and monitor the activities related to bio-medical waste management, either through an existing committee or by forming a new committee and the Committee shall meet once in every 6 months and the record of the minutes of the meetings of this committee shall be submitted along with the annual report to the prescribed authority and the health care establishments having less than thirty beds shall designate a qualified person to review and monitor the activities relating to bio-medical waste management within that establishment and submit the annual report; (s) Maintain all record for operation of incineration, hydro or autoclaving etc., for a period of 5 years;

(t) (i) Establish a Bar Code System for bags or containers containing bio-medical waste to be sent out of the premises or place for any purpose within one year from the date of the notification of these rules; ■■■■

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Existing incinerators to achieve the standards for treatment and disposal of bio-medical waste as specified in Schedule II for retention time in secondary chamber and Dioxin and Furans within 2 years from the date of this notification.

AMERICAN FAMILY PHYSICIAN

Common Skin Rashes in Children AMANDA ALLMON, KRISTEN DEANE, KARI L. MARTIN

ABSTRACT Because childhood rashes may be difficult to differentiate by appearance alone, it is important to consider the entire clinical presentation to help make the appropriate diagnosis. Considerations include the appearance and location of the rash; the clinical course; and associated symptoms, such as pruritus or fever. A fever is likely to occur with roseola, erythema infectiosum (fifth disease), and scarlet fever. Pruritus sometimes occurs with atopic dermatitis, pityriasis rosea, erythema infectiosum, molluscum contagiosum, and tinea infection. The key feature of roseola is a rash presenting after resolution of a high fever, whereas the distinguishing features in pityriasis rosea are a herald patch and a bilateral and symmetric rash in a Christmas tree pattern. The rash associated with scarlet fever usually develops on the upper trunk, then spreads throughout the body, sparing the palms and soles. Impetigo is a superficial bacterial infection that most commonly affects the face and extremities of children. Erythema infectiosum is characterized by a viral prodrome followed by the “slapped cheek” facial rash. Flesh-colored or pearly white papules with central umbilication occur with molluscum contagiosum, a highly contagious viral infection that usually resolves without intervention. Tinea is a common fungal skin infection in children that affects the scalp, body, groin, feet, hands, or nails. Atopic dermatitis is a chronic, relapsing inflammatory skin condition that may present with a variety of skin changes.

Keywords: Childhood rashes, pruritus, fever, bacterial infection, viral infection, fungal skin infection, inflammatory skin condition

here are more than 12 million office visits annually for rashes and other skin concerns in children and adolescents, of which 68% are made to primary care physicians.1 Recognizing key features can help distinguish the different types of rashes (Table 1). This article includes common infectious and noninfectious inflammatory rashes in children. HISTORY AND PHYSICAL EXAMINATION The initial approach to a child with a rash begins with the history, which should include the duration of the rash, the initial appearance and how it has evolved, the location, and any treatments that have been used. Parents should also be asked if other household members have a similar rash and if there have been any new medication, product, or environmental exposures. The presence or absence of associated symptoms can help clinicians develop a differential diagnosis. A fever

AMANDA ALLMON, MD, is an associate professor of family medicine at the University of Missouri–Columbia School of Medicine. KRISTEN DEANE, MD, is an associate professor of family medicine at the University of Missouri–Columbia School of Medicine. KARI L. MARTIN, MD, is an assistant professor of dermatology and pediatrics at the University of Missouri–Columbia School of Medicine. Source: Adapted from Am Fam Physician. 2015;92(3):211-216.

is likely with roseola, erythema infectiosum, and scarlet fever. Pruritus sometimes occurs with atopic dermatitis, pityriasis rosea, erythema infectiosum, molluscum contagiosum, and tinea infection. On physical examination, certain clinical findings may be useful in determining a diagnosis. It is important to determine the type of lesions, such as macules, papules, vesicles, plaques, or pustules. Other important characteristics include location and distribution, arrangement, shape, color, and presence or absence of scale. ROSEOLA INFANTUM (EXANTHEMA SUBITUM) Roseola is most commonly caused by human herpesvirus 6 and affects infants and children younger than three years.2 It is characterized by the abrupt onset of high fever lasting one to five days. During this period, children often appear well with no focal clinical signs except possible mild cough, rhinorrhea, or mild diarrhea. Once the fever resolves, an erythematous macular to maculopapular rash usually appears, starting on the trunk and spreading peripherally. This rash is similar in appearance to that of rubeola (measles). In contrast with roseola, the rash associated with measles starts on the face (usually behind the ear) or mouth (Koplik spots) and moves downward.3

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AMERICAN FAMILY PHYSICIAN Table 1. Distinguishing Characteristics of Common Childhood Rashes Condition

Location

Appearance

Roseola infantum (exanthema subitum)

Trunk, spreads peripherally

Macular to maculopapular

Pityriasis rosea

Trunk, bilateral and symmetric, Christmas tree distribution

Herald patch on the trunk may present first, followed by smaller similar lesions; oval-shaped, rose-colored patches with slight scale

Scarlet fever

Upper trunk, spreads throughout body, spares palms and soles

Erythematous, blanching, fine macules, resembling a sunburn; sandpaper-like papules

Impetigo

Anywhere; face and extremities are most common

Vesicles or pustules that form a thick, yellow crust

Erythema infectiosum (fifth disease)

Face and thighs

Erythematous “slapped cheek” rash followed by pink papules and macules in a lacy, reticular pattern

Molluscum contagiosum

Anywhere; rarely on oral mucosa

Flesh-colored or pearly white, small papules with central umbilication

Tinea infection

Anywhere

Alopecia or broken hair follicles on the scalp (tinea capitis), erythematous annular patch or plaque with a raised border and central clearing on the body (tinea corporis)

Atopic dermatitis

Extensor surfaces of extremities, cheeks, and scalp in infants and younger children; flexor surfaces in older children

Erythematous plaques, excoriation, severely dry skin, scaling, vesicular lesions

Children with roseola usually appear well, whereas those with measles are typi cally more ill-appearing. Roseola is a self-limited illness requiring no treatment, and the diagnosis is clinical.4 PITYRIASIS ROSEA Approximately 80% of patients with pityriasis rosea present with a single oval-shaped, rose-colored patch, usually on the trunk. This lesion, commonly known as the herald patch, is typically 2 to 10 cm in diameter and may have a peripheral scale5 (Figure 1). It may be present for a few weeks before the development of smaller lesions that are similar to the herald patch, maintaining a classic peripheral scale overlying pink thin papules. The herald patch may be misdiagnosed as tinea corporis because of the annular lesion with raised edges, fine scale, and central clearing. There is usually a single plaque with tinea corporis, without eruptions of smaller lesions typical with pityriasis rosea. The rash of pityriasis rosea is usually bilateral and symmetric,

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Figure 1. Herald patch of pityriasis rosea (arrow). Photo courtesy of the Centers for Disease Control and Prevention’s Public Health Image Library.

distributed parallel to the Langer lines in a Christmas tree pattern. Children with pityriasis rosea may have a history of mild upper respiratory tract infection symptoms, and up to one-half have pruritus.6 A potassium hydroxide preparation can help distinguish pityriasis rosea from tinea infection or other rashes. The

AMERICAN FAMILY PHYSICIAN

Fever

Pruritus

Distinguishing features

Duration

High fever, usually greater than 102°F (39°C), precedes the rash; child is otherwise wellappearing

Can be confused with measles; measles rash begins on the face, and the child is usually ill-appearing

1 to 2 days

Occurs in up to one-half of patients

Often confused with tinea corporis; pityriasis rosea is typically widespread, whereas tinea corporis usually causes a single lesion

2 to 12 weeks

Occurs 1 to 2 days before rash develops

Usually no

Petechiae on palate; white strawberry tongue; test positive for streptococcal infection

Several weeks

Usually no

May be a primary or secondary infection; bullous form is typical in neonates, and nonbullous form is more common in preschool- and school-aged children

Usually self-limited but often treated to prevent complications and spread of the infection

Low grade

Yes

May be confused with scarlet fever; the slapped cheek rash can differentiate erythema infectiosum

Facial rash lasts 2 to 4 days; lacy, reticular rash may last 1 to 6 weeks

Yes, if associated with dermatitis

Usually resolves spontaneously without treatment

Months or up to 2 to 4 years

Yes

Often confused with pityriasis rosea; potassium hydroxide microscopy can help confirm diagnosis

Usually requires antifungal treatment

Yes

Emollients and avoidance of triggers are the mainstay of treatment; topical corticosteroids may be needed for flare-ups

Chronic, relapsing

rash associated with pityriasis rosea may be present for two to 12 weeks, and treatment is supportive.6 Although the etiology is not fully known, it is thought to be infectious, with some studies implicating human herpesvirus 6 and 7.5,7 SCARLET FEVER Scarlet fever is diagnosed in 10% of children presenting with streptococcal tonsillopharyngitis.8 It is caused by certain strains of group A betahemolytic streptococci that release a streptococcal pyrogenic exotoxin (erythrogenic toxin). Patients who have a hypersensitivity to the toxin may develop the characteristic rash associated with scarlet fever. Most children have a fever and sore throat one to two days before the rash develops on the upper trunk. The rash spreads throughout the body, sparing the palms and soles, with characteristic circumoral pallor. This differs from some viral exanthems that develop more slowly. The rash is characterized by confluent, erythematous, blanching, fine macules, resembling

Figure 2. Sandpaper-like papules associated with scarlet fever. Photo courtesy of the Centers for Disease Control and Prevention’s Public Health Image Library.

a sunburn, and sandpaper-like papules (Figure 2). In skinfolds, such as the axilla, antecubital fossa, and buttock creases, an erythematous, nonblanching linear eruption (Pastia lines) may develop. Petechiae on the palate may occur, as well as erythematous, swollen papillae with a white coating on the tongue (white strawberry tongue). Red strawberry tongue occurs

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AMERICAN FAMILY PHYSICIAN after desquamation of the white coating. After several weeks, the rash fades and is followed by desquamation of the skin, especially on the face, in skinfolds, and on the hands and feet, potentially lasting four to six weeks.9 With a sensitivity of 90% to 95%, throat culture is the first-choice method for diagnosis of group A streptococcal infection, but this is not always practical.8 Rapid antigen tests are routinely used in clinicians’ offices and have a sensitivity of approximately 86%.10 Cultures may be ordered when the suspicion for group A streptococcal infection is high, but the rapid antigen test result is negative.11 Penicillin is the therapy of choice for streptococcal infection. Those allergic to penicillin and cephalosporins may be treated with oral macrolides (erythromycin, azithromycin) or clindamycin.10 IMPETIGO Impetigo is a primary or secondary bacterial infection of the epidermis of the skin. Primary infections occur when bacteria enter breaks in the skin, whereas secondary infections develop at the site of an existing dermatosis. There are bullous and nonbullous forms of the infection, with the bullous form typically occurring in neonates and the nonbullous form most common in preschool- and school-aged children.12 Although Streptococcus pyogenes was once the most common cause of nonbullous impetigo, Staphylococcus aureus has surpassed it in more recent years. However, S. pyogenes may still be the pre dominant cause in warm and humid climates. S. aureus is the main source of bullous impetigo. Initially, children may develop vesicles or pustules that form a thick, yellow crust (Figure 3). With autoinoculation, the lesions may quickly spread. The face and extremities are most commonly affected. Although impetigo is usually a self-limited disease, antibiotics are often prescribed to prevent complications and spread of the infection.12 ERYTHEMA INFECTIOSUM Erythema infectiosum, or fifth disease, is caused by parvovirus B19. It is a common childhood infection characterized by a prodrome of low-grade fever, malaise, sore throat, headache, and nausea followed several days later by an erythematous “slapped cheek” facial rash (Figure 4). After two to four days, the facial rash fades. In the second stage of the disease process, pink patches and macules may develop in a lacy, reticular pattern, most often on the extremities. After one to six weeks, the rash resolves but may reappear

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Figure 4. Erythematous “slapped cheek” facial rash associated with erythema infectiosum.

with sun exposure, heat, or stress. Arthralgias occur in approximately 8% of young children with the disease but are much more common in teens and young adults. Patients are no longer considered infectious once the rash appears. Treatment is symptomatic and includes nonsteroidal anti-inflammatory drugs for arthralgias and antihistamines for pruritus.13 MOLLUSCUM CONTAGIOSUM Molluscum contagiosum is a skin infection caused by a poxvirus. This highly contagious viral infection most commonly affects children two to 11 years of age.14 It also occurs in sexually active adolescents. The lesions are flesh-colored or pearly white, small papules with central umbilication (Figure 5). The oral mucosa is rarely affected, but lesions may appear on the genital region and conjunctiva. Typically, children have 10 to 20 lesions, but occasionally there may be up to hundreds.14 Molluscum may also occur in conjunction with dermatitis. It can erupt and spread quickly in a child with underlying atopic dermatitis, or it can induce dermatitis in a child with previously clear skin (molluscum dermatitis). The diagnosis of molluscum contagiosum is made clinically. The condition is self-limited, but clinicians should advise parents to use gentle skin care products on the patient and that lesions may last for months or up to two to four years. Treatment options, including cryotherapy, imiquimod, and intralesional immunotherapy, are available if physical appearance is a concern. Dermatitis (occurring as molluscum dermatitis or a flare-up of atopic dermatitis) requires

AMERICAN FAMILY PHYSICIAN treatment to resolve pruritus and limit spread of the molluscum.14 TINEA INFECTION Tinea is a common fungal skin infection in children that may affect the scalp (tinea capitis), body (tinea corporis), groin (tinea cruris), feet (tinea pedis), hands (tinea manus), or nails (tinea unguium). The diagnosis is based on physical examination findings and is confirmed by potassium hydroxide microscopy, periodic acidâ&#x20AC;&#x201C;Schiff staining of hair follicles, or fungal culture. Tinea capitis, the most common skin infection in children in the United States, is characterized by scaling or circumscribed alopecia and broken hair follicles (Figure 6). Posterior cervical lymphadenopathy is another useful finding to distinguish tinea capitis from other causes of alopecia. The characteristic lesion found in children with tinea corporis is an erythematous annular patch or plaque with a raised border and central clearing; scaling along the border is common (Figure 7). This lesion is often referred to as ringworm.15 Tinea capitis is treated with oral griseofulvin and terbinafine, depending on the most common etiologic agent in the geographic area. Tinea corporis is usually effectively treated with topical antifungals, with oral agents reserved for severe cases.15

Figure 6. Tinea capitis. Alopecia with broken hair follicles.

ATOPIC DERMATITIS Atopic dermatitis is a common childhood inflammatory skin disease that affects approximately 20% of children in the United States.16 This chronic, pruritic skin disease is relapsing in nature. Atopic dermatitis typically presents in infancy and early childhood and may persist into adulthood. Children may present with a variety of skin changes, including erythematous plaques and papules, excoriations, severely dry skin, scaling, and vesicular lesions (Figure 8).

Figure 7. Tinea corporis. Note the annular patch with central clearing and raised border.

Figure 8. Erythematous plaques and papules of atopic dermatitis. Excoriations on the flexor surfaces are common.

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AMERICAN FAMILY PHYSICIAN The distribution of atopic dermatitis lesions can vary based on the age of the child. Infants and younger children often have lesions on the extensor surfaces of extremities, cheeks, and scalp. Older children and adults often present with patches and plaques on the flexor surfaces (antecubital and popliteal fossa). Hands and feet are also commonly affected. Thickened plaques with a lichenified appearance may be seen in more severe cases. Children with atopic dermatitis often have dry, flaky skin and are at risk of secondary cutaneous infections.16 The treatment is aimed at controlling, not curing, the disease with parent counseling on good skin care (e.g., liberal use of emollients and avoidance of triggers, such as cold weather, frequent hot baths, fragrant products, and harsh detergents). Despite good skin care practices, topical corticosteroids are usually needed during flareups. Atopic lesions that do not respond to traditional therapies should be biopsied or cultured if there is concern for infection.16 Note: For complete article visit: www.aafp.org/afp. REFERENCES 1. Krowchuk DP, Bradham DD, Fleischer AB Jr. Dermatologic services provided to children and adolescents by primary care and other physicians in the United States. Pediatr Dermatol. 1994;11(3):199-203. 2. Yamanishi K, Okuno T, Shiraki K, et al. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet. 1988;1(8594):1065-1067.

4. Okada K, Ueda K, Kusuhara K, et al. Exanthema subitum and human herpesvirus 6 infection. Pediatr Infect Dis J. 1993;12(3):204-208. 5. González LM, Allen R, Janniger CK, et al. Pityriasis rosea: an important papulosquamous disorder. Int J Dermatol. 2005;44(9):757-764. 6. Chuh AA, Dofitas BL, Comisel GG, et al. Interventions for pityriasis rosea. Cochrane Database Syst Rev. 2007;(2):CD005068. 7. Drago F, Broccolo F, Rebora A. Pityriasis rosea: an update with a critical appraisal of its possible herpesviral etiology. J Am Acad Dermatol. 2009;61(2):303-318. 8. Ferri FF. Scarlet fever. In: Ferri’s Clinical Advisor. Philadelphia, Pa.: Elsevier; 2014. 9. Festekjian A, Pierson SB, Zlotkin D. Index of suspicion. Pediatr Rev. 2006;27(5):189-194. 10. Shulman ST, Bisno AL, Clegg HW, et al. Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis [published correction appears in Clin Infect Dis. 2014;58(10):1496]. Clin Infect Dis. 2012;55(10):e86-e102. 11. Lean WL, Arnup S, Danchin M, et al. Rapid diagnostic tests for group A streptococcal pharyngitis. Pediatrics. 2014;134(4):771-781. 12. Geria AN, Schwartz RA. Impetigo update. Cutis. 2010;85(2):65-70. 13. Servey JT, Reamy BV, Hodge J. Clinical presentations of parvovirus B19 infection. Am Fam Physician. 2007;75(3):373-376. 14. Brown J, Janniger CK, Schwartz RA, et al. Childhood molluscum contagiosum. Int J Dermatol. 2006;45(2):93-99.

15. Andrews MD, Burns M. Common tinea infections in children. Am Fam Physician. 2008;77(10):1415-1420. 3. Lampell MS. Childhood rashes that present to the ED part I: viral and bacterial issues. Pediatr Emerg Med Pract. 16. Wolter S, Price HN. Atopic dermatitis. Pediatr Clin North Am. 2014;61(2):241-260. 2007;4(3):1-24. ■■■■

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Practice Guidelines CDC RELEASES 2015 GUIDELINES ON THE TREATMENT OF SEXUALLY TRANSMITTED DISEASES The Centers for Disease Control and Pre vention (CDC) has updated its 2010 recommendations to help guide physicians in preventing and treating sexually transmitted diseases (STDs). This summary practice guideline will focus on the updates, which include yearly screening for hepatitis C virus (HCV) in persons with human immunodeficiency virus (HIV) infection; vaccine recommendations and counseling for persons with human papillomavirus (HPV); diagnostic assessment of urethritis; nucleic acid amplification tests (NAATs) for diagnosing trichomoniasis; alternative treatments for Neisseria gonorrhoeae and genital herpes simplex virus (HSV); the role of Mycoplasma genitalium in urethritis and cervicitis and implications of treatment; STD management in persons who are transgendered; and retesting for repeat STDs.

New and Updated Recommendations HCV Screening in Persons with HIV Infection Although HCV is most commonly transmitted through exposure to infected blood, it can also be transmitted through sexual contact, especially in persons with HIV infection. Serologic screening for HCV should be performed in all persons with HIV infection on initial assessment, and should be considered periodically thereafter, and at least annually in persons at high risk of HCV infection. Measurement of alanine transami nase is not recommended for testing; however, if a patient whose alanine transaminase levels are being monitored has increased levels, he or she should be tested for acute HCV infection. Additionally, because some persons with HIV infection do not have HCV antibodies, persons with liver disease of unknown etiology and who are anti-HCV negative should be evaluated for HCV infection using RNA testing.

Source: Adapted from Am Fam Physician. 2016;93(2):144-54.

Vaccines and Counseling in Persons with HPV Vaccines. The bivalent vaccine protects against HPV types 16 and 18, which are responsible for more than 65% of cervical cancers; the quadrivalent vaccine protects against HPV types 6 and 11, which are responsible for 90% of genital warts, as well as types 16 and 18; and the 9-valent vaccine protects against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58, which include the strains responsible for an additional 15% of cervical cancers. The vaccine is given in three doses over six months, with the second dose given one to two months after the first dose, and the third dose given six months after the first dose. For girls, it is recommended that any of the vaccines be given at 11 to 12 years of age, but boys 11 to 12 years of age should receive the quadrivalent or the 9-valent vaccine. In both groups, the vaccine can be given as early as nine years of age. Females 13 to 26 years of age and males 13 to 21 years of age in whom the vaccine series was not provided or not completed should receive the vaccine. It should be noted that the vaccine is not licensed or recommended for persons older than 26 years. Counseling. When providing counseling to persons with HPV infection, there are many important points of discussion. Most persons who are sexually active will be infected with HPV at some point; however, many will not be aware of it. The infection typically resolves spontaneously, with no associated health problems; however, when symptoms and problems do occur, they can lead to genital warts, precancers, and cancers of the cervix, anus, penis, vulva, vagina, head, and neck. An HPV infection that causes genital warts is not the same as the infection that causes cancers. These conditions can be treated; however, HPV itself has no treatment. There are also no tests to help determine which infections will resolve and which will progress. In some cases, however, a test can help detect if a woman is at increased risk of developing cervical cancer, but these tests do not identify other problems associated with HPV infection, and are not helpful in women younger than 25 years or men. Many kinds of HPV are transmitted through anogenital (vaginal and anal sex) and genital to genital contact and oral sex. Anogenital infection is common and can

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AMERICAN FAMILY PHYSICIAN affect other parts of the body (e.g., mouth, throat). HPV does not cause difficulty in achieving or maintaining pregnancy, but some cancers caused by HPV, as well as their treatments, may decrease a woman’s ability to get pregnant or to have an uncomplicated delivery. Rarely, HPV can be passed from an infected mother to her infant during delivery. If a patient and his or her partner both have HPV, it may not be feasible to determine where the infection originated, and it should be noted that infection does not necessarily mean that one or both partners are having a sexual relationship outside the existing one. Condoms, if used correctly, can also lower the risk of HPV infection and its related conditions, but it should be noted that HPV can infect other areas that a condom would not cover. Abstinence from sexual activity is the most reliable way to avoid HPV infection; limiting the number of sex partners can reduce risk, but even persons with only one partner can be infected. Diagnosis of Urethritis When diagnosing what is suspected to be urethritis, physicians should assess the patient for urethral inflammation. If point-of-care diagnostic tests such as Gram stain are unavailable, NAAT should be performed, and the patient should receive medications that treat gonorrhea and chlamydia. Urethritis can be diagnosed based on the presence of mucoid, mucopurulent, or purulent discharge; at least two white blood cells per oil immersion field on Gram stain or methylene blue/ gentian violet stain of urethral secretions; or positive findings on a leukocyte esterase test of first-void urine or first-void urine with at least 10 white blood cells per high-power field on microscopic examination of sediment from a spun first-void urine sample. Men who are determined to have urethritis based on Gram or methylene blue/gentian violet stain (suspected gonococcal negative) and those who have at least one criterion for urethritis, should be tested for chlamydia or gonorrhea with NAAT and treated as nongonococcal urethritis. Those who meet urethritis criteria without the use of Gram or methylene blue/gentian violet stain, should be tested with NAAT and treated for both gonorrhea and chlamydia. If a patient has symptoms, but no inflammation, testing with NAAT for chlamydia and gonorrhea might help to determine if these infections are present. Nongonococcal urethritis can have many causes, and can be diagnosed in men who present with symptoms and stains of urethral secretions that

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suggest inflammation without gram-negative or purple diplococci. If nongonococcal urethritis is confirmed, testing for chlamydia and gonorrhea should be performed, with NAATs preferred. Testing for Trichomonas vaginalis should be considered in locations with a high prevalence of the infection. NAATS for Trichomoniasis NAATs are highly sensitive and are preferred for diagnosing T. vaginalis. In women, NAATs can be performed on vaginal, endocervical, and urine specimens and can typically identify three to five times more infections compared with wet-mount microscopy. Alternative Treatments for Gonorrhea The recommended treatment for uncomplicated N. gonorrhoeae infection is a single 250-mg dose of intramuscular ceftriaxone plus a single 1-g dose of oral azithromycin. Several regimens of injectable cephalosporins are considered safe and effective to treat uncompli cated urogenital and anorectal gonococcal infections. These include a single 500-mg dose of intramuscular ceftizoxime; a single 2-g dose of intramuscular cefoxitin combined with 1 g of oral probenecid; and a single 500-mg dose of intramuscular cefotaxime. None of these have a specific advantage over ceftriaxone, and coverage against pharyngeal infections is not fully known. Only if ceftriaxone is unavailable, a single 400-mg dose of oral cefixime combined with a single 1-g dose of oral azithromycin can be considered as an alternative treatment option. Alternative Treatments for Genital Herpes Antiviral chemotherapy is beneficial in most persons with symptoms of genital herpes and is the main treatment used. Signs and symptoms of first and recurrent episodes of genital herpes can be somewhat controlled with systemic antiviral medications; these medications are also beneficial when used as daily suppressive therapy. Acyclovir, valacyclovir, and famciclovir have been shown to provide benefit; however, it should be noted that, after discontinuation, they do not eliminate latent virus or have an effect on the risk, frequency, or severity of recurrent infection. Topical therapy is generally discouraged. If treatment with antivirals fails in persons with HSV, they should be managed with guidance from an infectious disease expert and receive an alternative treatment; 40 to 80 mg per kg of intravenous foscarnet every eight hours until clinical resolution is typically

AMERICAN FAMILY PHYSICIAN beneficial for genital herpes with resistance to acyclovir. Also, 5 mg per kg of intravenous cidofovir once weekly may be an option. Topical imiquimod and cidofovir 1% are also options, although cidofovir must be compounded at a pharmacy. M. genitalium in Urethritis and Cervicitis M. genitalium is one cause of male urethritis, and can also be found in the vagina, cervix, and endometrium. Infections in women typically cause no symptoms. In persons with persistent or recurrent urethritis or cervicitis, M. genitalium may be suspected. Antibiotics aimed at cell-wall biosynthesis (e.g., penicillins, cephalosporins) are not effective. The seven-day doxycycline treatment recommended for urethritis is generally not effective for M. genitalium infection (median cure rate of 31%); the single 1-g dose of azithromycin is more effective and is preferred over doxycycline. It should be noted, however, that azithromycin resistance is quickly developing, with the latest study indicating a median cure rate of 40% (down from 85%). Longer treatment with azithromycin (500 mg initially, then 250 mg per day for four days) may be slightly better than the single-dose regimen; however, those persons in whom the single dose is not effective are not likely to experience benefits from the longer course. Moxifloxacin, in a dosage of 400 mg per day for seven, 10, or 14 days, has been effective for

M. genitalium infection in patients in whom treatment failed previously. It should be noted, however, that moxifloxacin has been used for treatment in only a couple of cases and it has not been evaluated in clinical trials. Although moxifloxacin has been considered generally effective, treatment failures have been reported after the seven-day regimen in Japanese, Australian, and U.S. studies. Persons who are Transgendered Physicians should know about each patient’s anatomy and sexual behaviors before providing STD and HIV prevention counseling. Because the surgical affirming procedures, hormone use, and sexual behaviors vary in persons who are transgendered, physicians should know the symptoms of common STDs and should perform STD screening in asymptomatic persons based on history of behavior and sexual practices (e.g., women may retain a functional penis, men may have a vagina and cervix). Retesting Retesting for chlamydia, gonorrhea, and trichomoniasis should be performed a few months after diagnosis; this assists with identifying repeat infection. Men and women who have chlamydia or gonorrhea, and women who test positive for trichomoniasis should be rescreened three months after being treated. Persons with syphilis should have follow-up testing based on current recommendations.

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Photo Quiz A VIETNAMESE CHILD WITH A RASH ON THE BACK A nine-year-old Vietnamese girl presented with an erythematous rash on her back that appeared suddenly one day prior. She also had upper respiratory tract symptoms, including nasal congestion, sore throat, nonproductive cough, and a fever of 102°F (38.9°C) for three days. Her history was otherwise unremarkable. On physical examination, the patient appeared acutely ill. She had erythematous nasal turbinates and bilateral anterior cervi cal lymphadenopathy. The lungs were clear to auscultation. There were linear erythematous lesions located on her posterior thorax (Figure 1). The lesions included petechiae and were nontender to palpation. She had no other skin lesions.

Question Based on the patient’s history and physical examination findings, which one of the following is the most likely diagnosis? A. Atopic dermatitis. B. Child abuse.

Figure 1.

C. Coining therapy. D. Contact dermatitis. E. Viral exanthem.

Source: Adapted from Am Fam Physician. 2016;93(2):131-2.

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SEE THE FOLLOWING PAGE FOR DISCUSSION.

AMERICAN FAMILY PHYSICIAN DISCUSSION

Summary Table

The answer is C: coining therapy. Coining therapy, or cao gio, is a traditional practice used by many Vietnamese, Cambodian, and Laotian persons.1 Mentholated oils are applied to various parts of the body, including the back, and then a coin is rubbed on the skin in a fishbone pattern. This can result in ecchymosis, petechiae, and mild skin burns.2 Coining is used to treat symptoms such as cough, nausea and vomiting, and viral illnesses.3 The diagnosis is clinical, through identification of the characteristic pattern of petechial, ecchymotic streaking lesions along the spine and ribcage.4 A thorough history is important to rule out other diagnoses, such as child abuse.

Condition

Characteristics

Exposure

Atopic dermatitis

Dry skin and pruritus; most commonly on flexor surfaces

Dry environment

Child abuse

Lesions in multiple areas at various stages of healing; suspicious injury pattern

Bruises, bites, burns, fractures, abdominal and head trauma

Coining therapy

Medicated oil and Petechial to ecchymotic lesions; coin rubbing fishbone pattern on the back

Contact dermatitis

Sharply demarcated; erythema and superficial edema over area of exposure

Exposure to an agent, such as soaps, detergents, other cleaners, industrial solvents, acids or alkaline materials, fiberglass, mold

Viral exanthem

Maculopapular; starts centrally and progresses centrifugally

Viral illnesses

Atopic dermatitis is characterized by dry skin and pruritus. It is common in infancy, but the incidence is only 10% between six and 20 years of age. Its distribution is mostly on the flexor surfaces.2 Child abuse should be suspected if the history provided by the caregiver does not explain the child’s injuries, the history changes over time, there is history of self-inflicted trauma that does not correlate with development, or there is an inappropriate delay in seeking care.5 The possibility of abuse should also be pursued if there are injuries to multiple areas of the body, injuries in various stages of healing, or suspicious injury patterns.5 Contact dermatitis can occur after exposure to many agents, including soaps, detergents, other cleaners, industrial solvents, acids and alkali materials, fiberglass, and mold. Subjective symptoms occur within seconds of exposure or can be delayed up to eight to 24 hours. Lesions are localized to the area of exposure and include erythema and edema. The lesions evolve from erythema to vesicles, erosion, and then crusting. More severe contact dermatitis may result in necrosis.2 Many viruses can cause rashes in children, but the distribution of this child’s rash is not typical of an exanthem. Viral rashes are initially discrete and usually appear as pink papules and macules. They often start centrally and progress centrifugally, becoming confluent.2

REFERENCES 1. Davis RE. Cultural health care or child abuse? The Southeast Asian practice of cao gio. J Am Acad Nurse Pract. 2000;12(3):89-95. 2. Wolff K, Johnson R, Saavedra A, Fitzpatrick TB, eds. Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology. 7th ed. New York, NY: McGraw-Hill; 2013. 3. Shukla R. Dermatology’s changing face…and body. Practices adapt to demographic and racial shifts. American Academy of Dermatology. Young Physician Focus. Fall 2012. https://www.aad.org/file%20library/ global%20navigation/member%20tools%20and%20 benefits/publications/ypf/fall-2012-ypf.pdf. Accessed October 22, 2015. 4. Greenberg M. Greenberg’s Text-Atlas of Emergency Medicine. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2005:938.

5. McDonald KC. Child abuse: approach and management. Am Fam Physician. 2007;75(2):221-228. ■■■■

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A Comparative Study of Intravenous Lignocaine Hydrochloride and Dexmedetomidine in Prevention of Pain Due to Propofol Injection: A Double-blind Randomized Controlled Study BIPIN ARYA*, ANKESH†, ATUL DIXIT‡, SADHANA SANWATSARKAR#, PRACHI LAAD$, POOJA JAIN†

ABSTRACT Propofol is a very good and potent induction agent for general anesthesia and is the first choice of the anesthesiologists but the pain during intravenous (IV) injection is a serious drawback. To attenuate this pain, lignocaine, a local anesthetic is used for sometime but dexmedetomidine, an α1 agonist has been reported to be useful for the purpose and considering this property. A double-blind randomized controlled study was carried out in total of 90 patients, ASA I and II, aged between 18-70 years, undergoing general anesthesia. Total number of subjects were divided in groups of 30 patients each (n = 30). Group A - 5 mL of normal saline, Group B - lignocaine 0.5 mg/kg in 5 mL NS, Group C - dexmedetomidine 0.25 μg/kg in 5 mL NS. McCrirrik and Hunter scale was used to evaluate pain due to IV propofol. It was found to be 83.3% in control group. Pre-treatment with lignocaine and dexmedetomidine showed statistically significant reduction in incidence of pain and it was observed that lignocaine and dexmedetomidine were effective in decreasing the severity of pain and are comparable statistically and dexmedetomidine can be used as an alternative to lignocaine for the purpose of reducing pain due to IV propofol.

Keywords: Intravenous, lignocaine, dexmedetomidine, propofol, pain

ain interferes with a person’s quality-of-life and general functioning. Pure antinociception without side effects has long been an elusive goal. Pain has been the associated in 28-90% of patients, receiving propofol intravenously (IV).1-3 Despite various methods to reduce propofol injection, pain-effective methods have not been identified. Propofol, 'Blue-eyed boy' of most anesthesiologist’s had been jinxed due to its pain on injection.4 Various

*Assistant Professor †PG Resident ‡Professor #Professor and Head $Senior Resident Dept. of Anesthesiology Sri Aurobindo Medical College and PG Institute Indore, Madhya Pradesh Address for correspondence Dr Ankesh Dept. of Anesthesiology Sri Aurobindo Medical College and PG Institute Indore, Madhya Pradesh E-mail: ajit_igims@yahoo.co.uk

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drug have been used as pre-treatment to alleviate pain due to propofol like, ondansetron,5 ketamine6 and lignocaine.7,8 Dexmedetomidine has also been used by researchers for the purpose.9,10 AIMS AND OBJECTIVES ÂÂ

To compare and evaluate efficacy of lignocaine and dexmedetomidine in prevention of pain due to propofol injection.

ÂÂ

Incidence and severity of pain on IV injection of propofol.

ÂÂ

Effect of lignocaine and dexmedetomidine pretreatment in attenuating pain due to propofol injection.

ÂÂ

Recall of pain by patient after surgery.

MATERIAL AND METHODS The study was conducted on patients posted for elective surgical procedures under general anesthesia, Sri Aurobindo Medical College, Indore, after approval by Institutional Ethical Committee.

ANESTHESIOLOGY Sample Size Estimation ÂÂ Keeping alpha error of 0.05, power of 0.85, 26 patients were required in each group. Keeping in mind natural dropouts, 30 patients in each group were taken of American Society of Anesthesiologists (ASA) Group I and II between the age group of 18-70 years. ÂÂ Group A (n = 30) = Saline pre-treatment (control group). ÂÂ Group B (n = 30) = Lignocaine pre-treatment. ÂÂ Group C (n = 30) = Dexmedetomidine pre-treatment. McCrirrik and Hunter scale9 was used for scoring the severity of pain and level of attenuation by various drugs. Interventional Plan ÂÂ

ÂÂ

On arrival to preoperative room zz

20 g IV cannula was placed on dorsum of nondominant hand.

Monitors were attached and vitals recorded.

Patient shifted to OR zz

Arm with IV line was elevated for 15 seconds for gravity drainage of venous blood.

A pneumatic tourniquet was placed on same upper arm with pressure inflated to 70 mmHg to produce a venous occlusion (venipuncture mode).

Group A - 5 mL of normal saline (n = 30).

Group B - Group lignocaine (n = 30) 0.5 mg/kg diluted in 5 mL of NS.

Group C - Group dexmedetomidine (n = 30) 0.25 μg/kg in 5 mL of NS.

Drug was injected and tourniquet was left inflated for 2 minutes. After release of the tourniquet 25% of induction dose of propofol was administered.

Occurrence and severity of pain was assessed.

Tracheal intubation and balanced general anesthesia followed as per standard protocol.

Degree of pain Response None (0)

No response to questioning

Mild (1)

Pain reported in response to questioning only, without any behavioral signs

Moderate (2)

Pain reported in response to questioning and accompanied by a behavioral sign or pain reported spontaneously without questioning

Severe (3)

Strong vocal response or response accompanied by facial grimacing, arm withdrawal or tears

Baseline Characteristics of the Study Subjects The age of the patients ranged from 18 to 70 years. On comparing the data statistically, no significant difference was observed among the groups (p = 0.658) (Table 2). Male-to-female ratio in all three groups was comparable (Table 3). Distribution of mean weight among three groups was not statistically significant (Table 4). Table 1. Group-wise Distribution of Subjects Group

Drug (premedication)

No. of patients

Saline

33.3

A B

Lignocaine

33.3

Dexmedetomidine

33.3

Table 2. Age-wise Distribution of Subjects in Different Groups Group

Age range

Mean ± SD

P value P = 0.65

22-70

47.2 ± 10.15

20-70

37.9 ± 11.10

18-70

42.3 ± 11.00

Table 3. Sex-wise Distribution of the Subjects in Different Groups Sex

Saline

Lignocaine

Dexmedetomidine

Observations

Male

43.33

46.66

56.67

Female

56.67

53.33

43.33

The following parameters were observed and recorded: Scale for evaluation of propofol injection pain (McCrirrik and Hunter scale). Patients were followed up in recovery room and asked for recall, if there was pain during injection. Incidence of recall of pain was graded as:

Table 4. Weight-wise Distribution of Subjects in Different Groups No. of patients

Mean Wt ± SD (kg)

P value

60 ± 7.21

P = 0.74

0 - No recall of pain

59.83 ± 7.13

56.9 ± 8.17

1 - Recall of pain

Group

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ANESTHESIOLOGY RESULTS

DISCUSSION

Incidence of pain due to propofol was found to be 83.3% in control group. Premedication with lignocaine and dexmedetomidine showed statistically significant reduction in incidence of pain (Table 5.1 and 5.2). Incidence of pain in Group B and Group C was 30% and 23.3%, respectively. The difference in incidence of pain between Group B and C was not statistically significant (Table 5.3). Comparing the severity of pain among three groups, 50% of patients in Group A, while none in Group B and Group C felt severe pain (pain score 3). Only 16.7% of patients of Group A while 70% and 76.7% of Group B and Group C, respectively felt no pain (pain score 0). Incidence of side effects was comparable in all the three groups. Although incidence of hypotension and dizziness was comparable in all the groups. Postoperative nausea and vomiting (PONV) was not seen in Group B and Group C (Table 6).

In our study, incidence of pain in (placebo-saline) Group A was found to be 83.3% and that in Group B was 30% and Group C was 23.3%. On comparing, all the groups incidence of pain was highly significant in Group A (p < 0.001). No patient in pre-treatment group experienced severe pain. Similar study by Zahedi et al reported overall incidence of pain to be 82.2% in the saline group and concluded that pain intensity was significantly less in patients receiving drugs for pretreatment (p = 0.001).5

Table 5.1. Incidence of Pain During Propofol Injection in Group A and B Saline

Lignocaine

Pain present

83.3

Pain absent

16.7

P value P < 0.001

χ2 = 17.36

Table 5.2. Incidence of Pain During Propofol Injection in Group A and C Saline

Lignocaine

P value

Pain present

83.3

23.3

Pain absent

16.7

76.7

χ2 =

P < 0.001

21.69

In a study by Turan et al incidence of pain in saline group (Group I) was 86.66% and that in Group II (lignocaine) was 33.3% and in Group III (dexmedetomidine) was 23.33%, which is similar to our finding. Study by He et al shows dexmedetomidine an effective choice for pre-treatment to alleviate pain but at the same time.9 Ayoglu et al found no benefit of pre-treatment with dexmedetomidine.10 Lignocaine, the most used drug has been found to be effective and still drug of choice for pre-treatment and in my study also lignocaine has slight edge over dexmedetomidine, though insignificant. Incidence of adverse reactions was negligible. Most common side effect was hypotension, but the on the whole these incidences were negligible. The incidence of recall of pain was reported to be 66.7% in Group A (placebo), 13.3% in Group B (lignocaine) and 23.3% in, Group C (dexmedetomidine). The difference of recall of pain between Group A (placebo) and Group B was highly significant statistically (p < 0.001), difference between Group A and Group C (dexmedetomidine) is also highly significant (p < 0.001). There was no significant difference between Group B and Group C (p > 0.05). CONCLUSION

Table 5.3. Incidence of Pain During Propofol Injection in Group B and C

Lignocaine Dexmedetomidine N

Pain present

23.3

Pain absent

76.7

P value P < 0.559

Table 6. Incidence of Any Side Effect Side effect group Saline Lignocaine Dexmedetomidine

122

PONV Hypotension Dizziness Other 2 Nil Nil

5 4 5

1 1 1

Indian Journal of Clinical Practice, Vol. 27, No. 2, July 2016

Lignocaine and dexmedetomidine were effective in decreasing the severity of pain.

ÂÂ

Dexmedetomidine effectively reduced pain on propofol injection.

ÂÂ

Effects of lignocaine and dexmedetomidine are comparable statistically.

ÂÂ

Dexmedetomidine can be used as an alternative to lignocaine for the purpose of reducing propofol pain.

ANESTHESIOLOGY REFERENCES 1. Singh D, Jagannath S, Priye S, Shivaprakash, Kadli C, Reddy D. Prevention of propofol injection pain: Comparison between lidocaine and ramosetron. J Anaesthesiol Clin Pharmacol. 2014;30(2):213-6. 2. Jalota L, Kalira V, George E, Shi YY, Hornuss C, Radke O, et al; Perioperative Clinical Research Core. Prevention of pain on injection of propofol: systematic review and metaanalysis. BMJ. 2011;342:d1110. 3. Kang HJ, Kwon MY, Choi BM, Koo MS, Jang YJ, Lee MA. Clinical factors affecting the pain on injection of propofol. Korean J Anesthesiol. 2010;58(3):239-43. 4. Fechner J, Schwilden H, Schüttler J. Pharmacokinetics and pharmacodynamics of GPI 15715 or fospropofol (Aquavan injection) - a water-soluble propofol prodrug. Handb Exp Pharmacol. 2008;(182):253-66.

6. Thukral S, Gupta P, Lakra A, Gupta M. Dexmedetomidine versus ketamine infusion to alleviate propofol injection pain: A prospective randomized and double-blind study. Indian J Anaesth. 2015;59(8):488-92. 7. Madenoglu H, Yildiz K, Dogru K, Boyaci A. Efficacy of different doses of lidocaine in the prevention of pain due to propofol injection: a randomized, open-label trial in 120 patients. Curr Ther Res Clin Exp. 2003;64(5):310-6. 8. Picard P, Tramèr MR. Prevention of pain on injection with propofol: a quantitative systematic review. Anesth Analg. 2000;90(4):963-9. 9. He L, Xu JM, He T, Liu L, Zhu R. Dexmedetomidine pretreatment alleviates propofol injection pain. Ups J Med Sci. 2014;119(4):338-42. 10. Ayoğlu H, Altunkaya H, Ozer Y, Yapakçi O, Cukdar G, Ozkoçak I. Does dexmedetomidine reduce the injection pain due to propofol and rocuronium? Eur J Anaesthesiol. 2007;24(6):541-5.

5. Zahedi H, Maleki A, Rostami G. Ondansetron pretreatment reduces pain on injection of propofol. Acta Med Iran. 2012;50(4):239-43. ■■■■

CDC Awards $26 Million to Academic Medical Centers, Drives Innovation to Protect Patients The Centers for Disease Control and Prevention (CDC) has awarded $26 million to support applied research at five academic medical centers as part of a patient safety effort known as Prevention Epicenters Program. Together with CDC, these Prevention Epicenters develop and test innovative approaches to preventing infections and improving patient safety in healthcare settings. The new funding more than doubles previous awards and expands and extends the Prevention Epicenters program to 2020. Examples of new research the Epicenters are conducting to prevent healthcare-associated infections (HAIs) and the spread of dangerous bacteria include: ÂÂ

Determining factors that predict which patients in intensive care units (ICUs) will become colonized with an antibiotic-resistant germ, specifically looking at the role of environmental and personal microbiomes

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Discovering how antibiotics disrupt the gut microbiome of ICU patients, putting them at risk for infections

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Testing new strategies for regional, rather than single-facility, approaches to prevent infections and track transmission of antibiotic-resistant germs, including carbapenem-resistant Enterobacteriaceae (CRE)

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Finding the best way to disinfect patient skin to prevent infections in ICU patients

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Determining how microbiome restoration can treat infections caused by antibiotic-resistant germs

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Automatically detecting outbreaks from lab data.

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A Rare Case of Infective Endocarditis by Mycobacterium abscessus (NTM) VISHAL SADATIA*, MAYANK THAKKAR*, TUSHAR PATEL*

ABSTRACT We report a case of naive bicuspid aortic valve endocarditis due to Mycobacterium abscessus in an immunocompetent patient. The diagnosis was based on culture isolation of acid-fast bacilli from peripheral blood, and their identification as M. abscessus by a LPAM (Reverse Phase Hybridization) revealing an amplification product of fragment of 230 bp within 23S rRNA gene. These are rapidly growing mycobacterium. Immediate diagnosis and combination therapy are essential to minimize mortality due to this pathogen. Combination therapy was started with clarithromycin, moxifloxacin and linezolid. The patient became afebrile after therapy and underwent aortic valve replacement. This report shows that M. abscessus should also be considered in the differential diagnosis of infective endocarditis.

Keywords: Infective endocarditis, acid-fast bacilli, M. abscessus, naive bicuspid aortic valve

rare case of naive valve endocarditis in post coronary angiography patient with no previous history of abnormal valves or heart murmur. Application of molecular methods identified the etiological agent as Mycobacterium abscessus. Nontuberculous mycobacterial disease occurs infrequently in immunocompetent individuals. Despite their ubiquitous presence in soil and water, the occurrence of various nontuberculous mycobacteria (NTM) species varies greatly by geographic region. Based on their growth rates, NTM have been classified into slowly growing or rapidly growing mycobacteria. Rapidly growing mycobacteria grow within 7 days on solid media. More than 70% of rapidly growing mycobacterial infections are attributed to M. abscessus, Mycobacterium fortuitum and Mycobacterium chelonae. However, conventional methods are time-consuming and do not reliably differentiate some species such as M. abscessus and M. chelonae. CASE REPORT A 40-year-old male patient from Qatar (UAE), with no significant past medical history of major medical

*Consultant Intensivist and Critical Care Physician Shree Giriraj Hospital, Rajkot, Gujarat Address for correspondence Dr Vishal Sadatia 27, Navjyot Park Corner, 150 Feet Ring Road, Rajkot, Gujarat E-mail: drvvsadatia@gmail.com

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illness presented with a prolonged pyrexia, abdominal pain, cough which had remained undiagnosed and unresponsive to standard antimicrobial treatment. A history of coronary angiography had been performed 3 months earlier, which showed normal coronary anatomy. Since last 8 weeks, patient developed moderate to high-grade fever for which standard investigations, routine blood cultures, and imaging were performed and were inconclusive. He was transferred to our care with his febrile illness and no clear diagnosis. On examination, the patient was febrile and lethargic. The investigations revealed hemoglobin - 12.6 g/dL, white blood cells - 6,400 cells/mm3, platelets 3.34,000/mm3, serum creatinine level - 0.9 mg/dL and erythrocyte sedimentation rate (ESR) - 49 mm/hour. Urine analysis showed - 3-5 red blood cells/hpf. On ultrasonography, the kidney size were normal with mild hepatosplenomegaly but there was no evidence of focal lesions in the spleen or liver. Chest roentgenogram revealed mildly prominent pulmonary vasculature but no significant lung parenchymal pathology. The 2-dimensional echocardiography (2D Echo) done at previous hospital showed functional bicuspid aortic valve with aortic valve endocarditis and left ventricular ejection fraction (LVEF) 60%. There was no evidence of cusp perforation or any ring abscess. The other cardiac valves were normal. Transesophageal echo confirmed the above findings. Antinuclear antibodies (anti-ANA), anti-double stranded DNA (anti-dsDNA) antibodies and antinucleophilic cytoplasmic antibodies (anti-ANCA)

CARDIOLOGY were negative and complement levels (C3 and C4) were within the normal range. The thyroid profile was normal. Computed tomography (CT) abdomen showed bulky kidneys with changes of acute kidney injury. The patient was treated for infective endocarditis and was started on ceftriaxone at a dose of 2 g twice-daily and vancomycin 1 g twice-daily intravenously as empirical treatment for infective endocarditis. Routine serial bacterial blood cultures did not show any growth. Procalcitonin was negative Bactec Myco/F Lytic medium was used, which demonstrated the rapidly growing organisms nontubercular mycobacterium. Linezolid, moxifloxacin and clarithromycin were empirically added while awaiting the sensitivity and speciation of the NTM. Meanwhile, species identification using the line probe assay technique revealed the organism to be M. abscessus and drug sensitivities were subsequently obtained. The organism was found to be sensitive to amikacin, clarithromycin, linezolid, tobramycin, cefoxitin but was found to be resistant to imipenem, ceftriaxone, minocycline and amoxicillin-clavulanic acid. The three antibiotics (linezolid, moxifloxacin and clarithromycin) were continued. Initially, serum creatinine increased up to 2.6 then came down after 3 weeks of therapy with the combination of 3 antibiotics. The valvular vegetations; however, were present and aortic valve replacement surgery was considered and performed when patient became afebrile. A repeat 2D Echo at 4 weeks post-treatment, showed no vegetation and the patient was discharged. DISCUSSION Tuberculous valvular endocarditis is exceptionally rare; only 16 cases have been reported in the literature. It usually presents in the context of miliary tuberculosis, and in all but one case the diagnoses were made at autopsy. The rare cases reported involved congenital defects of the aortic valves, prosthetic valves and ventriculoatrial shunts. Nontuberculous mycobacterial endocarditis involves mostly porcine or prosthetic valves. We found seven cases of prosthetic valve endocarditis due to M. chelonae. Six cases of prostheticvalve endocarditis due to M. fortuitum. One case of prosthetic-valve endocarditis due to Mycobacterium gordonae and one case of Mycobacterium avium intracellulare-induced naive-valve endocarditis. To our knowledge, only two cases involving damaged naive valves have been reported. Post-procedure mycobacterial infections have been often reported, especially in India where glutaraldehyde is used as a

sterilizing solution for surgical and other equipments. Cardiac catheterization is now increasingly performed in smaller centers. Risk factors for bacteremia following catheterization include obesity, duration of the procedure, the number of balloons used and the number of skin punctures performed. The disease occurs within 6 months of valve replacement and can be traced to valve contamination at surgery. In some cases, Mycobacterium spp. were found to contaminate porcine valves after inadequate sterilization during manufacturing and storage. Other cases have been associated with sternal wound infections following surgery. Infections complicating coronary angiography include sepsis, endocarditis, suppurative pancarditis, stent infection, septic arthritis, epidural abscess, necrotizing fasciitis and groin wound infection. The most common causative organism of bacteremia following cardiac catheterization is Staphylococcus aureus, particularly in the obese. Naive valve endocarditis with NTM such as M. abscessus is rare and often missed without appropriate blood cultures. In cases of post-procedure endocarditis, the aortic valve is predominantly affected (as seen in our case). Early diagnosis and prolonged combination therapy are obligatory to minimize mortality, as M. abscessus is inherently resistant to multiple antibiotics. Although there are no specific drug protocols for treatment of pulmonary M. abscessus disease, a macrolidebased regimen is often used combined with surgical debridement for successful therapy. Evidence-based management for other nonpulmonary diseases and specifically for M. abscessus endocarditis is lacking due to sheer rarity of the condition and treatment is based on in vitro drug susceptibility. Linezolid and imipenem are also effective against nearly 50% of clinical isolates. Combination therapy is mandatory and should be administered for at least 2-4 months. Tigecycline and linezolid are newer antibiotics with efficacy against M. abscessus and the recommended treatment length with these drugs is 6-12 months. Endocarditis caused by M. abscessus generally has a very poor prognosis despite combination antimicrobial therapy, as only two of the 10 documented cases described in the literature have survived after treatment. Surgical intervention to replace the infected valve would have been worth attempting if the patient had been willing. As in our case, patient underwent aortic value replacement surgery and at present, after 3 months, he is absolutely healthy.

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CARDIOLOGY SUGGESTED READING 1. Nessar R, Cambau E, Reyrat JM, Murray A, Gicquel B. Mycobacterium abscessus: a new antibiotic nightmare. J Antimicrob Chemother. 2012;67(4):810-8. 2. Petrini B. Mycobacterium abscessus: an emerging rapidgrowing potential pathogen. APMIS. 2006;114(5): 319-28. 3. Cope AP, Heber M, Wilkins EG. Valvular tuberculous endocarditis: a case report and review of the literature. J Infect. 1990;21(3):293-6. 4. Geraci JE, Anderson M, Karlson AG. Endocarditis due to a rapidly growing chromogenic Mycobacterium. Mayo Clin Proc. 1968;43(2):124-33. 5. Singh M, Bofinger A, Cave G, Boyle P. Mycobacterium fortuitum endocarditis in a patient with chronic renal failure on hemodialysis. Pathology. 1992;24(3):197-200. 6. Landymore RW, Murphy DA, Marrie TJ, Johnston BL. Mycobacterium avium-intracellulare endocarditis causing rupture: replacement and repair with aortic homograft. Can J Cardiol. 1992;8(7):729-32. 7. Lohr DC, Goeken JA, Doty DB, Donta ST. Mycobacterium gordonae infection of a prosthetic aortic valve. JAMA. 1978;239(15):1528-30. 8. Lombardo JA, O'Rourke MF, Shanahan MX, Harkness JL. Endocarditis due to an atypical mycobacterium following porcine heart valve replacement. Aust N Z J Med. 1980;10(4):432-4.

9. Kuritsky JN, Bullen MG, Broome CV, Silcox VA, Good RC, Wallace RJ Jr. Sternal wound infections and endocarditis due to organisms of the Mycobacterium fortuitum complex. Ann Intern Med. 1983;98(6):938-9. 10. Rumisek JD, Albus RA, Clarke JS. Late Mycobacterium chelonei bioprosthetic valve endocarditis: activation of implanted contaminant? Ann Thorac Surg. 1985;39(3):277-9. 11. Spell DW, Szurgot JG, Greer RW, Brown JW 3rd. Native valve endocarditis due to Mycobacterium fortuitum biovar fortuitum: case report and review. Clin Infect Dis. 2000;30(3):605-6. 12. Shaw JP, Eisenberg MJ, Azoulay A, Nguyen N. Reuse of catheters for percutaneous transluminal coronary angioplasty: effects on procedure time and clinical outcomes. Catheter Cardiovasc Interv. 1999;48(1):54-60. 13. Mahajan S, Mishra V, Sorabjee J. Mycobacterium abscessus: causing fatal endocarditis after cardiac catheterization. J Postgrad Med. 2015;61(2):131-3. 14. Jayasuriya S, Movahed MR. Infectious endocarditis with systemic septic embolization as a rare complication of cardiac catheterization. Exp Clin Cardiol. 2009;14(1):e17-20. 15. Gayathri R, Therese KL, Deepa P, Mangai S, Madhavan HN. Antibiotic susceptibility pattern of rapidly growing mycobacteria. J Postgrad Med. 2010;56(2):76-8.

16. Tsai WC, Hsieh HC, Su HM, Lu PL, Lin TH, Sheu SH, et al. Mycobacterium abscessus endocarditis: a case report and literature review. Kaohsiung J Med Sci. 2008;24(9):481-6. ■■■■

FDA Advisory Committee Narrowly Okay Empagliflozin Cardiovascular Mortality Claim The Endocrinologic and Metabolic Drugs Advisory Committee voted 12-11 on June 28 that the data in the EMPA-REG OUTCOME study provided substantial evidence to establish that empagliflozin, sodium-glucose cotransporter-2 (SGLT-2), reduced cardiovascular mortality in the population studied, those with type 2 diabetes and established cardiovascular disease.

Early Removal of Nanostim Leadless Pacemaker is Safe A new research presented June 8, 2016 at the recent European Heart Rhythm Association (EHRA) EUROPACECARDIOSTIM 2016 meeting in Nice, France has shown that it is feasible and safe to remove the Nanostim leadless pacemaker (St Jude Medical) up to 3.2 years after implantation. The procedural success rate was 93.3% among 15 patients who underwent a retrieval attempt at a mean of 256 days (range 1-1188 days) at 12 centers with 12 different operators.

Sacubitril-valsartan Cost-effective in Patients with Low-EF Heart Failure Treatment with the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan (Entresto, Novartis) is as cost-effective as other high-value and accepted cardiovascular interventions used in practice today, and its use should be optimized in the setting of heart failure with reduced ejection fraction (HFrEF), suggests a new analysis of the PARADIGM-HF trial published June 22 in JAMA Cardiology.

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2016

DIABETOLOGY

SGLT2 Inhibitors: A Novel Therapy for Type 2 Diabetes Mellitus PG RAMAN

ABSTRACT Sodium-linked glucose transporter (SGLT)2 inhibitors are new antidiabetic drugs with an insulin-independent mechanism of action. They increase urinary glucose excretion without inducing hypoglycemia, thereby promoting body weight reduction due to loss of ~300 kcal/day. Several drug candidates have been developed or are currently undergoing clinical trials, including dapagliflozin, canagliflozin, ipragliflozin, tofogliflozin, empagliflozin, remogliflozin etabonate and ertugliflozin. Of these dapagliflozin and canagliflozin have been launched in India recently.

Keywords: SGLT2 inhibitors, insulin-independent mechanism, dapagliflozin, canagliflozin

odium-linked glucose transporter (SGLT)2 inhibitors are new antidiabetic drugs with an insulin-independent mechanism of action. They increase urinary glucose excretion without inducing hypoglycemia, thereby promoting body weight reduction due to loss of ~300 kcal/day.1

Several drug candidates have been developed or are currently undergoing clinical trials, including dapagliflozin, canagliflozin, ipragliflozin, tofogliflozin, empagliflozin, remogliflozin etabonate and ertugliflozin.2 REGULATION OF GLUCOSE HOMEOSTASIS BY THE KIDNEYS3 The kidneys regulate the homeostasis of numerous substances of the body. The role of the kidneys in glucose metabolism is important and includes, gluconeogenesis, glucose utilization, glucose filtration and reabsorption.4 Daily 180 g is filtered and recovered afterwards. This mechanism was important for survival in times of food scarcity. Glucose recovery is mediated by a tubular transport system that can reabsorb glucose in combination with sodium. This mechanism is not

Ex-Professor and HOD MGM Medical College, Indore, Madhya Pradesh Address for correspondence Dr PG Raman 72, Dhar Kothi, Indore - 452 001, Madhya Pradesh E-mail: drpgraman@yahoo.com

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an unique feature of renal tubules, but also exists in other organs, such as the intestine. Whereas in the gastrointestinal tract especially SGLT1 is expressed, renal tubules express SGLT2.5 Both transporters are able to reabsorb glucose. However, they show significant differences in affinities and transport capacity: SGLT2 has a greater transport capacity and reabsorbs glucose in combination with sodium in the ratio 1:1. SGLT1 has a higher affinity for glucose and reabsorbs glucose in combination with sodium in the ratio 1:2. These different transport properties are used by the kidneys to reabsorb all energy, leading to glucose-free urine. SGLT2 is localized mainly in the first two segments of the proximal tubular system (S1 and S2 segment). Owing to its high transport capacity, it is capable of reabsorbing about 90% of glucose from the urine. Ten percent of initially filtered glucose is recovered in the third section of the proximal tubule (S3 segment) by SGLT1 because of its high affinity. Both transporters are secondarily active owing to their dependence on the activity of the Na+/K+-ATPase in the basolateral membrane for the active removal of sodium. Glucose transporters (GLUT2 and GLUT1) facilitate glucose transport across the basolateral membrane in the early and more distal regions of the proximal tubule.6 Inhibition of the SGLT transport system results in increased urinary glucose excretion due to reduced glucose reabsorption. As a consequence plasma glucose levels are lowered, resulting in loss of calories.

DIABETOLOGY Table 1. The Salient Features of SGLT2 Inhibitors, Canagliflozin and Dapagliflozin Canagliflozin

Dapagliflozin

Indication

T2DM

Dose

100-300 mg

5-10 mg

Renal impairment

Contraindicated in end-stage renal disease

Hepatic disorders

Not to be used

Drug interaction

With digoxin

No significant interaction

Oral administration

Prior to first meal

Morning with/without food

Pharmacokinetics

Onset of action within 24 hours

90% protein bound

91% protein bound

Oral bioavailability 65%

Oral bioavailability 78%

Half-life 13.1 hours

Half-life 12 hours

Hyperkalemia

UTI and genital infection

Adverse reactions

UTI UTI = Urinary tract infection.

Table 2. SGLT2 Inhibitors Advantages

Disadvantages

Acts by noninsulin pathway

Genital infection

Weight loss

UTI

BP reduction

Hypotension

No hypoglycemia

Hyperkalemia

SGLT2 INHIBITION In type 2 diabetes mellitus (T2DM), renal glucose handling and transport is increased, likely due to upregulation of SGLT2. As a result, glucose excretion in the urine occurs only at higher plasma glucose levels, causing conservation of glucose and prolongation of hyperglycemia. Inhibition of SGLT2 activity reduces reabsorption of filtered glucose and lowers the blood glucose concentration at which glucose is no longer reabsorbed from the proximal tubule but is instead excreted. This concentration is known as the renal threshold for glucose.7-9 The salient features of canagliflozin and dapagliflozin, the two SGLT2 inhibitors are summarized in Table 1. The advantages and disadvantages of SGLT2 inhibitors are given in Table 2. PHARMACOKINETICS OF CANAGLIFLOZIN8 Canagliflozin has an oral bioavailability of 65% with a maximum effect after 30-120 minutes. Its pharmacokinetic profile is independent of age, body weight, gender, ethnicity and administration with food. Importantly, the amount of glucose filtered in

the glomerulus depends not only on plasma glucose levels, but also on the glomerular filtration rate (GFR). Therefore, it can be expected that with decreasing renal function a decrease of activity is paralleled. Unlike with other antidiabetic drugs, such as metformin or glimepiride, with impaired renal function there is no risk to the patient, but the treatment becomes gradually ineffective. As a consequence, canagliflozin therapy should not be initiated in patients with end-stage renal disease, on dialysis or with renal impairment at an estimated GFR 60 mL/min/1.73 m2. PHARMACOLOGY OF CANAGLIFLOZINâ&#x20AC;&#x201D;EFFECTS ON GLUCOSE METABOLISM, BODY WEIGHT AND THE CARDIOVASCULAR SYSTEM10,11 Canagliflozin is a competitive, reversible, highly selective SGLT2 inhibitor with a 250-fold selectivity towards SGLT2 over SGLT1. Inhibition of SGLT2 by canagliflozin leads to a reduction of glucose reabsorption. The induced glucosuria of ~70 g/day results in a loss of glucose and optimized plasma glucose control. Canagliflozin is indicated in patients with T2DM to improve glycemic control as monotherapy and in patients for whom the use of metformin is considered inappropriate owing to intolerance or contraindications. It is indicated as add-on therapy with other antihyperglycemic medicinal products including insulin. In poorly controlled diabetic patients even a reduction of up to - 2.42% was achieved. The favorable effect on glycosylated hemoglobin (HbA1C) values was consistent with an improvement

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DIABETOLOGY of secondary endpoints such as fasting plasma glucose. The efficacy of canagliflozin was reduced in patients with moderate renal impairment. The weight loss is caused by loss of fat mass and not osmotic diuresis. The weight reducing characteristics of SGLT2 inhibitors in T2DM patients also might be effective in nondiabetic overweight subjects. This creates the option to widen the indication for the use of SGLT2 inhibitors as antiobesity drugs. SAFETY OF

CANAGLIFLOZIN12,13

ÂÂ

Low risk for hypoglycemia.

ÂÂ

Carbohydrate malabsorption.

ÂÂ

Increased calcium absorption from the gut probably causing hyperosteosis and renal tubular tumors in rats.

ÂÂ

Urinary tract infections.

ÂÂ

Female mycotic genital infections.

ÂÂ

Osmotic diuresis and subsequent water loss.

ÂÂ

Decrease in blood pressure and increased in hemoconcentration reflected by increased hemoglobin and hematocrit.

ÂÂ

Dehydration and unstable blood pressure or syncope.

ÂÂ

Bladder cancer (with dapagliflozin) (0.16%) versus (0.03%) placebo.

ÂÂ

Does not increase cardiovascular risk.

ÂÂ

SGLT2 inhibitors slightly increase HDL and LDL cholesterol due to hemoconcentration.

ÂÂ

In rats, long-term use lead to excessive bone growth (hyperostosis) and renal tubular tumor.

HbA1C reduction with SGLT2 inhibitors range between 0.5-1.5%.

2. Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91(2): 733-94. 3. Mather A, Pollock C. Glucose handling by the kidney. Kidney Int Suppl. 2011;(120):S1-6. 4. Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010;27(2):136-42. 5. Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med. 2007;261(1):32-43. 6. Oliva RV, Bakris GL. Blood pressure effects of sodiumglucose co-transport 2 (SGLT2) inhibitors. J Am Soc Hypertens. 2014;8(5):330-9. 7. Polidori D, Sha S, Mudaliar S, Ciaraldi TP, Ghosh A, Vaccaro N, et al. Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: results of a randomized, placebo-controlled study. Diabetes Care. 2013;36(8):2154-61. 8. Invokana [package insert]. Gurabo, PR: Janssen Ortho, LLC; 2013. 9. Farxiga [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2014. 10. Ghosh RK, Ghosh SM, Chawla S, Jasdanwala SA. SGLT2 inhibitors: a new emerging therapeutic class in the treatment of type 2 diabetes mellitus. J Clin Pharmacol. 2012;52(4):457-63. 11. Musso G, Gambino R, Cassader M, Pagano G. A novel approach to control hyperglycemia in type 2 diabetes: sodium glucose co-transport (SGLT) inhibitors: systematic review and meta-analysis of randomized trials. Ann Med. 2012;44(4):375-93. 12. Elmore LK, Baggett S, Kyle JA, Skelley JW. A review of the efficacy and safety of canagliflozin in elderly patients with type 2 diabetes. Consult Pharm. 2014;29(5):335-46.

13. Sinclair A, Bode B, Harris S, Vijapurkar U, Mayer C, Fung A, et al. Efficacy and safety of canagliflozin REFERENCES compared with placebo in older patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. 1. Chao EC, Henry RR. SGLT2 inhibition - a novel strategy for BMC Endocr Disord. 2014;14:37. diabetes treatment. Nat Rev Drug Discov. 2010;9(7):551-9. ■■■■

Physical Activity Important to Ward Off Diabetes A new analysis of data from the 3-year Diabetes Prevention Program (DPP) and its 12-year extension, the DPP Outcomes Study (DPPOS), reports that physical activity, independent of weight loss, prevented diabetes in some individuals with prediabetes. In this racially and geographically diverse sample of prediabetic, overweight, or obese middle-aged men and women, every added 1.5-hours of brisk walking a week (or equivalent activity) reduced their likelihood of developing diabetes by 2%, whether or not they lost weight. Individuals who were inactive to start with (doing less than 150 min of at least moderate physical activity each week) were more likely to see this benefit. The results of the 15-year Combined DPP and DPPOS were presented June 14, 2016 at the recent American Diabetes Association (ADA) 2016 Scientific Sessions in New Orleans, Louisiana.

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ENDOCRINOLOGY

Insulin Resistance MUKESH MEHRA

ABSTRACT Insulin resistance may be defined as subnormal glucose response to both endogenous and exogenous insulin. Insulin resistance, rather than being a complication of treatment of diabetes, is now recognized as a component of several disorders. It would be useful to identify obese patients who are insulin-resistant, as they are at definitive high risk for development of type 2 diabetes mellitus, cardiovascular disease and certain malignancies (e.g., colon, breast, endometrial cancers). Hyperglycemia despite large doses of insulin is the classical presentation, but many patients with extreme resistance to insulin do not have overt hyperglycemia.

Keywords: Insulin resistance, subnormal glucose response, type 2 diabetes mellitus, hyperinsulinemia

nsulin resistance can be broadly defined as subnormal response to normal insulin concentration. By this definition, it may relate to many biotic actions of insulin in many tissues of the body. Pathophysiologically, insulin resistance refers to a state in which there is alteration in its structure, exogenous or endogenous antibodies to insulin or its receptors; there may be defect in post receptor signal transduction in the target tissue.1,2 Typically, however in clinical practice, it refers to a state in which a given concentration of insulin is associated with subnormal glucose response.3 The term 'insulin resistance' came in several years after introduction of insulin therapy in 1922 to describe occasional diabetic patients who required increasingly large doses of insulin to control hyperglycemia. Most of these patients developed insulin resistance secondary to antibodies directed against therapeutic insulin, which at that time was both impure and derived from nonhuman species4 as antibodies are rare in patients treated with recombinant insulin. SPECTRUM OF INSULIN RESISTANCE Insulin resistance, rather than being a complication of treatment of diabetes, is now recognized as a component of several disorders as mentioned here.

Senior Consultant Max Super Speciality Hospital, Patparganj, New Delhi Address for correspondence Dr Mukesh Mehra B-27, Surajmal Vihar, Delhi - 110 092 E-mail: drmukeshmehra@rediffmail.com

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ÂÂ

Extreme insulin-resistance syndromes—such as type B syndrome with autoantibodies against the insulin receptor5 and rare inherited disorders such as leprechaunism with insulin receptor mutations6 and lipodystrophic states.7

ÂÂ

Impaired glucose tolerance and type 2 diabetes mellitus.

ÂÂ

Secondary insulin resistance: Stress, infection, uremia, acromegaly, glucocorticoid excess and pregnancy.

ÂÂ

Common disorders such as metabolic syndrome hypertension, dyslipidemia, coronary artery disease, dysglycemia, the polycystic ovary syndrome and hyperuricemia8 in which the mechanism of associated hyperinsulinemia is not known. Insulin resistance is associated with hyperleptinemia, prothrombotic state and a proinflammatory state (high C-reactive protein levels).9-13

DEFINITION AND QUANTIFICATION Insulin resistance may be defined as subnormal glucose response to both endogenous and exogenous insulin.

Resistance to Endogenous Insulin Resistance to endogenous insulin is identified by high serum insulin concentration with blood glucose concentration that are high or normal. In practice, we measure insulin only when evaluating patients with clinical features of extreme insulin resistance. To confirm the diagnosis, it is also necessary to determine that the structure and biological activity of patient’s insulin is normal. There are rare cases of mutations in

ENDOCRINOLOGY the production of insulin that has subnormal bioactivity but normal immunoactivity. These insulins circulate at high concentrations simulating insulin resistance, but the response to exogenous insulin is normal.14

However, all three of them are impractical for routine clinical use.

In a Clinical Setting In nondiabetics, normotensive individuals:

Resistance to Exogenous Insulin A reduced response to exogenous insulin is readily evident in insulin-treated patients who require higher doses to prevent hyperglycemia, even though the insulin dose in a given patient is an imperfect means for quantitating the degree of insulin resistance. However, most patients with insulin resistance are not treated with insulin. In them, resistance to exogenous insulin can be assessed and quantified by techniques such as intravenous glucose tolerance test, insulin suppression test or the euglycemic insulin clamp technique. With the latter, insulin induced glucose uptake is measured while blood glucose is maintained at a steady state (via exogenous dextrose infusion) to avoid confounding effects of counter regulatory hormones such as epinephrine and glucagon (Fig. 1).15

ÂÂ

Serum triglyceride concentration >130 mg/dL

ÂÂ

Ratio of triglyceride/high-density (HDL) >3.0

ÂÂ

Fasting insulin >15.7 µU/mL.

lipoprotein

Sensitivity and specificity for cut-off were 67%, 64%, 57%, respectively and 71%, 68%, and 85%, respectively.18

In Large Epidemiological Studies ÂÂ

Glucose to insulin ratios.

ÂÂ

Homeostasis model assessment of insulin resistance (HOMA-IR or HOMA).

LIMITATIONS Lack of standardized universal insulin assays, lack of data, change in beta cell function over time. As a result, none of these are recommended for clinical use.

DIAGNOSIS OF INSULIN RESISTANCE

CLINICAL SPECTRUM

It would be useful to identify obese patients who are insulin-resistant, as they are at definitive high risk for development of type 2 diabetes mellitus, cardiovascular disease and certain malignancies (e.g., colon, breast, endometrial cancers).

Insulin resistance can present in a variety of ways. Hyperglycemia despite large doses of insulin is the classical presentation, but many patients with extreme resistance to insulin do not have overt hyperglycemia. However, nearly all patients have one or more clinical features suggesting the presence of severe insulin resistance (Table 1 and Fig. 2).

In a Research Setting ÂÂ

Euglycemic insulin clamps - gold standard test for insulin resistance

ÂÂ

Intravenous glucose tolerance test (IVGTT) and insulin tolerance test (ITT) - most frequently used.16,17

Glucose homeostasis

Reproductive

yy Variable including overt diabetes yy Impaired glucose tolerance yy Hypoglycemia

yy Amenorrhea yy Hirsutism/virilization yy Infertility

Cutaneous

Adipose tissue

300

Type 2 diabetes with insulin

yy Acanthosis nigricans yy Skin tags yy Alopecia

yy Obesity yy Lipoatrophy yy Lipodystrophy

200

Type 2 diabetes

Musculoskeletal

Lipid metabolism

yy Cramps yy Muscle hypertrophy yy Pseudoacromegaly

yy Hypertriglyceridemia

Metabolic syndrome

Linear growth

Normal

400 Glucose disposal rate (mg/m2 per minute)

Table 1. Clinical Manifestations of Insulin Resistance

100

1,000

10,000

Plasma insulin concentration (µU/mL)

Figure 1. Insulin suppression test.

yy Variable including normal, decreased or increased

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ENDOCRINOLOGY

Beta cell 2 Increased glucose 3 Increased insulin

1 Insulin-resistant glucose disposal Impaired insulin clearance Classical targets

IGF-R Hybrid IR Excessive signaling

Skin - acanthosis nigricans Ovary - hyperthecosis Cartilage - pseudoacromegaly

Figure 2. Clinical manifestations of insulin resistance.

Abnormal Glucose Metabolism This varies from normal to extremely abnormal viz. from hypoglycemia to normoglycemia and diabetes mellitus. In clinical scenario, it implies diabetics receiving high dose of insulin to diabetics not receiving insulin but having component of impaired pancreatic beta cell function. Also due to presence of autoantibody against insulin receptor actually have hypoglycemia.19

Cutaneous Abnormalities Acanthosis nigricans, the most specific can be seen as black velvety hyperkeratotic plaques seen in the back of the neck, axilla, groin, elbows, sparing only the palms and soles. Apart from this, skin tags are the common manifestations of insulin resistance.

Hyperandrogenism and Reproductive Abnormalities Men with insulin resistance are not known to have disorders of reproductive system but females commonly present with reproductive abnormalities.20 These females, usually have hyperandrogenismâ&#x20AC;&#x201C; presenting with amenorrhea, virilism, hirsutism and infertility. The ovary shows hyperthecosis.21 The cause of the association between ovarian abnormality and insulin resistance is not known and there is no clear association between the severity of two disorders.22 While androgen excess can cause a modest reduction of insulin sensitivity,23 the primary abnormality is insulin resistance that is causing ovarian abnormality. Insulin receptors and the closely related receptors for insulinlike growth factor 1 (IGF-1) are present on ovarian cells and stimulation of these receptors increase androgen production.24 Reducing insulin resistance by metformin or a thiazolidinedione lowers serum testosterone concentrations and reduces cytochrome P450c17 (17-hydroxylase) activity in the ovaries.25,26

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Linear Growth It is normal in insulin resistance except in two pediatric disorders, leprechaunism and Rabson-Mendenhall syndrome in which growth is impaired.27,28 Pseudoacromegaly is a syndrome in which there is accelerated linear growth due to continued activation of IGF-1 receptors by insulin.

Adipose Tissue It may be normal but in some their may be obesity and/ or abdominal obesity. High secretion of free fatty acids, tumor necrosis factor (TNF)-Îą or decreased production of protective adipocytokines such as adiponectin have been postulated in development of insulin resistance. In leptin deficient patients with lipodystrophy, decreased production of leptin by adipose tissue may also be implicated in the pathogenesis of insulin resistance. Administration of leptin to these subjects in the context of open label, nonrandomized, uncontrolled clinical trials has been shown to potentially improve severity of their metabolic abnormalities.29,30 In addition, subjects with lipodystrophy and/or insulin resistance may also have low levels of adiponectin, another adipocyte secreted hormone that functions as a insulin sensitizer.31 Adiponectin levels are decreased with intra-abdominal fat accumulation and increased dietary fat patterns and decreased exercise.32-34 Peroxisome proliferator-activated receptor gamma activators, including thiazolidinediones, increase adiponectin levels in humans.35

Musculoskeletal Changes Some patients with severe insulin resistance have muscle cramps unrelated to exercise.36 The severity of muscle cramps can be reduced by phenytoin.

Metabolic Syndrome There is apparent association between abdominal obesity, insulin resistance and a variety of abnormalities that impact the cardiovascular system such as type 2 diabetes mellitus, hypertriglyceridemia, low HDL and coronary disease. CONCLUSION Insulin resistance hyperinsulinemia, and faulty glucose stimulated insulin release are naturally linked. Basically hyperinsulinemia causes insulin resistance by multiple mechanisms. Free fatty acids and other inducers of insulin secretion have been demarcated; these factors

ENDOCRINOLOGY might be the initial insults that stimulate the excess insulin secretion. Knowing the pathophysiology of basal hyperinsulinemia may provide help in the development of effective and specific therapies to solve the problem of insulin resistance. REFERENCES 1. Mari A, AhrĂŠn B, Pacini G. Assessment of insulin secretion in relation to insulin resistance. Curr Opin Clin Nutr Metab Care. 2005;8(5):529-33. 2. Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev. 1995;75(3):473-86. 3. Moller DE, Flier JS. Insulin resistance - mechanisms, syndromes, and implications. N Engl J Med. 1991;325(13):938-48. 4. Kahn CR, Rosenthal AS. Immunologic reactions to insulin: insulin allergy, insulin resistance, and the autoimmune insulin syndrome. Diabetes Care. 1979;2(3):283-95. 5. Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, Martin MM, et al. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med. 1976;294(14):739-45. 6. Musso C, Cochran E, Moran SA, Skarulis MC, Oral EA, Taylor S, et al. Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective. Medicine (Baltimore). 2004;83(4):209-22. 7. Tsiodras S, Mantzoros C, Hammer S, Samore M. Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study. Arch Intern Med. 2000;160(13):2050-6. 8. Reaven G, Abbasi F, McLaughlin T. Obesity, insulin resistance, and cardiovascular disease. Recent Prog Horm Res. 2004;59:207-23. 9. de Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Lett. 2008;582(1):97-105. 10. Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulin resistance. Mol Med. 2008;14 (3-4):222-31. 11. Florez H, Castillo-Florez S, Mendez A, Casanova-Romero P, Larreal-Urdaneta C, Lee D, et al. C-reactive protein is elevated in obese patients with the metabolic syndrome. Diabetes Res Clin Pract. 2006;71(1):92-100 12. Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev. 2007;8(1):21-34.

15. Bergman RN, Finegood DT, Ader M. Assessment of insulin sensitivity in vivo. Endocr Rev. 1985;6(1):45-86. 16. Buchanan TA, Watanabe RM, Xiang AH. Limitations in surrogate measures of insulin resistance. J Clin Endocrinol Metab. 2010;95(11):4874-6. 17. Tritos NA, Mantzoros CS. Clinical review 97: Syndromes of severe insulin resistance. J Clin Endocrinol Metab. 1998;83(9):3025-30. 18. McLaughlin T, Abbasi F, Cheal K, Chu J, Lamendola C, Reaven G. Use of metabolic markers to identify overweight individuals who are insulin resistant. Ann Intern Med. 2003;139(10):802-9. 19. Taylor SI, Grunberger G, Marcus-Samuels B, Underhill LH, Dons RF, Ryan J, et al. Hypoglycemia associated with antibodies to the insulin receptor. N Engl J Med. 1982;307(23):1422-6. 20. Poretsky L, Piper B. Insulin resistance, hypersecretion of LH, and a dual-defect hypothesis for the pathogenesis of polycystic ovary syndrome. Obstet Gynecol. 1994;84(4):613-21. 21. Dunaif A, Hoffman AR, Scully RE, Flier JS, Longcope C, Levy LJ, et al. Clinical, biochemical, and ovarian morphologic features in women with acanthosis nigricans and masculinization. Obstet Gynecol. 1985;66(4):545-52. 22. Dunaif A, Xia J, Book CB, Schenker E, Tang Z. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest. 1995;96(2):801-10. 23. Cohen JC, Hickman R. Insulin resistance and diminished glucose tolerance in powerlifters ingesting anabolic steroids. J Clin Endocrinol Metab. 1987;64(5):960-3. 24. Barbieri RL, Smith S, Ryan KJ. The role of hyperinsulinemia in the pathogenesis of ovarian hyperandrogenism. Fertil Steril. 1988;50(2):197-212. 25. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med. 1996;335(9): 617-23. 26. Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab. 1996;81(9):3299-306.

13. Rifai N. High-sensitivity C-reactive protein: a useful marker for cardiovascular disease risk prediction and the metabolic syndrome. Clin Chem. 2005;51(3):504-5.

27. Elders MJ, Schedewie HK, Olefsky J, Givens B, Char F, Bier DM, et al. Endocrine-metabolic relationships in patients with leprechaunism. J Natl Med Assoc. 1982;74(12): 1195-210.

14. Steiner DF, Tager HS, Chan SJ, Nanjo K, Sanke T, Rubenstein AH. Lessons learned from molecular biology of insulin-gene mutations. Diabetes Care. 1990;13(6): 600-9.

28. Rabson SM, Mendenhall EN. Familial hypertrophy of pineal body, hyperplasia of adrenal cortex and diabetes mellitus; report of 3 cases. Am J Clin Pathol. 1956;26(3):283-90.

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ENDOCRINOLOGY 29. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346(8):570-8. 30. Mantzoros CS. Whither recombinant human leptin treatment for HIV-associated lipoatrophy and the metabolic syndrome? J Clin Endocrinol Metab. 2009;94(4):1089-91. 31. Brennan AM, Mantzoros CS. Leptin and adiponectin: their role in diabetes. Curr Diab Rep. 2007;7(1):1-2. 32. Gavrila A, Chan JL, Yiannakouris N, Kontogianni M, Miller LC, Orlova C, et al. Serum adiponectin levels are inversely associated with overall and central fat distribution but are not directly regulated by acute fasting or leptin administration in humans: cross-sectional and interventional studies. J Clin Endocrinol Metab. 2003;88(10):4823-31.

patterns is associated with higher circulating total and high-molecular-weight adiponectin and lower resistin concentrations in women from the Nurses' Health Study. Am J Clin Nutr. 2008;88(5):1213-24. 34. Blüher M, Williams CJ, Klöting N, Hsi A, Ruschke K, Oberbach A, et al. Gene expression of adiponectin receptors in human visceral and subcutaneous adipose tissue is related to insulin resistance and metabolic parameters and is altered in response to physical training. Diabetes Care. 2007;30(12):3110-5. 35. Magkos F, Mantzoros CS. Body fat redistribution and metabolic abnormalities in HIV-infected patients on highly active antiretroviral therapy: novel insights into pathophysiology and emerging opportunities for treatment. Metabolism. 2011;60(6):749-53.

36. Flier JS, Young JB, Landsberg L. Familial insulin resistance with acanthosis nigricans, acral hypertrophy, 33. Fargnoli JL, Fung TT, Olenczuk DM, Chamberland JP, Hu FB, Mantzoros CS. Adherence to healthy eating and muscle cramps. N Engl J Med. 1980;303(17):970-3. ■■■■

Performance of Dexcom vs. Enlite Systems in Type 1 Diabetes Patients A study was performed to analyze the efficacy of two commonly used continuous glucose monitoring systems, Dexcom G4 Platinum (Dexcom) and Medtronic Paradigm Veo Enlite system (Enlite) in patients with type 1 diabetes. The accuracy of these systems was assessed during exercise as well as at rest. The results printed in the Diabetes Technology & Therapeutics journal showed that the performance of both these systems was similar during rest and physical activity. However, more data pairs met the International Organization for Standardization criteria for Dexcom and Enlite at rest (73.6% and 76.9%) in contrast to that during exercise (48.2% and 53.9%). This warrants the need for better tuning of their performance while exercising.

Determining Factors that Increase the Risk of Hepatocellular Carcinoma Si WK and coworkers conducted a study in the diabetic individuals to evaluate the various factors implicated in the development of hepatocellular carcinoma. The study cohort involved diabetic patients without chronic viral hepatitis or alcoholic cirrhosis. The results demonstrated that age > 65 years, low triglyceride concentrations and high gamma-glutamyl transferase levels are likely to be associated with enhanced risk of hepatocellular carcinoma, findings published in the Plos One journal.

Evaluating the Association Between Adiposity Measures and Subclinical Atherosclerosis in Type 2 Diabetes Recently, a study investigated the link between measures of adiposity including waist circumference, body mass index, pericardial, visceral and subcutaneous adipose tissue and subclinical atherosclerosis in African Americans and European Americans with type 2 diabetes mellitus. The results printed in the Obesity (Silver Spring) journal revealed the presence of gender and ethnic-specific differences in these 5 parameters in African Americans and European Americans with diabetes. A positive relation was reported only between pericardial adipose tissue and coronary arteries in African Americans while paradoxical inverse associations were evident between other adiposity measures and subclinical cardiovascular disease.

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GASTROENTEROLOGY

Nonalcoholic Fatty Liver Disease, Cardiovascular Risks and Therapeutic Approaches PRAGATI KAPOOR*, PANKAJ KUMAR†, AK KAPOOR‡

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is a fairly common, slowly progressive liver disease having cardiovascular risks implications and meets diagnostic criteria for metabolic syndrome. NAFLD is histologically categorized into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Although the pathogenesis of NAFLD remains unclear yet ‘two hits’ theory has been proposed for NASH, which being modified by the ‘multiple parallel hits’. A number of factors have been implicated for NAFLD development including metabolic alterations, hormones, inflammation, diet and physical activity and rare genetic conditions. Interestingly, NAFL is generally benign whereas NASH can progress to cirrhosis, liver failure and liver cancer. Liver biopsy remains the gold standard in the diagnosis of NAFLD though noninvasive measures like serum biomarkers, ultrasonography and magnetic resonance spectroscopy may be helpful. Patient with NAFLD and NASH are at increased risk of cardiovascular disease and these constitute most common cause of death. The controllable risk factors include weight, insulin resistance and metabolic syndrome. It may be emphasized that NAFLD without steatohepatitis is not an indication for treatment. The treatment strategies for NAFLD and cardiovascular disease are similar, aimed primarily at reducing insulin resistance and modifying the associated cardiometabolic risk factors. Different drug treatment approaches/modalities have been discussed.

Keywords: Nonalcoholic fatty liver disease, nonalcoholic fatty liver, nonalcoholic steatohepatitis, liver biopsy, cardiovascular disease

urrently nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease representing over 75% of the chronic liver disease in United States.1 The increasing incidence of NAFLD is tied to the snowballing epidemic of obesity and the subsequent metabolic alterations consequent to it. Besides, it is also one of the most common indications for liver transplantation, contributing to major financial burden and is projected as a growing public health problem worldwide. NAFLD encompasses the entire spectrum of fatty liver disease in individuals without significant alcohol consumption, ranging from fatty

*Assistant Professor Dept. of Cardiothoracic Surgery Nizam Institute of Medical Sciences, Hyderabad, Andhra Pradesh †Assistant Professor ‡Professor Dept. of Pharmacology Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh Address for correspondence Dr AK Kapoor Professor Dept. of Pharmacology Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh E-mail: drakkapoor@rediffmail.com

liver to steatohepatitis and cirrhosis. Currently, there is growing body of evidence suggesting that cardiovascular disease (CVD) is the leading cause of death in patients with advanced NAFLD and that NAFLD is associated with increased risk of incident CVD that is independent of risk conferred by traditional risk factors and components of metabolic syndrome.2 Moreover, patients with NAFLD, both adults and children, typically meet the diagnostic criteria for metabolic syndrome (i.e., abdominal obesity, hypertension, atherogenic dyslipidemia and dysglycemia) and therefore have multiple risk factors for CVD.3,4 Increase in morbidity and mortality from CVD are probably among the most important clinical features associated with NAFLD.2 Moreover, liver related illness is the third leading cause of death in liver patients. DEFINITION OF NAFLD The definition of NAFLD requires that: a) There is an evidence of hepatic steatosis, either by imaging or by histology and b) there are no causes for secondary hepatic fat accumulation such as significant alcohol consumption (>20 g/day for men and 10 g/day for women), use of steatogenic medication or

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GASTROENTEROLOGY hereditary disorders. NAFLD is histologically further categorized into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NAFL is defined as the presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes. NASH is defined as the presence of hepatic steatosis and inflammation with hepatocytes injury (ballooning) with or without fibrosis.5 Steatosis is the presence of lipid within the cytoplasm of hepatocytes, the criteria for which is defined as either hepatic lipid levels above the 95th percentile of healthy individuals (about >55 mg/g liver), greater than 5% of liver’s weight or found in greater than 5% of hepatocytes histologically.6 Approximately 10-29% of patients with NASH will develop cirrhosis within a 10-year period.7 A key feature of NASH is the presence of inflammation and subsequent fibrosis. PREVALENCE IN GENERAL POPULATION Briefly, worldwide prevalence of NAFLD ranges from 6.3% to 33% with a median of 20% in the general population, based on a variety of assessment methods and that the estimated prevalence of NASH ranges between 3-5%.8 A very high prevalence of NAFLD can be seen in type 2 diabetes patients and patients with dyslipidemia as also in cases of excessive body mass index (BMI) and visceral obesity.5 Moreover, the prevalence of NAFLD has nearly doubled over the last 20-years.1 Prevalence of NAFLD increases with age.9 Male gender is a risk factor for fatty liver disease,8 and that prevalence of NAFLD was 31% in men and 16% in women.10 Given the increasing prevalence of the disease, adequate knowledge regarding the pathogenesis of the disease as well as its diagnosis, preventive and therapeutic approaches for the management of NAFLD is becoming important for physicians. PATHOGENESIS The liver is one of the principal regulators of lipid in the body. Fatty acids in the liver used for the synthesis of triglycerides are provided by diet, adipose tissue or de novo synthesis from excess glucose. A net retention of lipids within hepatocytes, mostly in the form of triglycerides is a prerequisite for the development of NASH. The primary metabolic abnormality leading to lipid accumulation is not well-understood. Insulin resistance represents the most reproducible factor for the development of NAFLD, and that insulin resistance and oxidative stress play a critical role in the pathogenesis of NAFLD. Although the pathogenesis of NAFLD remains unclear yet some investigators

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have proposed ‘two hits’ theory in the development of NASH. While the ‘first hit’ involves insulin resistance and results in the accumulation of fat in the liver, the ‘second hit’ includes oxidative stress resulting in lipid peroxidation, hepatocellular degeneration, cell death, hepatic stellate cell activation and fibrogenesis.11,12 However, ‘two hit’ pathophysiological theory has been challenged. It has been suggested that the hepatic steatosis may represent an epiphenomenon of several distinct injurious mechanisms rather than a true ‘first hit’. For this reason, the initial ‘two hit’ theory for explaining the progression from NAFLD to NASH is now being modified by the ‘multiple parallel hits’ hypothesis.13 Hyperinsulinemia, caused by insulin resistance, results in an increased hepatic de novo lipogenesis and impaired inhibition of adipose tissue lipolysis that ultimately leads to an increased efflux of free fatty acids from adipose tissue to the liver. After initial hepatic infiltration, the liver becomes extremely vulnerable to a series of hits that may follow, leading to hepatocytes injury and finally progressing from simple steatosis to NASH and fibrosis. The multiple pathogenetic factors may include oxidative damage, dysregulated hepatocytes apoptosis, activation of the profibrogenic transforming growth factors (TGF)-β pathway, dysregulation of multiple adipokines and hepatic stellate cell activation.13 All these factors collectively act in a complicated way to enhance the development and progression of the hepatic lesions through the NAFLD spectrum.14

Genetic Conditions A number of rare genetic conditions alter processing of lipids by liver and can cause steatosis. Thus, mutations which either cause an increase in lipid synthesis/uptake or a decrease in hydrolysis/export were associated with NAFLD, for example, glycogen storage diseases, adipose triacylglycerol lipase (ATGL) defects or very low-density lipoproteins mutations.6 Since, majority of genetic mutations are rare, hence these do not explain the vast majority of the cases of NAFLD, though heritability of NAFLD has been demonstrated.

Metabolic Alterations The nuclear receptors, peroxisome proliferatoractivated receptors (PPAR) are involved in regulation of fatty acid metabolism and storage. PPAR-α increases the β-oxidation thus creates energy, as also uptake and clearance of fatty acids. Whereas PPAR-γ is involved in insulin sensitivity and triglyceride storage, PPAR-α has been implicated in development of steatosis, thus

GASTROENTEROLOGY fibrates which are agonists at PPAR-α have been tried as treatment option. PPAR-γ too have some relation to NAFLD and thiazolidinediones are the activators of PPAR-γ.6

Gut Microbiota

Hormones

Other Factors

Insulin resistance is commonly and concurrently encountered in metabolic syndrome, obesity and/or diabetes and can be characterized as a prime factor in developing hepatic steatosis.6 However, whether the insulin resistance is caused by NAFLD or vice versa is controversial.15 Two major biochemical pathways, which insulin affects in liver and concerned with pathogenesis of fatty liver are: lipogenetic pathway which remains sensitive to effects of insulin while the gluconeogenesis pathway, which is normally inhibited by insulin become resistant. This process results in hyperglycemia, which stimulates the body to produce more insulin. This insulin hypersecretion stimulates lipogenesis as sterol regulatory element-binding protein-1c (SREBP-1c)mediated pathway maintains its response.6

Inflammation The progression of steatosis to NASH is frequently associated with change of concentration in several inflammatory cytokines especially tumor necrosis factor (TNF)-α, which has been linked to both insulin resistance and progression to NASH.16 TNF-α mediated insulin resistance has been correlated with increased levels of SREBP-1c and hepatic steatosis.17 Besides, TNF-α levels have been correlated to increased levels of inflammation, steatosis and histological damage in patients with NASH.18 Thus, anti-TNF-α therapy may be useful in the management of NAFLD.6 Another cytokine, interleukin (IL)-6 is also increased in fatty liver disease and has been correlated to development of insulin resistance, diabetes and fatty liver.6 IL-6 on long-term is being held as a mediator of inflammation, apoptosis and liver damage/scarring.19

Diet and Physical Activity The pathogenesis of fatty liver disease has also been linked to diet and physical activity since increased caloric intake and sedentary lifestyle are associated with metabolic syndrome and insulin resistance, and consequently with NAFLD.6,20 Further, individuals with NAFLD have lower activity levels. Besides, low intake of antioxidants such as vitamin E, zinc and polyunsaturated fatty acids have also been shown to have a connection with NAFLD.21

It has been observed that intestinal flora has a role in obesity and that modification of intestinal flora has an effect on NAFLD.

There are data to suggest that hypothyroidism, hypopituitarism, hypogonadism, obstructive sleep apnea and polycystic ovary syndrome independent of obesity are important risk factors for the presence of NAFLD.5 Deficiency of choline, a micronutrient found in legumes and egg yolk probably has an association with NAFLD; however, it is unclear if choline supplementation can reverse the associated fatty liver.22

Regarding Alcohol Consumption The precise definition of significant alcohol consumption in patient with NAFLD is uncertain and inconsistent, and ranged from >1 alcoholic drink (~10 g of alcohol/ drink) per day to >40 g/day.5 SYMPTOMS Patients with NAFLD are typically asymptomatic and often diagnosed incidentally. Vague symptoms such as fatigue and abdominal discomfort may be noted. Since, there exists an association between metabolic syndrome and NAFLD, hence clinical indications of insulin resistance should raise suspicion for NAFLD. It is useful to examine risk factors for NAFLD such as increased BMI, weight and raised blood pressure. Moreover, in majority of patients, NAFLD is associated with metabolic risk factors such as obesity, diabetes mellitus and dyslipidemia and that presence of metabolic syndrome is a strong predictor for the presence of steatohepatitis in patients with NAFLD.23

Disease Outcomes and Prognosis The long-term outcomes include the most common cause of death in patients with NAFLD, NAFL and NASH is CVD and secondly patients with NASH (but not NAFL) have an increased liver-related mortality rate.5 Basically, NAFL is generally benign whereas NASH can progress to cirrhosis, liver failure and liver cancer.5 Prognosis depends on the severity of liver damage found on liver biopsy. Patients with pure steatosis seem to have best prognosis, whereas NASH or more advanced fibrosis are associated with worse prognosis. It is established that some patients with NAFL (simple steatosis) follow a relatively benign course whereas; in some others (NASH) the disease progresses to cirrhosis

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GASTROENTEROLOGY and its complication.8 NAFLD is a slowly progressing disease, and it may either regress or stay at baseline for years and simple steatosis cases progressing to clinically significant cirrhosis is approximately 1-2%.6,24 On the other hand, NASH patients are at increased risk of developing hepatic decompensation and liver failure.25 NASH may subsequently proceed to liver cirrhosis or hepatocellular carcinoma or end-stage liver disease. Oxidative stress and lipid peroxidation are key factors in the development and progression from steatosis to more advanced stage of liver damage.

Screening Screening for NAFLD, even in higher risk individuals is not recommended owing to uncertainties surrounding diagnostic tests, treatment options, long-term benefits as well as cost-effectiveness of screening. Moreover, liver biochemistries can be within normal ranges in patients with NAFLD and NASH, and these may not be sufficiently sensitive to serve as screening tests.5 Furthermore, systematic screening of family members for NAFLD is also currently not recommended.5

Prediction Models The natural history of NAFLD is fairly dichotomous, and the diagnosis is heterogeneous and relies on a variety of assessment tools, including liver biopsy, radiological tests such as ultrasonography and blood tests such as liver enzymes.8 EVALUATING NEWLY SUSPECTED NAFLD PATIENTS It is important to exclude co-existing etiologies for chronic liver disease including hemochromatosis, autoimmune liver disease, chronic viral hepatitis and Wilson disease.23 The presence metabolic syndrome is a strong predictor for the presence of steatohepatitis in patients with NAFLD.23 Noninvasive scoring models are being used to assess fibrosis in NAFLD. The most widely acceptable and externally validated test model is the NAFLD fibrosis score, which incorporates six variables (e.g., age, BMI, aspartate transaminase/alanine transaminase [AST/ALT] ratio, hyperglycemia, platelet count and albumin).5 However, one major limitation of the scoring system is that about 25% of patients were indeterminate.

Serum Markers Mild-to-moderate elevation of serum aminotransferases (ALT, AST) is the most common and often the only laboratory abnormality found in patients with NAFLD. The AST/ALT ratio is useful in differentiating NAFLD

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from alcoholic liver disease.26 Thus, raised ALT and AST levels may indicate the presence of hepatic steatosis, inflammation or fibrosis; however, their utility in the diagnosis of NASH is limited because of their low specificity, sensitivity and prognostic value.27 Therefore, other diagnostic methods are required to confirm the diagnosis of NAFLD. Serum markers such as cytokeratin - 18 fragments are most promising in the diagnosis of NASH. Cytokeratin -18 (CK-18) fragments are novel biomarkers for the presence of steatohepatitis in patients with NAFLD. CK-18 fragments are markedly increased in patients with NASH compared with patients with simple steatosis or normal biopsies. CK-18 levels have a sensitivity of 78%, specificity of 87%, and an area under the receiver operative curve (AUROC) of 0.82 for steatohepatitis in patients with NAFLD.5 Other serum biomarkers being used in the diagnosis of NASH include various cytokines such as IL-6, TNF-Îą and CC-chemokine ligand-2. Despite a raised IL-6 and TNF-Îą, these lack clinical utility, due to inconsistent correlation. Adiponectin which has antilipogenic and anti-inflammatory effects and is thought to be reduced in NASH also exhibited conflicting results.18,28 Acute phase reactants, C-reactive protein (CRP) and pentatrix-3 have been studied in the diagnosis of NASH, yet more extensive studies are required to prove their overall clinical utility. Hypoalbuminemia, elevated serum bilirubin and prolonged prothrombin time suggest advanced disease.26

Radiological Evaluation Ultrasonography is a cheap, fast, noninvasive method for evaluating and diagnosing steatosis and NASH. Ultrasonography has a sensitivity ranging from 60% to 94% and a specificity of 66% to 95%. Contrastenhanced ultrasonography provides increased sensitivity in finding fatty liver infiltration. Liver ultrasonography is useful in patients with increased levels of Îł-glutamyltransferase not only for the diagnosis of NAFLD but also for better cardiovascular - risk stratification. Transient elastography (TE), which is used to measure liver stiffness via ultrasound non-invasively, can also be used in steatosis and NASH, and is a valuable diagnostic tool. It has a higher failure rate in individuals with higher BMI. Computed tomography (CT) without contrast is a useful tool for assessing the presence and amount of steatosis, with a sensitivity ranging from 82% to 95% and a specificity approximately 100%.

GASTROENTEROLOGY However, the CT scans are expensive and expose patient to ionizing radiation.6 Magnetic resonance spectroscopy (MRS) is the most sensitive and specific imaging modality with both values being greater than 90% and almost 100% accuracy in detecting steatosis.29 It has the advantage that one can calculate the fraction of liver composed of fat and a fraction greater than 5.56% is considered abnormal.29 Recent studies using MR spectroscoping to assess changes in hepatic fat in response to life-style changes observed that the degree of hepatic fat reduction is proportional to the intensity of the life-style intervention and generally required a weight loss ranging 5-10%.29 However, MRS is costly and exposes patients to radiation like CT.6 It may be emphasized that serum aminotransferase levels and imaging tests such as ultrasound, CT, MR do not reliably assess steatohepatitis and fibrosis in patients with NAFLD.5

Liver Biopsy NAFLD is histologically indistinguishable from the liver damage resulting from alcohol abuse.26 Features of liver biopsy include steatosis, mixed inflammatory cell infiltration, hepatocytes ballooning and necrosis, glycogen nuclei, Mallory’s hyaline and fibrosis.26 The presence of fibrosis suggests a more advanced and severe liver injury. The pattern of fibrosis in NAFLD is a characteristic feature. Collagen is first laid down in the pericellular space around the central vein, and in the perisinusoidal region. Progressive injury in NAFLD results in portal fibrosis, central-portal and portalportal septum formation and eventually cirrhosis. Most patients with NASH will show some degree of fibrosis, whereas Mallory’s hyaline may or may not be present.26 Currently, liver biopsy remains the gold-standard for differentiating hepatic steatosis from steatohepatitis.6 In hepatic steatosis, there is presence of intracellular fat in more than 5% of hepatocytes, whereas steatohepatitis has Mallory hyaline, hepatocyte ballooning as well as the presence of polymorphonuclear leukocytes and perisinusoidal fibrosis in zone 3 of the acinus.6 However, liver biopsy is expensive, and studded with sampling error, interobserver/intraobserver variability and risk of morbidity and very rarely mortality and other major risks.6 A liver biopsy should be performed only in patients who are at increased risk to have steatohepatis and advanced fibrosis for example who have metabolic syndrome as well as a suggestive NAFLD fibrosis score.

NAFLD AND RISK OF CVD Patients with NAFLD and NASH are at increased risk for CVD and several studies have established CVD as their most common cause of death.30 Accumulating evidences suggest that CVD dictates the outcome (or outcomes) in patients with NAFLD more frequently and to a greater extent than does the progression of liver disease.3 Hence, management of cardiovascular risk factors including dyslipidemia should be taken care of accordingly. It has been observed that cardiovascular risk is greater among patients with NASH than among those with simple steatosis. Moreover, a strong association of NAFLD with metabolic syndrome has added fuel to fire because of multiple risk factors in the development and progression of CVD.3,4 However, it is not known whether ameliorating NAFLD will ultimately prevent or slow the development and progression. Patients with NAFLD not only meet the diagnostic criteria for the metabolic syndrome (i.e., abdominal obesity, hypertension, atherogenic dyslipidemia and dysglycemia) but also have impaired flow-mediated vasodilation and increased carotid-artery intimal medial thickness - two reliable markers of subclinical atherosclerosis that are independent of obesity and other established risk factors.31 In addition, the histological severity of NASH was associated with the degree of carotid-artery intimal medial thickness, independently of classical cardiovascular risk factors, insulin resistance and metabolic syndrome components.2 In a community-based cohort of 2,088 male workers, the presence of ultrasonographically diagnosed NAFLD was independently associated with an increased prevalence of ischemic heart disease (IHD).32 Data from various studies have shown that CVD is a serious threat to patients with NASH.2 The current body of evidence suggest careful monitoring and evaluation of the risk of CVD in all patients of NAFLD. In a meta-analysis of 11 prospective studies, Fraser et al33 confirmed that an elevated serum γ-glutamyl transferase level (a marker of NAFLD and oxidative stress) was an independent, long-term predictor of incident cardiovascular events in both genders. In comparison, increased serum ALT level is less predictive of incident CVD than is an increased serum γ-glutamyl transferase level, a biomarker for NAFLD as well as oxidative stress.3,4 It was also demonstrated that NAFLD is linked to an increased risk of cardiovascular events both in patients without diabetes and in those with type 2 diabetes. Moreover, insulin resistance is a pathogenic factor in the development and progression of NAFLD and also

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GASTROENTEROLOGY plays a major role in the development of metabolic syndrome and CVD. Moreover, liver inflammation plays a role in the pathogenesis of CVD and that NAFLD may also contribute to cardiovascular risk through abnormal lipoprotein metabolism, especially during the postprandial phase. PREVENTION AND MANAGEMENT Since, the leading cause of death in patients with NAFLD is CVD;30 hence, various comorbidity factors be tackled adequately. However, the prevention of NAFLD poses a difficult problem since pathogenesis of the disease is not clearly understood hence prevention and management of patients with NAFLD includes treating liver disease as well as the associated-metabolic comorbidity.6 The controllable risk factors include weight, insulin resistance and metabolic syndrome. Therefore, lifestyle changes such as diet and exercise, weight reduction are the mainstay for the prevention of NAFLD. It may be emphasized that NAFLD without steatohepatitis is not an indication for treatment though associated comorbidities in steatosis alone should be tackled, as also with steatohepatitis. Further, the hepatitis vaccines A and B may be used in patients of NAFLD and NASH to prevent further insult to already damaged liver.6

Lifestyle Modifications Diet and exercise are the two prime factors of lifestyle changes for the management of steatosis and NASH. An improvement in NAFLD activity score (NAS) as well as ALT was noted in patients who have lost 7-10% of their body weight as compared to controls.34 Diet and exercise are successful in preventing steatosis progression to NASH. The positive effect of weight loss to improve liver histology in NASH has been reported in participants who lost >9% body weight improved steatosis, necrosis and inflammation but not fibrosis, whereas individuals with >7% weight loss had significant improvement in steatosis, lobular inflammation, ballooning and NAS.34 Further, American Gastroenterology Association recommends both exercise and weight loss as a modality for NASH. Many studies indicate that lifestyle modifications may reduce aminotransferases and improve hepatic steatosis when measured either by ultrasound35,36 or MR imaging and spectroscopy.37,38 The degree of fatty infiltration usually improve with weight loss in most patients, although the degree of necroinflammation and fibrosis may worsen. Orlistat (an enteric lipase inhibitor) in conjunction with lifestyle modification have shown equivocal results.

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Dietary Supplementation Antioxidants like vitamin E probably have beneficial effects in NASH, since oxidative stress is the cause of hepatocellular injury. Several studies with vitamin E has reported consistent decrease in ALT and improvement in liver histology.39 Vitamin E causes decrease in aminotransferases, improvement in steatosis, inflammation and ballooning and resolution of steatohepatitis in adults with NASH though, it has no effect on hepatic fibrosis. However, no significant histological benefits with vitamin E also have been observed.40 Vitamin E (800 IU) should be considered as first-line pharmacotherapy in nondiabetic adults with biopsy proven NASH as it improves liver histology though, vitamin E is not recommended to treat NASH in diabetic patients, NASH cirrhosis or NAFLD without biopsy.5 Furthermore, controversial data have been reported that high dose vitamin E cause an increase in all-cause mortality, but others noted no association. Besides, 400 IU/day vitamin E increased the risk of prostate cancer in relatively healthy men. Caffeine and coffee use has been correlated to decreased fibrosis, decreased progression to steatohepatitis as well as decreased incidence of the disease.41,42 Probiotics have also been shown to lower aminotransferases, total cholesterol, TNF-Îą and improve insulin resistance in NAFLD.43 Ursodeoxycholic acid, omega-3 and several other supplements have also shown beneficial effects but lack significant histological improvements. High dose niacin therapy may prevent steatohepatitis and may record a potential promising agent for NAFLD.44 Preliminary evidence supports a role for antioxidants, anticytokine agents and hepatoprotectants including bile acids; however, due to insufficient data these cannot be recommended as standard therapy for NAFLD. DRUGS USED IN THE TREATMENT OF NAFLD The treatment strategies for NAFLD and CVD are similar, aimed primarily at reducing insulin resistance and modifying the associated cardiometabolic risk factors.3,4,45 Thus, the treatment revolves round the management of associated condition as well as discontinuation of potentially hepatotoxic drugs known to produce NAFLD. Pharmacotherapy for NAFLD should probably be reserved for patients with NASH, who are at greater risk for disease progression; though owing to insufficient data definitive recommendations cannot be made for treatment of NASH. Primarily weight reduction by means of diet and exercise and treatment of individual components of metabolic syndrome are being recommended. Hence, in patients with diabetes mellitus or hyperlipidemia,

GASTROENTEROLOGY good metabolic control is always required but rarely effective in reversing NAFLD. Inspite of this, the use of medications that improve insulin sensitivity (insulin sensitizers) for type 2 diabetes, drugs directed at rennin-angiotensin-aldosterone system to control hypertension and increase antioxidant chemical species may be of potential benefit in the treatment of patients with NASH. Besides bariatric surgery may be opted for obesity. It may be noted that rapid weight loss may worsen NASH; therefore, use of medication that can directly reduce or reverse liver damage independently of weight loss are reasonable alternatives. Briefly all patients with NASH should get early aggressive treatment aimed at their associated cardiovascular risk factors to avoid major cardiovascular events and mortality before advanced liver disease develops.

Insulin Sensitizing Agents Metformin Metformin, a insulin-sensitizing agent, is commonly being used as there is a link between insulin resistance and NAFLD. Several studies have shown that in patients with fatty liver metformin caused a decrease in ALT and an increase in insulin sensitivity.46,47 with improvement in histology in some cases.48 In a small long-term study (48-week treatment), metformin exhibited lack of efficacy in NASH patients.49 Other studies also failed to show major benefit for metformin on hepatic insulin sensitivity, aminotransferases or liver histology.49,50 A recent meta-analysis concluded that metformin plus lifestyle intervention did not improve aminotransferases or liver histology, compared with lifestyle intervention alone, independently of metformin dose or the presence of diabetes.8 In brief, metformin has no significant effect on liver histology and is not recommended as specific treatment in adults with NASH.5 Thiazolidinediones Thiazolidinediones especially pioglitazone and rosiglitazone are also insulin-sensitizing agents and are activators of PPAR-γ receptors, which appeared to be down-regulated in NAFLD models. FLIRT trial (2008) and FLIRT 2 trial (2010) showed improvement in steatosis, transaminase levels, ballooning and inflammation scores with rosiglitazone but not necroinflammation or fibrosis.51 A study has demonstrated that pioglitazone improved fibrosis in NASH.52 Thiazolidinediones increased weight and rosiglitazone may cause congestive heart failure and myocardial infarction and death. Belfort et al53 observed that pioglitazone (45 mg/day) in patients with

NASH, who have impaired glucose tolerance or type 2 diabetes millitus, caused significant improvement in aminotransferases, steatosis, ballooning, inflammation and NAS. The pioglitazone or vitamin E for NASH study (PIVENS) in nondiabetic patients with NASH demonstrated that pioglitazone (30 mg/day) for 24 months caused histological benefits and resolution of NASH, a key secondary endpoint, which was achieved in significantly higher number of patients compared to placebo though it was associated with weight gain.54 Moreover, pioglitazone has not been associated with an increased risk of cardiovascular events, thus pioglitazone may be considered thiazolidinedione of choice as evidence suggests beneficial effects in NASH.

Fibrates Fibrates are agonist of PPAR-α. A pilot study, conducted by Miranda et al55 demonstrated that in patients with NAFLD, treatment with fenofibrate for 48 weeks in doses used to decrease triglycerides, is safe and improves metabolic syndrome, lipid profile, glucose and liver tests, though effect on liver histology are minimal, ballooning improved mildly and NAS index did not show any significant changes. This small study also demonstrated a significant decrease in ALT in patients taking fenofibrate with an improvement in hepatocellular ballooning but not in the amount of steatosis or fibrosis.55 Large studies with histopathological improvement data are still lacking. Further, a recently developed dual PPARα/-δ agonist (GFT505) demonstrated decreased hepatic and peripheral insulin sensitivity in obese patients along with decrease in ALT levels.56 Despite promising results, human data with GFT505 are not available.

Statins NAFLD is commonly associated with adverse cardiovascular manifestations. Statins are HMG-Co-A reductase inhibitors and are commonly administered as safe preventive treatment in patients with cardiovascular risk factors in patients with NAFLD.57 They are basically used for the treatment of dyslipidemia and thus exhibit cardiovascular risk reduction in patients with NAFLD. Several studies have demonstrated that statins may improve liver biochemistries and histology in patients with NASH.57 The Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study in 2010 using statins demonstrated a significant reduction in liver enzymes as well as a reduction in chance of having an adverse cardiovascular event and improve cardiovascular outcomes.58 Presently, statins cannot be

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GASTROENTEROLOGY advocated to be used in NASH as histopathological data are scarce and needs further research.59 Although, there is no convincing evidence that lipid-lowering agents, including statins are beneficial for patients with NASH, these can be safely prescribed in diabetes and high cardiovascular risk patients.59 Inspite of this, all patients with NASH should get early treatment of their liver disease but also for early, aggressive treatment aimed at their associated cardiovascular risk factors to avoid major cardiovascular events and mortality before advanced liver disease develops.

based on selectively burning hepatic fat. However, it is possible that burning hepatic fat with a liver specific thyromimetic may not be effective enough to achieve these goals in NASH.63 Pentoxifylline, an anti-TNF therapy, in small studies has shown improvement in aminotransferases and histopathological features.64 In another study, a plant supplement, chlorella vulgaris has been shown to decrease levels of transaminases and increase insulin sensitivity.65

Surgery

1. Younossi ZM, Stepanova M, Afendy M, Fang Y, Younossi Y, Mir H, Srishord M. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol. 2011;9(6):524-530.e1; quiz e60.

Weight reduction is one of the prime therapeutic modality for patients with NAFLD. Bariatric surgery has shown a significant decrease in steatohepatitis and that NASH improves following bariatric surgery.60,61 Foregut bariatric surgery is a potential treatment option for NASH. Mathurin et al60 observed that compared to baseline, there was a significant improvement in the prevalence and severity of steatosis and ballooning at 1 and 5 years following bariatric surgery. A metaanalysis evaluating the effect of bariatric surgery on the liver histology in patients with NAFLD showed that steatosis, steatohepatitis and fibrosis, appear to improve or completely resolve after bariatric surgery. It is premature to consider foregut bariatric surgery as established option to specifically treat NASH.5 Liver transplantation is a life-extending therapeutic alternative and is the only option for patients with NAFLD progressing to end-stage liver disease; though NAFLD can recur after transplant or develop de novo.6

Other Potential Treatment Approaches With the growing prevalence of the disease, the potential future therapeutic options, though still in their infancy include, a mixture of high molecular weight beeswax alcohols, D-002 which has shown to improve symptoms in patients with NAFLD along with an improvement in ultrasonographic findings, insulin resistance as well as NAFLD symptoms. Obeticholic acid, a farnesoid X receptor agonist, improves insulin sensitivity and reduces markers of liver inflammation and fibrosis in patients with diabetes and NAFLD.62 Liver selective thyroid hormone receptor (THR) agonists especially thyroid hormone receptor beta-1 (THRÎ˛-1) agonists exert beneficial effects including lowering of low-density lipoprotein cholesterol and a reduction in whole body adiposity and weight. Moreover, selective activation of hepatic THR prevents or reverses fatty liver and points to a new approach to treat NAFLD

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REFERENCES

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41. Birerdinc A, Stepanova M, Pawloski L, Younossi ZM. Caffeine is protective in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2012;35(1):76-82.

54. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675-85.

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49. Haukeland JW, Konopski Z, Eggesbø HB, von Volkmann HL, Raschpichler G, Bjøro K, et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol. 2009;44(7):853-60.

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INTERNAL MEDICINE

Acute Kidney Injury: A Rarity in Methemoglobinemia R UMARANI*, BABURAJ K†, JINO VINCENT‡, SARAVANAN M‡

ABSTRACT Methemoglobinemia can be due to some drugs, poisoning or congenital metabolic errors. Methylene blue is used as anti-dote for symptomatic methemoglobinemia. Diagnosis depends on clinical features and saturation gap seen in arterial blood gas and pulse oximeter values as co-oximetry and sophisticated investigations may not be readily available in all peripheral hospitals. Methemoglobinemia causing acute kidney injury, though documented in the past, is a very rare entity.

Keywords: Methemoglobinemia, nitrobenzene, methylene blue, acute kidney injury

CASE REPORT A 45-year-old male was brought to the casualty with alleged history of consumption of insecticide with suicidal intent. Patient was immediately intubated as he was cyanosed, not responding to painful stimuli and Glasgow coma scale (GCS) was only 3/15. Post intubation vital examination revealed blood pressure of 120/70 mmHg, pulse rate was 70/min and SpO2 was 84% with 100% FiO2. Arterial blood gas (ABG) analysis revealed pH - 7.21, PaO2 - 523 mmHg, SaO2 - 100%, PCO2 - 41.4 mmHg and cHCO3 - 17 mmol/L. The insecticide compound was identified as 20% nitrobenzene.

showed normal left ventricular (LV) function with an ejection fraction of 60%. During course of intensive care unit (ICU) stay, he was treated with methylene blue 50 mg IV (1 mg/kg), ascorbic acid 500 mg, antibiotics, IV fluids and 1 unit of fresh blood was transfused. Patient had a transient improvement in pulse oximeter saturation values (from 84% to 94%), which again transiently dropped low after few hours and improved again with further administration of methylene blue.

A provisional diagnosis of methemoglobinemia was made based on cyanosis and saturation gap1 in ABG analysis. Initial evaluation revealed, blood sugar of 129 mg/dL, complete hemogram showed hemoglobin of 11.2 g/dL, total count of 8,100 cells/mm3, platelet count was 1.70 lakhs/mm3. Renal function test, electrolytes and liver function tests were normal at the time of admission. Urine analysis was negative for albumin, sugars and ketones, with 2-3 pus cells and 1-2 epithelial cells. Ultrasonogram of abdomen showed normal study. Electrocardiography at admission was sinus rhythm with no dynamic changes and echocardiography

*Professor †Reader ‡Post Graduate Dept. of Medicine Rajah Muthaiah Medical College and Hospital, Chidambaram, Tamil Nadu Address for correspondence Dr Jino Vincent Dept. of Medicine Rajah Muthaiah Medical College and Hospital, Chidambaram, Tamil Nadu E-mail: jino_vincent@yahoo.co.in

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INTERNAL MEDICINE Table 1. Serial RFT Values Urea (mg/dL)

108

Creatinine (mg/dL)

0.8

0.9

1.1

2.6

3.0

4.2

Sodium (mmol/L)

132

142

145

143

147

145

Potassium (mmol/L)

4.0

4.7

3.8

4.5

5.2

6.0

Chloride (mmol/L)

102

116

102

110

111

107

CrCl* (mL/min)

107

32.9

2.7

*Creatinine clearance as per Cockgraft-Gault equation.

Urea (mg/dL)

0.8 0

4.2

2.6

1.1

0.9

108

Creatinine (mg/dL)

Figure 1. Progressive deterioration of renal parameters.

Patient developed oliguria and hypotension on the second day of admission and hence was started on inotropes. Acute kidney injury was substantiated by progression to anuria and raise in renal parameters (Table 1 and Fig. 1). Urine analysis showed albumin 1+, with erythrocytic casts and granular casts. Renal biopsy was not done. Inspite of optimum treatment with methylene blue and other supportive measures patient developed refractory hypotension. Dialysis was planned but patient deteriorated rapidly and patient could not be revived. DISCUSSION When hemoglobin loses an electron and becomes oxidized, the iron atom is converted to the ferric state (Fe3+), resulting in the formation of methemoglobin.2 The physiological level of methemoglobin in the blood is 0-2%.3 Methemoglobin concentrations of 10-20% are tolerated well, but levels above this are often associated with symptoms. Methemoglobinemia can cause headache, dyspnea, chest pain, tachypnea, tachycardia, confusion, lethargy and metabolic acidosis occurs leading to coma, seizures, bradycardia and arrhythmias. Anemic or glucose-6-phosphate dehydrogenase (G6PD) deficient patients suffer more severe symptoms.4 Levels above 70% may cause death. Methemoglobin causes shifting of oxygen dissociation curve to left,

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implying increase in oxygen affinity. This results in anemic hypoxia, where oxygen carrying capacity is impaired though PaO2 is normal or elevated.5 There is a difference between the SpO2 that has been measured by means of pulse oximeter and the SO2 that has been calculated by means of ABG analysis. Methylene blue is used as first choice of antidote in methemoglobinemia poisoning. At pharmacologic doses it has reducing properties (1-2 mg/kg). Hence, it is used to reduce methemoglobin to hemoglobin. Normally, through the NADH or NADPH-dependent methemoglobin reductase enzymes, methemoglobin is reduced back to hemoglobin. When large amounts of methemoglobin occur secondary to toxins, methemoglobin reductases are overwhelmed. Methylene blue, when injected intravenously as an antidote, is itself first reduced to leucomethylene blue, which then reduces the heme group from methemoglobin to hemoglobin. However at high doses (>7 mg/dL), it acts as an oxidizing agent and induces methemoglobinemia, reversing this pathway.6 Methylene blue, as antidote in methemoglobinemia is associated with good G6P

NADP+

Leucomethylene blue

NADPH

Methylene blue

Fe++ - Hb

G6 PD 6PG

Fe+++ - Hb

INTERNAL MEDICINE Table 2. ABG Analysis At admission

PaCO2 (mmHg)

PaO2 (mmHg)

HCO3

SaO2%*

SpO2%†

7.21

41.4

523

100

After 12 hours

7.18

150

16.2

After 24 hours

7.004

62.1

153

15.1

97.3

After 36 hours

6.964

52.3

136.8

11.6

95.6

*Saturation

as measured in ABG.

†Saturation

as recorded in pulse oximeter.

SaO2

After IV methylene blue

105 100

100

SpO2

At admission

80 0

Figure 2. “Saturation gap” getting corrected on treatment with methylene blue.

clinical outcomes, is well-documented. In our patient, though the saturation improved with methylene blue (Table 2 and Fig. 2), ascorbic acid and blood transfusion, patient’s clinical outcome was hampered by acute kidney injury (AKI), clinically ascertained by oliguria, rising renal parameters, persistent hypotension and metabolic acidosis. CONCLUSION AKI secondary to myoglobinemia and hemoglobinemia is well-known. AKI secondary to methemoglobinemia is known to occur in animals and laboratory settings. Human case presentations are rare, but have been documented as secondary to topical benzocaine use and renal replacement therapy was necessitated.7 This case is presented for rarity of methemoglobinemia-induced AKI and to emphasis the need for heightened awareness for occurrence of AKI in methemoglobinemia, as prompt dialysis may significantly improve the outcome. REFERENCES

child: a case report and literature review. Pan Afr Med J. 2012;11:49. 2. Herman MI, Chyka PA, Butler AY, Rieger SE. Methylene blue by intraosseous infusion for methemoglobinemia. Ann Emerg Med. 1999;33(1):111-3. 3. Yawata Y, Ding L, Tanishima K, Tomoda A. New variant of cytochrome b5 reductase deficiency (b5RKurashiki) in red cells, platelets, lymphocytes, and cultured fibroblasts with congenital methemoglobinemia, mental and neurological retardation, and skeletal anomalies. Am J Hematol. 1992;40(4):299-305. 4. Qureshi AH, Soberon DJ, Asif A, Vachharajaniand T, Nayer A. Methemoglobinemia-induced acute kidney injury. Open Urol Nephrol J. 2013;6:36-41. 5. Hypoxemia versus Hypoxia. Available at: http://media. lanecc.edu/users/driscolln/RT127/Softchalk/Oxygen_ transport_softchalk/Oxygen_Transport_Lesson7. html#hypoxemichypoxia–decreasedo2content(cao2) 6. Brent J (Ed.).Critical care toxicology: diagnosis and management of the critically poisoned patient. Mosby; 2005.

7. Chongtham DS, Phurailatpam J, Singh MM, Singh TR. Methaemoglobinemia in nitrobenzene poisoning. J Postgrad Med. 1997;43(3):73-4. ■■■■

1. Nabukeera-Barungi N, Mworozi E. Sudden onset methaemoglobinaemia in a previously well Ugandan

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Every citizen of India should have the right to accessible, affordable, quality and safe heart care irrespective of his/her economical background

Sameer Malik Heart Care Foundation Fund An Initiative of Heart Care Foundation of India

E-219, Greater Kailash, Part I, New Delhi - 110048 E-mail: heartcarefoundationfund@gmail.com Helpline Number: +91 - 9958771177

“No one should die of heart disease just because he/she cannot afford it” About Sameer Malik Heart Care Foundation Fund

Who is Eligible?

“Sameer Malik Heart Care Foundation Fund” it is an initiative of the Heart Care Foundation of India created with an objective to cater to the heart care needs of people.

Objectives Assist heart patients belonging to economically weaker sections of the society in getting affordable and quality treatment. Raise awareness about the fundamental right of individuals to medical treatment irrespective of their religion or economical background. Sensitize the central and state government about the need for a National Cardiovascular Disease Control Program. Encourage and involve key stakeholders such as other NGOs, private institutions and individual to help reduce the number of deaths due to heart disease in the country. To promote heart care research in India.

All heart patients who need pacemakers, valve replacement, bypass surgery, surgery for congenital heart diseases, etc. are eligible to apply for assistance from the Fund. The Application form can be downloaded from the website of the Fund. http://heartcarefoundationfund.heartcarefoundation. org and submitted in the HCFI Fund office.

Important Notes The patient must be a citizen of India with valid Voter ID Card/ Aadhaar Card/Driving License. The patient must be needy and underprivileged, to be assessed by Fund Committee. The HCFI Fund reserves the right to accept/reject any application for financial assistance without assigning any reasons thereof. The review of applications may take 4-6 weeks. All applications are judged on merit by a Medical Advisory Board who meet every Tuesday and decide on the acceptance/rejection of applications. The HCFI Fund is not responsible for failure of treatment/death of patient during or after the treatment has been rendered to the patient at designated hospitals.

To promote and train hands-only CPR.

Activities of the Fund Financial Assistance

The HCFI Fund reserves the right to advise/direct the beneficiary to the designated hospital for the treatment.

Financial assistance is given to eligible non emergent heart patients. Apart from its own resources, the fund raises money through donations, aid from individuals, organizations, professional bodies, associations and other philanthropic organizations, etc.

The financial assistance granted will be given directly to the treating hospital/medical center.

After the sanction of grant, the fund members facilitate the patient in getting his/her heart intervention done at state of art heart hospitals in Delhi NCR like Medanta – The Medicity, National Heart Institute, All India Institute of Medical Sciences (AIIMS), RML Hospital, GB Pant Hospital, Jaipur Golden Hospital, etc. The money is transferred directly to the concerned hospital where surgery is to be done.

Drug Subsidy

The HCFI Fund has the right to print/publish/webcast/web post details of the patient including photos, and other details. (Under taking needs to be given to the HCFI Fund to publish the medical details so that more people can be benefitted). The HCFI Fund does not provide assistance for any emergent heart interventions.

Check List of Documents to be Submitted with Application Form Passport size photo of the patient and the family A copy of medical records Identity proof with proof of residence Income proof (preferably given by SDM)

The HCFI Fund has tied up with Helpline Pharmacy in Delhi to facilitate

BPL Card (If Card holder)

patients with medicines at highly discounted rates (up to 50%) post surgery.

Details of financial assistance taken/applied from other sources (Prime Minister’s Relief Fund, National Illness Assistance Fund Ministry of Health Govt of India, Rotary Relief Fund, Delhi Arogya Kosh, Delhi Arogya Nidhi), etc., if anyone.

The HCFI Fund has also tied up for providing up to 50% discount on imaging (CT, MR, CT angiography, etc.)

Free Diagnostic Facility

Free Education and Employment Facility

The Fund has installed the latest State-of-the-Art 3 D Color Doppler EPIQ 7C Philips at E – 219, Greater Kailash, Part 1, New Delhi.

HCFI has tied up with a leading educational institution and an export house in Delhi NCR to adopt and to provide free education and employment opportunities to needy heart patients post surgery. Girls and women will be preferred.

This machine is used to screen children and adult patients for any heart disease.

Laboratory Subsidy HCFI has also tied up with leading laboratories in Delhi to give up to 50% discounts on all pathological lab tests.

About Heart Care Foundation of India

Help Us to Save Lives The Foundation seeks support, donations and contributions from individuals, organizations and establishments both private and governmental in its endeavor to reduce the number of deaths due to heart disease in the country. All donations made towards the Heart Care Foundation Fund are exempted from tax under Section 80 G of the IT Act (1961) within India. The Fund is also eligible for overseas donations under FCRA Registration (Reg. No 231650979). The objectives and activities of the trust are charitable within the meaning of 2 (15) of the IT Act 1961.

Heart Care Foundation of India was founded in 1986 as a National Charitable Trust with the basic objective of creating awareness about all aspects of health for people from all walks of life incorporating all pathies using low-cost infotainment modules under one roof. HCFI is the only NGO in the country on whose community-based health awareness events, the Government of India has released two commemorative national stamps (Rs 1 in 1991 on Run For The Heart and Rs 6.50 in 1993 on Heart Care Festival- First Perfect Health Mela). In February 2012, Government of Rajasthan also released one Cancellation stamp for organizing the first mega health camp at Ajmer.

Objectives Preventive Health Care Education Perfect Health Mela Providing Financial Support for Heart Care Interventions Reversal of Sudden Cardiac Death Through CPR-10 Training Workshops Research in Heart Care

Donate Now... Heart Care Foundation Blood Donation Camps The Heart Care Foundation organizes regular blood donation camps. The blood collected is used for patients undergoing heart surgeries in various institutions across Delhi.

Committee Members

Chief Patron

President

Raghu Kataria

Dr KK Aggarwal

Entrepreneur

Padma Shri, Dr BC Roy National & DST National Science Communication Awardee

Governing Council Members Sumi Malik Vivek Kumar Karna Chopra Dr Veena Aggarwal Veena Jaju Naina Aggarwal Nilesh Aggarwal H M Bangur

Advisors Mukul Rohtagi Ashok Chakradhar

Executive Council Members Deep Malik Geeta Anand Dr Uday Kakroo Harish Malik Aarti Upadhyay Raj Kumar Daga Shalin Kataria Anisha Kataria Vishnu Sureka

This Fund is dedicated to the memory of Sameer Malik who was an unfortunate victim of sudden cardiac death at a young age.

Rishab Soni

HCFI has associated with Shree Cement Ltd. for newspaper and outdoor publicity campaign HCFI also provides Free ambulance services for adopted heart patients HCFI has also tied up with Manav Ashray to provide free/highly subsidized accommodation to heart patients & their families visiting Delhi for treatment.

http://heartcarefoundationfund.heartcarefoundation.org

OBSTETRICS AND GYNECOLOGY

Laparoscopic Evaluation of Endometriosis in Infertility and Chronic Pelvic Pain in a Tertiary Care Center: An Observational Study PARMJIT KAUR*, RUBY BHATIA†, RAJWINDER KAUR‡, AMAN DEV#, SURINDER KUMARI$

ABSTRACT Objective: To find out prevalence of endometriosis and to evaluate effectiveness of laparoscopy in diagnosis and staging of endometriosis in infertility and chronic pelvic pain. Material and methods: An observational study carried out on 100 patients of infertility and chronic pelvic pain in Dept. of Obstetrics and Gynecology, Rajindra Hospital, Patiala with effect from January 2011 to June 2012. Patients were subjected to laparoscopy under anesthesia. Diagnosis, staging and management of endometriosis was done as required. Results: Prevalence of endometriosis was found to be 23%. Majority of cases (34.78%) had severe endometriosis followed by stage I and II (26.09%) each. Endometriosis was detected in 24.07% and 16.12% in relation to primary and secondary infertility, respectively, while 33.3% cases with chronic pelvic pain had endometriosis. Majority of cases had minimal endometriosis, stage I (46.38%) followed by stage IV (30.77%) in primary infertility compared to 60% in stage II followed by 20% each in stage III and IV in secondary infertility. Sixty percent patients with chronic pelvic pain had severe endometriosis. Conclusion: Laparoscopy remains gold standard for diagnosis and management of endometriosis in evaluation of infertility and chronic pelvic pain.

Keywords: Endometriosis, infertility, chronic pelvic pain, laparoscopy

ndometriosis is presence and growth of functioning endometrial tissue containing glandular and stromal elements in places other than uterus that often results in severe pain and infertility.1 It is 7 to 10 times more common in infertile women and encountered in 70% of women with chronic pelvic pain. Seventeen percent of women with primary infertility are diagnosed with endometriosis.2 Endometriosis affects 6-10% of women of reproductive age. It was seen that 69.6% teenagers who underwent diagnostic laparoscopy for chronic pelvic pain had

*Professor †Associate Professor ‡Senior Resident Dept. of Obstetrics and Gynecology #Postgraduate Student Dept. of Preventive and Social Medicine $Ex-Professor Dept. of Obstetrics and Gynecology Govt. Medical College and Rajindra Hospital, Patiala, Punjab Address for correspondence Dr Parmjit Kaur 40, Mohindra Complex, Kheri Gujjran Road Opp. Khokhar Complex, Patiala -147 001, Punjab E-mail: dr.parmjit.obg@gmail.com

endometriotic implants. A genetic component has been suggested with 6.9% occurrence rate in firstdegree relatives.3 Alcohol usage, smoking and low body mass index are other risk factors. Dysmenorrhea, dyspareunia, infertility and chronic pelvic pain remain characteristics of endometriosis. Premenstrual spotting, dysuria, dyschezia, sciatica are associated symptoms. The most common sites of endometriosis in decreasing order are the ovaries, anterior and posterior cul-desac, broad ligament and uterosacral ligaments, uterus, fallopian tubes, sigmoid colon and appendix. The growth of implants is dependent on steroids produced in the ovarian tissue. It varies in appearance from a few minimal lesions in an otherwise intact pelvic organs to a massive ovarian endometriotic cyst with deep infilterating endometriosis. Clinical history along with gynecological examination, laboratory tests and transvaginal ultrasound may suggest the diagnosis.4 The greatest difficulty lies in diagnosing minimal and mild lesions. In these cases, the ideal access for confirmation is always laparoscopic. Assessment of the accuracy of laparoscopy for diagnosing endometriosis has demonstrated that it is highly precise in ruling out the disease.5

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153

OBSTETRICS AND GYNECOLOGY MATERIAL AND METHODS

A detailed history with special reference to dysmenorrhea, dyspareunia, dysuria, menorrhagia, premenstrual spotting and dyschezia was taken. Patients were selected for single/double puncture laparoscopic evaluation under general/regional anesthesia in postmenstrual phase after routine investigations including transvaginal sonography. An informed consent was taken for the procedure. Hemodynamically unstable, cardiorespiratory disease, uterine height â&#x2030;Ľ16 weeks size of the pregnant uterus, acute reproductive tract infections were excluded from the study. Presence of powder burn lesions, adhesions to pelvic wall, to the posterior broad ligament or to both, superficial endometriosis with adjacent puckering, endometriomas <12 cm, tarry chocolate-colored fluid content were taken as visual diagnostic parameters to confirm endometriosis. Staging of endometriosis was done as per the American Society for Reproductive Medicine (ASRM) revised classifications of endometriosis.6 RESULTS AND OBSERVATIONS A total of 100 patients were subjected to single or double puncture laparoscopy; 54% patients presented with primary infertility, 31% with secondary infertility and 15% with chronic pelvic pain. The mean age in the study group was 30.17 Âą 4.77 years (Fig. 1). Majority of patients were nulliparous (54%) from urban background (57%) and were of low or middle socioeconomic status (86%) (Table 1). Congestive dysmenorrhea (35%) was the most common associated complaint followed by premenstrual spotting in 18%, menorrhagia in 12%, dyspareunia in 6% (Table 2). Prevalence of endometriosis was found to be 23% on laparoscopy followed by pelvic inflammatory disease (16%), adhesions, fibroid uterus and genital tuberculosis, while 15% cases had normal study (Fig. 2). Majority of endometriosis patients in our study were

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Indian Journal of Clinical Practice, Vol. 27, No. 2, July 2016

40 No. of cases

The present study was carried out on 100 patients with chief complaints of infertility/chronic pelvic pain admitted in the Dept. of Obstetrics and Gynecology, Govt. Medical College, Rajindra Hospital, Patiala to evaluate effectiveness of laparoscopy in diagnosis and staging of endometriosis and to find out prevalence of endometriosis in infertility and chronic pelvic pain. It was an observational study with effect from January 2011 to June 2012.

30 20

10 2

0 20-25

25-30

30-35

35-40

40-45

Age (years)

Figure 1. Age-wise distribution (total 100).

Table 1. Sociodemographic Profile (Total 100) Number

Percentage (%)

Nulliparous

Para 1

Para 2 and above

Urban

Rural

Low

Middle

High

Parity Unmarried

Residence

Socioeconomic status

Table 2. Presenting Complaints (Total 100) Presenting complaints Infertility

Number

Percentage (%)

Primary infertility

Secondary infertility

Chronic pelvic pain Associated complaints Congestive dysmenorrhea Menstrual irregularity

Premenstrual spotting

Menorrhagia

Dyspareunia

Dysuria

Dyschezia

No complaints

OBSTETRICS AND GYNECOLOGY

No. of cases

20 16

7 4

pi nx C pr hro eg ni na c e nc ct y op ic M ul le ria n ag en es is No rm al st ud y

t en

va ria

Hy dr os al

rg e

se a

e ov ar ia

lyc ys tic

Pe l

vic

Tu b

tu b

er cu l

oc ka d

os is

ds br oi

ns es io Ad h

m m

P di elvi se c as in e fla

En d

et rio

at or y

sis

Figure 2. Clinical diagnosis in laparoscopic evaluation (total 100).

Table 3. Prevalence and Staging of Endometriosis in Relation to Infertility/Chronic Pelvic Pain (Total 23) Diagnosis

Endometriosis

Staging of endometriosis Stage I

Stage II

Stage III N

Stage IV N

Primary infertility

100

24.07

46.16

15.38

7.69

30.77

Secondary infertility

100

16.12

Chronic pelvic pain

100

33.33

8 7

No. of cases

5 4

DISCUSSION

3 2 1 0 Stage I (Minimal)

Stage II (Mild)

Stage III (Moderate)

with mild-to-moderate (Stage II and III) endometriosis. 33.3% patients with chronic pelvic pain were diagnosed endometriosis, 60% (3 cases) of them in stage IV disease (Table 3).

Stage IV (Severe)

Figure 3. Staging of endometriosis (total 23) (ASRM revised classification 1994).

stage IV, while 6 cases each were stage I and stage II (26.09%) (Fig. 3). Out of 54 patients with primary infertility 24.07% (13 cases) were diagnosed as endometriosis of these 46.16% had minimal disease, while 4 cases (30.77%) were stage IV endometriosis (endometriomas and deep infiltrating endometriosis). A total of 16.12% patients with secondary infertility had endomteriosis, 80% of them

The prevalence of endometriosis in our study was 23% out of a total of 100 cases with infertility and chronic pelvic pain on laparoscopic evaluation. The mean age in our study was 30.17 Âą 4.77 years with a range of 20-45 years. The age of peak diagnosis of endometriosis based on presenting symptoms as pelvic pain, age 15-24 years; infertility, age 25-34 years and dysfunctional uterine bleeding, age 35-44 years.6 Endometriosis is traditionally diagnosed after 2nd or 3rd decade; approximately one-third of patient with confirmed endomteriosis experience their first symptom before 15 years of age.7 Salehpour et al reported 36% prevalence of endometriosis in infertility and chronic pelvic pain.8 In our study, dysmenorrhea was the major associated complaint in 35% of cases of infertility and chronic

Indian Journal of Clinical Practice, Vol. 27, No. 2, July 2016

155

OBSTETRICS AND GYNECOLOGY pelvic pain followed by premenstrual spotting in 18%, menorrhagia in 12% and dyspareunia in 6%. The clinical features of endometriosis are varied and the presentation depends on site of growth and severity of disease. The classic triad of dysmenorrhea, dyspareunia and infertility has been described as characteristic of the disease.1 In a study conducted by Khawaja et al among infertile women with laparoscopy is staging of endometriosis, 36.8% cases had dysmenorrhea.9 Prevalence of endometriosis in infertility and chronic pelvic pain in our study was 23%. Naseer-ud-din, 200010 and Salehpour et al8 reported 24.88% and 36% prevalence of endometriosis, respectively. Majority of cases (34.78%) in our study were stage IV with severe disease followed by 26.09% in stage I with minimal disease. Tsuji et al 200911 found majority of the cases in stage I. Almeida Filho et al, 200812 reported 51.01% and 32.46% cases of infertility in stage II and III, respectively. The difference could be because ours is a referral tertiary care center catering to poor people who usually report late as is the case in developing countries. Endometriosis was diagnosed in 24.07% (13 cases) in relation to primary infertility and 16.12% in secondary infertility in our study. Majority of these cases (46.16) were in stage I followed by 30.77% cases in stage IV with severe endometriosis. Haider et al 201013 reported endometriosis 55% in primary infertility and 20% in secondary infertility, while Aziz 201014 reported endometriosis in 12.5% and 11.11%, respectively. Prevalence of endometriosis varied from 9% to 50% in infertility in various studies.1 In our study, 33.3% patients with chronic pelvic pain were diagnosed with endometriosis, with 60% of these in stage IV severe disease. Incidence of endometriosis was reported to be 17.47% in chronic pelvic pain by Almida Filho et al.12 Among women with pelvic pain, the prevalence range approximately from 30-80%.1 CONCLUSION Laparoscopy remains gold standard for diagnosis of endometriosis. It is an excellent tool in evaluation of patients with infertility and chronic pelvic pain as diagnosis and treatment can be accomplished in one sitting. Early diagnosis and management of endometriosis is need of the hour to prevent catastrophic sequalae. It will go a long way to prevent progression of the disease to severe form hence reducing the morbidity significantly.

REFERENCES 1. John HW, Rock JA (Eds.). Endometriosis (Chap. 22). Te Linde’s Operative Gynaecology. 11th Edition, Philadelphia, USA: Wolters Kluwer; 2015. pp. 402-38. 2. Cramer DW, Missmer SA. The epidemiology of endometriosis. Ann N Y Acad Sci. 2002;955:11-22; discussion 34-6, 396-406. 3. Simpson JL, Elias S, Malinak LR, Buttram VC Jr. Heritable aspects of endometriosis. I. Genetic studies. Am J Obstet Gynecol. 1980;137(3):327-31. 4. Abrão MS, Neme RM, Averbach M. Rectovaginal septum endometriosis: a disease with specific diagnosis and treatment. Arq Gastroenterol. 2003;40(3):192-7. 5. Wykes CB, Clark TJ, Khan KS. Accuracy of laparoscopy in the diagnosis of endometriosis: a systematic quantitative review. BJOG. 2004;111(11):1204-12. 6. Leibson CL, Good AE, Hass SL, Ransom J, Yawn BP, O'Fallon WM, et al. Incidence and characterization of diagnosed endometriosis in a geographically defined population. Fertil Steril. 2004;82(2):314-21. 7. Ballweg ML. Impact of endometriosis on women's health: comparative historical data show that the earlier the onset, the more severe the disease. Best Pract Res Clin Obstet Gynaecol. 2004;18(2):201-18. 8. Salehpour S, Zhaam H, Hakimifard M, Khalili L, Gashb YZ. Evaluation of diagnostic visual findings at laparoscopy in endometriosis. Iranian J Fertil Steril. 2007; 1(3):123-6. 9. Khawaja UB, Khawaja AA, Gowani SA, Shoukat S, Ejaz S, Ali FN, et al. Frequency of endometriosis among infertile women and association of clinical signs and symptoms with the laparoscopic staging of endometriosis. J Pak Med Assoc. 2009;59(1):30-4. 10. Naseer-ud-Din, Khan A, Illahi N. Prevalence and presentation of endometriosis in patients admitted in Nishtar Hospital, Multan. JAMC. 2000;12(3):22-5. 11. Tsuji I, Ami K, Miyazaki A, Hujinami N, Hoshiai H. Benefit of diagnostic laparoscopy for patients with unexplained infertility and normal hysterosalpingography findings. Tohoku J Exp Med. 2009;219(1):39-42. 12. Almeida Filho DP, Oliveira LJ, Amaral VF. Accuracy of laparoscopy for assessing patients with endometriosis. Sao Paulo Med J. 2008;126(6):305-8. 13. Haider G, Rani S, Talpur S, Zehra N, Munir A. Laparoscopic evaluation of female infertility. J Ayub Med Coll Abbottabad. 2010;22(1):136-8.

14. Aziz N. Laparoscopic evaluation of female factors in infertility. J Coll Physicians Surg Pak. 2010;20(10):649-52. ■■■■

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OBSTETRICS AND GYNECOLOGY

Comparison of Serum Anti-mullerian Hormone with Ultrasound as a Diagnostic Marker in Polycystic Ovarian Syndrome ANEESHA AWASTHY*, SHIKHA SINGH†, REKHA RANI‡

ABSTRACT Objectives: To study the sensitivity and specificity of serum anti-mullerian hormone (AMH) as a diagnostic marker in comparison with ultrasound in diagnosed cases of polycystic ovarian syndrome (PCOS). Material and methods: The study was conducted in patients attending the OPD of Dept. of Obstetrics and Gynecology of SN Medical College and Hospital, Agra. Three hundred eighty patients attending OPD with complaints of menstrual irregularities, and/or hirsutism and/or infertility were screened and 80 diagnosed cases of PCOS according to revised Rotterdam criteria (2003) were taken for study. All women included in the study underwent ultrasound for polycystic ovarian morphology (PCOM) and serum AMH levels were measured. Both of them were compared for their sensitivity and specificity in diagnosing PCOS. Study design: This study was a prospective comparative study. Results: The levels of serum AMH were found significantly high (>5 ng/mL) in 93.75% of cases compared to 75% cases being diagnosed with PCOM. Conclusion: Serum AMH is more sensitive and specific in diagnosis of PCOS as compared to ultrasound.

Keywords: Anti-mullerian hormone, polycystic ovarian syndrome, ultrasonography

olycystic ovarian syndrome (PCOS) is the most common endocrine disorder in women of reproductive age group. The prevalence among women of fertile age group is 6-10% using National Institute of Health (NIH) criteria1 and 14-17% using the revised Rotterdam criteria.2 For many years, different combinations of clinical (irregular menstrual cycles, hirsutism), biological (elevated serum testosterone or androstenedione levels or increased luteinizing hormone/follicle-stimulating hormone [LH/FSH] ratio) and ultrasound (US) criteria have been proposed with very little international consensus.3 The aim of the study was to evaluate how anti-mullerian hormone (AMH) actually performs when used instead of polycystic ovarian morphology (PCOM) when diagnosing PCOS in the age group in which it is most prevalent (20-35 years).

*3rd Year Resident †Associate Professor ‡Assistant Professor Dept. of Obstetrics and Gynecology, SN Medical College, Agra, Uttar Pradesh Address for correspondence Dr Aneesha Awasthy D/o Dr KD Sharma H. No. 104, Rajendra Nagar, Bharatpur, Rajasthan

MATERIAL AND METHODS The study was conducted in patients attending indoor and outdoor of Dept. of Obstetrics and Gynecology, SN Medical College and Hospital, Agra and ethical clearance was taken for the same. Three hundred eighty patients attending OPD with complaints of menstrual irregularities, and/or hirsutism and/or infertility were screened and 80 diagnosed cases of PCOS according to revised Rotterdam criteria (2003) were taken for study. The criteria being at least 2 of (1) clinical and/or biochemical signs of hyperandrogenism (HA) (2) oligo and/or ovulation (3) polycystic ovaries. All women included in the study underwent ultrasound for PCOM. Ultrasound machine used was US (Medison 8000 SR) and transvaginal scan (TVS) was preferred for diagnosis. In patients in whom TVS was not possible transabdominal scan (TAS) (3.5-5 MHz) was done. PCOM was identified according to the Rotterdam European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE/ASRM)-sponsored PCOS Consensus Workshop Group, 2003. PCOM as described below was used as diagnosing PCOS. ÂÂ

Presence of either 12 or more follicles measuring 2-9 mm in diameter

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OBSTETRICS AND GYNECOLOGY ÂÂ

An ovarian volume (OV) 10 mL in one or both ovaries.

TVS/TAS was performed by a single observer on the same day that the blood sample was obtained. Measurements were performed in real time, using the highest possible magnification to view the ovaries. Serum AMH levels were measured using an ultrasensitive Generation II enzyme-linked immunosorbent assay (ELISA) (AMHEIA, Beckman Coulter) according to the supplier’s instructions. Results were expressed in nanograms per milliliter. There are no internationally acceptable levels of serum AMH for diagnosis of PCOS. An arbitrary cutoff of 5 ng/mL was taken as positive for the diagnosis of PCOS in our study.

Statistical Analysis Results were reported as mean and standard deviation. Comparisons of means were carried out using the Student’s t-test. P-value <0.05 was considered significant. Sensitivity, specificity, positive and negative predictive values were used to evaluate the results. RESULTS AND OBSERVATIONS Eighty cases having PCOS after screening 380 women were included in the study. Forty-two percent cases belonged to age group of 20-25 years and 58% between 26-35 years (Table 1).

anovulation the mean serum AMH was found to be 7.01 ± 1.10 ng/mL; and in cases having PCOM on USG, hyperandrogenism and anovulation was 6.94 ± 0.99 ng/mL and in cases having only hyperandrogenism and anovulation but no PCOM in USG was 6.73 ± 1.39 ng/mL (Table 4). Maximum number of cases were diagnosed by two important criteria of Rotterdam that are oligo/ anovulation in 96% of cases and USG findings of PCOM, which were positive in 75% of cases while hyperandrogenism was present in 66% of patients (Table 5). Seventy-five PCOS cases in the study group Table 2. Distribution of Cases According to Menstrual Cycle Patterns Menstrual cycle abnormality

No. of cases

Percentage (%)

Amenorrhea

Oligomenorrhea

Polymenorrhea

Polymenorrhagia

Normal cycle

Hypomenorrhea

Total

100

Table 3. Distribution of Cases According to Serum AMH Level

Oligomenorrhea was most common complaint (54%). Amenorrhea (26%) was second most common complaint. Hypomenorrhea was found in (10%) of the cases and polymenorrhea was found in (2%) cases, polymenorrhagia was found in (2%) cases, while normal cycles were seen in (6%) of the cases (Table 2). Majority of the cases (62.5%) had serum AMH level between 5-6.4 ng/mL (Table 3).

Serum AMH (ng/mL) 3.5-4.9 5-6.4 6.5-7.9 ≥8 Total

In our study population, mean serum AMH values in cases having (PCOM) on ultrasound and hyperandrogenism was 7.11 ± 1.14 ng/mL, in those having PCOM in ultrasonography (USG) and

Table 4. Correlation of Mean Serum AMH Values in Cases According to Different Criteria Positivity of Revised Rotterdam Consensus Criteria

No. of cases Percentage (%) 5 6.25 50 62.5 20 25 5 6.25 80 100

Mean serum AMH 4.28 5.64 7.68 8.86

Positivity criteria

No. of patients

Mean serum AMH

Table 1. Distribution of Cases of PCOS According to Age

PCOM in USG + Hyperandrogenism

7.11 ± 1.14

Age (years)

PCOM in USG + Anovulation

7.01 ± 1.10

PCOM in USG + Hyperandrogenism + Anovulation

6.94 ± 0.99

Hyperandrogenism + Anovulation

6.73 ± 1.39

Cases No. of cases

Percentage (%)

20-25

26-30

31-35

Total

100

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OBSTETRICS AND GYNECOLOGY Table 5. Distribution of Cases According to Serum AMH Levels Serum AMH (ng/mL)

No. of patients

Percentage (%)

93.75

6.25

Total

100

Table 6. Comparison of Serum AMH with PCOM (According to Different Statistical Parameters) in Diagnosing PCOS Comparative parameter Sensitivity Specificity

Serum AMH

PCOM in USG

93.75

PPV

0.967

0.89

NPV

0.15

0.60

PPV = Positive predictive value; NPV = Negative predictive value.

had serum AMH levels higher than cut-off (>5 ng/mL), so 75 cases out of 80 tested positive by serum AMH evaluation. While 5 PCOS cases had serum AMH level less than cut off for our study. Seventy-five percent cases, who had PCOM in USG had a mean serum AMH of 7.2 ng/mL, while 25% cases who didn’t have PCOM in USG also had high serum AMH level (6.7 ng/mL). Approximately 62.5% could be diagnosed by both PCOM in USG and serum AMH. But an additional, 21.5% cases could be diagnosed by serum AMH alone. Out of the 6.25% cases not detectable by serum AMH only 2.5% cases had PCOM in USG (Table 6). DISCUSSION This study was an attempt to study the sensitivity and specificity of serum AMH as a diagnostic marker in comparison with PCOM on ultrasound in diagnosed cases among Indian PCOS women and to find a suitable cut-off level of serum AMH. In our study, 42% of patient belonged to age group of 20-25 years and 58% between 26-35 years, thus our study was in accordance with other investigators, who also found PCOS to be common in the age group of 15-39 years, Sharquie et al (2007)4 and 18-35 years according to Vandermolen (2001).5 In our study, PCOS subjects were defined by Revised Rotterdam 2003 criteria. In our study, it was seen that mean serum AMH was higher than the cut-off for all women with different criteria positive. Twenty-five percent cases that didn’t have PCOM in USG and were diagnosed on

the basis of HA and oligo/anovulation also had a mean serum AMH value of 6.73 ± 0.39 ng/mL. In our study; in ultrasound; follicle number (FN) of size 2-5 mm were 13.6 on an average corresponding to high levels of serum AMH. In a study by Dewailly et al,6 it was 12.8. AMH level was 2- to 3-fold higher in PCOS than in controls, an increase of the same order of magnitude as the one of FN in the 2- to 5-mm range. Only the 2- to 5-mm FN remained significantly related to the AMH level. In our study, levels of serum AMH were found in 93.75% cases to be >5 ng/mL while only 6.25% had serum AMH less than the cut-off. Most of the cases (62.5%) had a serum AMH level between 5-6.4 ng/mL. This corresponds to a study by Eilertsen et al,7 where the mean serum AMH level in PCOS-R women is 44.8 pmol/L. Approximately 72.5% cases could be diagnosed by PCOM in USG who also had a serum AMH level >5 ng/mL. But 21.25% cases despite having a serum AMH level >5 ng/mL; couldn’t be detected by PCOM in USG. So, AMH has higher sensitivity in diagnosing PCOS. A study by Wiweko et al,8 also shows that PCOS cases who do not have PCOM in USG also have high serum AMH level (6.0-17.1 ng/mL). Our study shows that AMH could be used as an alternative diagnostic tool in PCOS patients. In a similar study, Pigny et al found that the specificity and sensitivity of serum AMH measurement reached 92% and 67%, respectively.9 Lin et al obtained the cut-off AMH level of 7.3 ng/mL, giving 76% specificity and 70% sensitivity to predict PCOS.10 There exists a good correlation between AMH and PCOM. Van Rooij et al, in a study of 119 patients found serum AMH levels highly correlating with the PCOM.11 Laven et al,12 in a study of PCOS women (n = 128), also found AMH levels to significantly correlate with the mean PCOM. In our study, sensitivity of serum AMH was found to be 93.75% and that of ultrasound was found to be 75% while specificity was 84% and 62%, respectively. In a similar study, Dewailly et al concluded that a serum AMH level of >4.9 ng/mL could be able to replace the finding of PCOM in PCOS.6 Eilertsen et al7 suggested a cut-off value of 4.8 ng/mL for PCOM in PCOS, with 80% sensitivity and 72% specificity, which also corresponds to our study. In a similar study, Homburg et al13 found that a serum AMH threshold of 6.72 ng/mL had an excellent (98%) specificity while using PCOM for PCOS diagnosis.

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OBSTETRICS AND GYNECOLOGY However, this excellent (98%) specificity appeared at the expense of a poor (60%) sensitivity. Casadei et al14 using ROC analysis yielded a threshold cut-off of AMH >4.64 ng/mL for diagnosis of PCOM in PCOS with 95% sensitivity and 95% specificity. These findings open the possibility of a simpler way to diagnose PCOS. According to the high prevalence of the syndrome, the high level of undiagnosed women and the long-term health risk these women face, this seems necessary. If there were an easy way to obtain hyperandrogenism as well, diagnosis could be obtained by a simple question about menstrual regularity and a blood sample. CONCLUSION Our study found serum AMH to be more sensitive and specific than PCOM in diagnosing PCOS. Obtaining good data on ovarian morphology demands a time and resource consuming ultrasound examination by a specialist with appropriate skills. There has been a lack of standardization in assessing PCOM leading to intraobserver and interobserver variations and TVS (transvaginal ultrasound) is required for better diagnosis and TVS is not feasible in unmarried women, so there is need of a serum marker for diagnosis of PCOS, which can make diagnosis easier and uniform. This study was planned to compare sensitivity and specificity of serum AMH with PCOM on ultrasound for diagnosing PCOS cases and found serum AMH to be a useful, noninvasive way of diagnosing PCOS. Larger studies with more number of cohorts need to be done to establish internationally accepted cut-off levels of serum AMH for diagnosis of PCOS. REFERENCES 1. Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab. 1998;83(9):3078-82. 2. Tehrani FR, Simbar M, Tohidi M, Hosseinpanah F, Azizi F. The prevalence of polycystic ovary syndrome in a community sample of Iranian population: Iranian PCOS prevalence study. Reprod Biol Endocrinol. 2011;9:39.

clinical and biochemical characterization of the three major clinical subgroups. Fertil Steril. 2005;83(6):1717-23. 4. Sharquie KE, Al-Bayatti AA, Al-Ajeel AI, Al-Bahar AJ, Al-Nuaimy AA. Free testosterone, luteinizing hormone/ follicle stimulating hormone ratio and pelvic sonography in relation to skin manifestations in patients with polycystic ovary syndrome. Saudi Med J. 2007;28(7): 1039-43. 5. Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma SW, Nestler JE. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril. 2001;75(2):310-5. 6. Dewailly D, Gronier H, Poncelet E, Robin G, Leroy M, Pigny P, et al. Diagnosis of polycystic ovary syndrome (PCOS): revisiting the threshold values of follicle count on ultrasound and of the serum AMH level for the definition of polycystic ovaries. Hum Reprod. 2011;26(11):3123-9. 7. Eilertsen TB, Vanky E, Carlsen SM. Anti-Mullerian hormone in the diagnosis of polycystic ovary syndrome: can morphologic description be replaced? Hum Reprod. 2012;27(8):2494-502. 8. Wiweko B, Maidarti M, Priangga MD, Shafira N, Fernando D, Sumapraja K, et al. Anti-mullerian hormone as a diagnostic and prognostic tool for PCOS patients. J Assist Reprod Genet. 2014;31(10):1311-6. 9. Pigny P, Jonard S, Robert Y, Dewailly D. Serum antiMullerian hormone as a surrogate for antral follicle count for definition of the polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91(3):941-5. 10. Lin YH, Chiu WC, Wu CH, Tzeng CR, Hsu CS, Hsu MI. Antimüllerian hormone and polycystic ovary syndrome. Fertil Steril. 2011;96(1):230-5. 11. van Rooij IA, Broekmans FJ, te Velde ER, Fauser BC, Bancsi LF, de Jong FH, et al. Serum anti-Müllerian hormone levels: a novel measure of ovarian reserve. Hum Reprod. 2002;17(12):3065-71. 12. Laven JS, Mulders AG, Visser JA, Themmen AP, De Jong FH, Fauser BC. Anti-Müllerian hormone serum concentrations in normoovulatory and anovulatory women of reproductive age. J Clin Endocrinol Metab. 2004;89(1):318-23. 13. Homburg R, Ray A, Bhide P, Gudi A, Shah A, Timms P, et al. The relationship of serum anti-Mullerian hormone with polycystic ovarian morphology and polycystic ovary syndrome: a prospective cohort study. Hum Reprod. 2013;28(4):1077-83.

14. Casadei L, Madrigale A, Puca F, Manicuti C, Emidi E, Piccione E, et al. The role of serum anti-Müllerian 3. Chang WY, Knochenhauer ES, Bartolucci AA, Azziz R. hormone (AMH) in the hormonal diagnosis of polycystic Phenotypic spectrum of polycystic ovary syndrome: ovary syndrome. Gynecol Endocrinol. 2013;29(6):545-50. ■■■■

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OBSTETRICS AND GYNECOLOGY

Predictive Factors for Pregnancy After Controlled Ovarian Hyperstimulation and Intrauterine Insemination: A Prospective Study SHIKHA JAIN

ABSTRACT Intrauterine insemination (IUI), a widely used technique, a step between the simpler ovulation induction and the more advanced in vitro fertilization, has become the first-line assisted reproductive therapeutic option for infertile couples. Several prognostic factors with regard to IUI have been identified such as patient profile, duration of infertility, type of infertility, follicular response, endometrial thickness, timing of IUI and semen parameters. An observational study was conducted in Dept. of Obstetrics and Gynecology, SMS Medical College, Jaipur from the year January 2013 to January 2014 to find out predictive factors for pregnancy after controlled ovarian hyperstimulation and IUI.

Keywords: Intrauterine insemination, ovulation induction, clomiphene citrate, human chorionic gonadotropin

nfertility affects more than 10% of the population and has a major psychological impact leading to depression and anxiety symptoms. Intrauterine insemination (IUI) is a widely used technique. It has become the first-line assisted reproductive therapeutic option for infertile couples. It is a step between the simpler ovulation induction and the more advanced in vitro fertilization. IUI and ovulation induction are often combined in order to increase the effectiveness and likelihood of infertility treatment. Ovulation induction increases the number of oocytes available for fertilization, thus increasing the chances of pregnancy. Ovulation may be induced with clomiphene citrate (CC) and CC + human chorionic gonadotropin (hCG).

IUI has also been used to treat a variety of physiological and psychological male and female infertility disorders such as severe hypospadias and retrograde ejaculation. Ovulation occurs anytime from 24 to 56 hours after the onset of luteinizing hormone surge with a mean time of 36 hours. After an injection of Î˛-hCG, follicle ruptures after 36-48 hours.

IUI is a therapeutic process of placing washed spermatozoa transcervically into the uterine cavity. Those who benefit the most are young women with patent fallopian tubes, no ovulatory disorder, no endometriosis of moderate or severe degree and no severe degree of male factor infertility.

MATERIAL AND METHODS

Consultant Gynecologist Deen Dayal Upadhyay Hospital, New Delhi Address for correspondence Dr Shikha Jain Consultant Gynecologist Deen Dayal Upadhyay Hospital, New Delhi - 110 064 E-mail: shikhajaingwalior@gmail.com

Several prognostic factors with regard to IUI have been identified such as patient profile, duration of infertility, type of infertility, follicular response, endometrial thickness, timing of IUI and semen parameters but endometrial thickness was found to be most statistically significant.

This hospital-based descriptive type of observational study was conducted in Dept. of Obstetrics and Gynecology, SMS Medical College, Jaipur from the year January 2013 to January 2014. Written informed consent by each subject was taken before the study. All couples included in study group had at least 1 year of infertility and had undergone basic infertility evaluation consisting of hormonal study, hysterosalpingography, ovulation study, thyroid levels, prolactin levels, ultrasonography and semen analysis. Patients with known bilateral tubal factor infertility were excluded from the study. The protocol for ovulation induction included clomiphene citrate. Tablet clomiphene citrate 50 mg was given

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OBSTETRICS AND GYNECOLOGY from Day 2 of menstrual cycle for 5 days. On Day 9, assessment of follicular development was performed using transvaginal ultrasonography. Once a follicle reached a size of 20 mm, injection hCG 5000 IU was given as an ovulation trigger and IUI was perfomed 36 hours later under aseptic conditions using IUI catheter with a semen volume of 0.5 mL prepared with density gradient method. If menstrual cycle was delayed, urine pregnancy test was carried out. Luteal phase was supported by daily vaginal administration of 200 mg progesterone for 14 days. When urine pregnancy test was positive, transvaginal sonography was performed 2 weeks later to confirm a clinical pregnancy, which is defined as intrauterine gestational sac.

ovary syndrome (PCOS) group. So, pregnancy rate was 20.83% in male factor infertility group and 21.50% in PCOS group. In patients with unexplained infertility and endometriosis, pregnancy rate was 8.71% and 5.88%, respectively. Pregnancy rate was 50.05% in case of combined male factor and unexplained infertility. The difference was statistically significant (p <0.001) (Table 2).

RESULTS

Table 4 shows that out of 27 people in whom endometrial thickness was <6 mm, only 2 achieved pregnancy with a pregnancy rate of 7.40%. The pregnancy rate was 14.28% and 16.18% in people in whom endometrial thickness was 6 to <8 mm and 8 to <10 mm, respectively. Out of 34 people who had endometrial thickness between 10-12 mm, only 1 achieved pregnancy with a pregnancy rate of 8.33%. The difference was statistically significant (p value 0.03).

Table 1 shows that out of 86 people who were in the age group 17-25 years, only 14 achieved pregnancy with a pregnancy rate of 16.27%. Pregnancy rate was 14.11% and 6.06% in people of age group 26-35 years and 36-40 years, respectively. Out of 12 people aged more than 40 years only 1 achieved clinical pregnancy with a pregnancy rate of 8.33%. However, the difference was not stastistically significant (p = 0.14). Total no. of 386 stimulated cycles were analyzed. The overall pregnancy rate was 14.5%. Fifteen out of 72 patients with male factor infertility achieved pregnancy and 20 out of 93 achieved pregnancy in polycystic Table 1. Distribution of Cases According to Age Age

No. of cycles

Clinical Rates (%) pregnancy

P value* 0.14

Table 3 shows that out of 219 patients in whom duration of infertility was less than 6 years, 65 achieved pregnancy compared to 42 people out of 167 in whom duration of infertility was greater than 6 years. Pregnancy rate was 16.8% in first group and 10.8% in second group. However, the difference was not statistically significant.

Table 5 shows that out of 167 cycles which had homogenous endometrial pattern, only 22 achieved pregnancy with a pregnancy rate of 13.17%. Out of 219 cycles, 34 achieved pregnancy with trilaminar pattern of endometrium with a pregnancy rate of 15.5%. Table 3. Distribution of Cases According to Duration of Infertility Duration of infertility

No. of cycles

Clinical Rates (%) pregnancy

17-25

16.27

26-35

255

14.11

â&#x2030;¤6

219

16.8

36-40

6.06

167

10.8

>40

8.33

P value* 0.32

*P value for chi-square for trend test.

Table 2. Distribution of Cases According to Etiology Etiology

No. of cycles

Clinical Rates (%) pregnancy

P value*

Endometrial thickness <6

No. of cycles

Clinical pregnancy

Rates (%)

P value*

7.40

0.03

Male factor

20.83

PCOS

21.50

6 to <8

140

14.28

Endometriosis

5.88

8 to <10

173

16.18

Unexplained

195

8.71

10 to <12

14.70

50.05

â&#x2030;Ľ 12

8.33

M + PCOS

<0.001

Table 4. Distribution of Cases According to Endometrial Thickness

*P value for chi-square for trend test.

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*P value for chi-square for trend test.

OBSTETRICS AND GYNECOLOGY Table 5. Distribution of Cases According to Endometrial Pattern Pattern of endometrium

No. of cycles

Clinical pregnancy

Rates (%)

Homogeneous

167

13.17

Trilaminar

219

15.5

DISCUSSION In our study, the mean age of patients, who had a positive outcome with IUI was 26.84 years, while in the patients who had a negative outcome with IUI was 28.58 years. The age of the patient significantly affected the pregnancy outcome (i.e., younger age was significantly associated with a better pregnancy outcome). Several studies have shown an association between increasing maternal age and poor pregnancy rates following IUI. Horbay et al (1991) showed a significant decline in pregnancy rate after IUI in women more than 36 years age. Campana et al (1996) also found that outcome of IUI was adversely affected if the woman’s age was more than 39 years. Brzechtta et al (1997) found that increased female age more than 35 years negatively influenced pregnancy rates. Stone et al (1999) found that patient’s age was the main determinant of pregnancy outcome. Dickey et al (2002) found significantly lower pregnancy rates with IUI in women more than 43 years age. Bellac et al (2008) also found that advanced maternal age had a negative effect on pregnancy rate. Demir et al (2011) showed that pregnancy rate was the highest in IUI cycles when woman was less than 25 years old. With decreasing costs and increase in safety in vitro fertilization has become a favored option in women with age more than 35 years. In our study, the mean duration infertility in the positive outcome group was 6.0 years while in the negative outcome group it was 7.79 years. Table 3 shows that increased duration of infertility negatively influences pregnancy rates following IUI. However, the results were not significant statistically. Nuojua-Huttunen et al (1999) stated that duration of infertility is one of the five variables that affect pregnancy outcome following IUI. Iberico et al (2004) showed that infertility duration ≥3 years was marginally associated with a lower pregnancy rate. Zadeh Modarres et al (2009) stated that duration of infertility was one of the three predictive variables as regards pregnancy following IUI cycles. Kamath et al (2010) found that duration of infertility significantly

influenced the clinical pregnancy rate in IUI cycles. There is significant consensus regarding the association between endometrial thickness and IUI results. While some researchers have found endometrial thickness to be a prognostic indicator of IUI success, others have found endometrial thickness on the day of hCG injection to have no such discriminative ability. Tomlinson et al (1996) identified endometrial thickness as one of the four significant IUI variables influencing pregnancy outcome. Habibzadeh et al (2010) stated that the pregnancy rate was higher in endometrial thickness 6 < ET ≤ 10 mm. The mean endometrial thickness in their study (with CC and gonadotropins) was 7.2 ± 1.8 mm. In our study, the pregnancy rate was higher in patients with male factor infertility as compared to unexplained infertility (1% vs. 11.11%). However, the difference was also significant (p = 0.001). Several studies have tried to ascertain whether the etiology of infertility has any prognostic significance with regards to the pregnancy rates achieved following IUI. Lucette et al (1998) found that the pregnancy rate for first IUI attempts were 5.0% for andrological indication and 10.00% for idiopathic indication. They used controlled ovarian hyperstimulation (COH) with CC, no hCG was administered and Percoll gradient technique was used for sperm preparation. In the group with andrological indication, all patients with a sperm count <20 million/mL were included and there was no lower limit. Nuojua-Huttunen et al (1999) found a pregnancy rate of 15.3% in patients with unexplained infertility and pregnancy of 11.8% in those with male factor infertility. They used a stimulation protocol of CC/human menopausal gonadotropin (hMG)/hCG and swim up or Percoll gradient technique for sperm preparation. If the progressive motile sperm count after preparation was <1 × 106 /mL, couples were not enrolled in IUI treatment. Liu et al (2006) found an overall pregnancy rate in the mild male factor infertility group to be 18.1%, which was greater than the pregnancy rate in the unexplained infertility group (11.2%). Bagis et al (2010) found a live birth rate of 14.89% in patients with unexplained infertility and 9.09% in patients with male factor infertility. Only cycles with multifollicular development were included. Kamath et al (2010) concluded that pregnancy rate per cycle of 10.6 in patients with anovulation, 5.37% in patients with male factor infertility, 7.89% in patients with endometriosis and 11.38% in patients with unexplained

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OBSTETRICS AND GYNECOLOGY infertility. The difference in pregnancy rates was not significant (Chi-square = 0.494). COH was done using CC and hMG, alone or in combination with or without hCG, semen was prepared using double-density gradient method. In our study, we found that endometrial pattern along with thickness also affects clinical pregnancy rate. Previous studies also showed similar results. The different pregnancy rates in our study in patients with male factor infertility compared to other studies may be attributed to the lack of standardization of semen analysis and different thresholds for semen parameters for performing IUI in different studies. On the other hand, various counting chambers are used with different methodologies (e.g., manual vs. computerized) to calculate these parameters. Consequently, the variation of results among centers may well be beyond acceptable, weakening the results reported by several studies.

infertility. Endometrial thickness with associated pattern are the most significantly correlate with positive pregnancy rate. We found no statistically significant association between husband's age, patient's body mass index (BMI), duration of infertility, number of preovulatory follicles on the day of hCG, type of infertility, etiology of infertility or prewash semen parameters and IUI outcome. SUGGESTED READING 1. Kamath MS, Bhave P, Aleyamma T, Nair R, Chandy A, Mangalaraj AM, et al. Predictive factors for pregnancy after intrauterine insemination: A prospective study of factors affecting outcome. J Hum Reprod Sci. 2010;3(3): 129-34. 2. Habibzadeh V, Nematolahi Mahani SN, Kamyab H. The correlation of factors affecting the endometrial thickness with pregnancy outcome in the IUI cycles. Iran J Reprod Med. 2011;9(1):41-6.

3. Bagis T, Haydardedeoglu B, Kilicdag EB, Cok T, Simsek E, Parlakgumus AH. Single versus double intrauterine insemination in multi-follicular ovarian hyperstimulation COH-IUI is an effective first-line method of treatment cycles: a randomized trial. Hum Reprod. 2010;25(7): in patients with mild male factor and unexplained 1684-90. ■■■■

CONCLUSION

Prehypertension in Pregnancy Increases Risk of Metabolic Syndrome A study from China reported in the journal Hypertension has shown that prehypertension among pregnant women can predict the development of postpartum metabolic syndrome. A single at-term measurement of diastolic blood pressure at the prehypertensive threshold of 80 mm Hg or higher was associated with an adjusted odds ratio of 2.94 for subsequent metabolic syndrome vs below 80 mmHg. Women with a diastolic blood pressure trajectory putting them in the prehypertensive range for much of their pregnancy were 6.5 times more likely to develop postpartum metabolic syndrome versus women who were classified as having lower or normal blood pressure while pregnant.

ACOG Issues New Recommendations on Obstetric Lacerations The American College of Obstetricians and Gynecologists (ACOG) has issued new recommendations for the prevention and management of obstetric lacerations at vaginal delivery. The document published in the July issue of Obstetrics & Gynecology provides evidence-based guidelines for the prevention, identification, and repair of obstetric lacerations and for episiotomy. The common, minor tears of the anterior vaginal wall and labia can be left unrepaired, but "periclitoral, periurethral, and labial lacerations that are bleeding or distort anatomy" should be repaired. If a clinician decides to repair these lacerations, recommended sutures are absorbable synthetic ones, such as polyglactin, and continuous suturing is best over interrupted suturing. For full-thickness external anal sphincter lacerations endto-end repair or overlap repair is acceptable. A single dose of antibiotics is also recommended when repairing obstetric anal sphincter injuries.

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OBSTETRICS AND GYNECOLOGY

Ectopic Pregnancy Presenting as True Gestational Epilepsy SHYAMAL G*, VIJAYALAKSHMI†, SUNIL KUMAR N‡, ANUDEEP REDDY‡

ABSTRACT Ectopic pregnancy refers to implantation of fertilized egg in a location outside of uterine cavity including fallopian tube, cervix, ovary, cornual region of uterus and abdominal cavity. It is a life-threatening condition. Though it is familiar to physicians when it presents with abdominal pain, amenorrhea, vaginal bleeding, but when it gets ruptured patients present with weakness, dizziness, near syncope and low blood pressure. Ectopic pregnancy, presenting as multiple episodes of seizures, is difficult to distinguish from other causes of seizures. Here we describe a previously normal 24-year-old female, with no previous history of seizures, who presented with 8 weeks of amenorrhea and sudden onset of seizures (true gestational epilepsy).

Keywords: Ectopic pregnancy, seizures, true gestational epilepsy

ctopic pregnancy refers to implantation of blastocyst anywhere else other than endometrial lining of uterus in the uterine cavity. It almost occurs 2 in every 100 pregnancies and over 95% involve oviduct. This is life- and fertility-threatening for further pregnancy. The rate of ectopic pregnancy was increased to 4-fold since 1970. The incidence of ectopic pregnancy for nonwhite is 1.5 times compared to whites. Although ectopic pregnancy is familiar to most of physicians, ectopic pregnancy presenting with atypical symptoms like new-onset seizures is very difficult to distinguish from other causes of seizures such as cerebral venous thrombosis, cerebrovascular accident, eclampsia, electrolyte disorders, neurocysticercosis, autoimmune encephalitis, anxiety, stress, hyperventilation, other structural disorders due to similar presentations. Here we describe a 24-year-old female with 2 months of amenorrhea who presented

*Professor Dept. of Medicine †Associate Professor Dept. of Obstetrics and Gynecology ‡Post Graduate Dept. of Medicine Vijayanagara Institute of Medical Sciences, Bellary, Karnataka Address for correspondence Dr Sunil Kumar N Post Graduate Dept. of Medicine Vijayanagara Institute of Medical Sciences, Bellary, Karnataka E-mail: sunil.kumar.n6@gmail.com

to emergency in altered sensorium after 7 episodes of generalized tonic-clonic seizures (GTCS) for which she was referred from a peripheral center. CASE REPORT A 24-year-old female presented to emergency department with altered sensorium following 7 episodes of GTCS. She had history of 2 months of amenorrhea and was a primi who was not aware of her pregnancy. On examination, her pulse rate was 95/min and blood pressure was 110/80 mmHg. Patient was pale and tachypneic. Patient was conscious and in postictal confusion with no other focal neurological deficits. Systemic examination was otherwise normal. Laboratory work-up revealed: Hemoglobin - 4.5 g/dL, leukocyte count - 8,900/mm3, platelet count - 1.2 lakh/µL. Blood urea levels of 48 mg/dL and creatinine level of 1.2 mg/dL. Sodium, potassium, chloride, calcium levels were 138 mEq/L, 3.3 mEq/L, 108 mEq/L, 4.0 mEq/dL, respectively; urine albumin was negative. Vanillylmandelic acid (VMA) levels were normal. Chest X-ray and CT brain with contrast were normal. Ultrasound abdomen showed an ill-defined hypoechoic lesion in pelvic region possibly due to ruptured ectopic pregnancy, 350 cc of volume collection. A diagnosis of ectopic pregnancy was made and patient was taken for emergency laparotomy. Laparotomy revealed clots and hemoperitoneum. Ampullary end of the left fallopian tube was found ruptured (Fig. 1 a and b). The clots, measuring about 550 g,

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OBSTETRICS AND GYNECOLOGY The incidence is higher in women between 35 and 44 years of age and it is counted as 27 per 1,000 reported pregnancies.4 Distribution of cases in percentage according to predisposing factors are pelvic inflammatory disease (47.5%), infertility treatment (22.5%), previous ectopic pregnancy (25%), tubal surgery (10%), lower-segment cesarean section (12.5%) and intrauterine contraceptive device (IUCD) insertion (12.5%).5 No single clinical feature accurately indicates ectopic pregnancy. Less than half of women with ectopic pregnancy exhibit the classic triad of a history of amenorrhea, abdominal pain and irregular vaginal bleeding. And, unfortunately, these features are seen commonly in patients with both viable (50%) and nonviable (25%) intrauterine pregnancies, as well as in threatened abortion, cervical irritation, infection and trauma.6

Figure 1 a and b. Ampullary end of fallopian tube was found ruptured at emergency laparotomy.

were removed and around 1,000 mL of peritoneal fluid was drained. Hemostasis was achieved and tubes were transfixed and ligated. She was resuscitated with blood. Antiepileptic, injection phenytoin 100 mg t.i.d., was administered for 8 days. Antibiotic coverage was given and further course in hospital was uneventful. On further follow-up, she was seizure-free for a period lasting more than 6 months. DISCUSSION Ectopic pregnancy, the implantation of a fertilized ovum outside the uterine cavity, has been increasing in numbers and now accounts for 2% of all pregnancies in the United States.1 Worldwide, ectopic pregnancy remains the leading cause of maternal death in the first trimester.2 Ectopic pregnancy continues to be an important contributor to maternal mortality, morbidity and early fetal wastage in the first trimester of pregnancy.3

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Abdominal pain and vaginal bleeding are highly sensitive for ectopic pregnancy, but are not specific for the disorder. Pain located in the hypogastrium or iliac fossa may be mild-to-severe. Vaginal bleeding, present in 50-80% of patients with ectopic pregnancy, can be mistaken for a normal menstrual period. Pregnancyassociated symptoms of nausea and vomiting, breast tenderness and fatigue may be present. Lower abdominal and adnexal tenderness can be elicited in most women with ectopic pregnancy. Cervical motion tenderness, peritoneal signs and adnexal masses are most specific for ectopic pregnancy, but are not sensitive. An adnexal mass is palpable in less than 10% of cases; when it is detected, one-third of patients will have a contralateral ectopic pregnancy on ultrasonography. Symptoms of hemodynamic compromise (orthostasis, hypotension, shock) are becoming uncommon with earlier diagnosis of ectopic pregnancy, facilitated by improved detection methods.6 The above-mentioned clinical features make the diagnosis of ectopic pregnancy easy, but when it presents with none of above-mentioned symptoms it, like our case, makes the diagnosis difficult. True gestational epilepsy is one of cause for seizures in pregnancy. An ectopic pregnancy can present as true gestational epilepsy like in our case. It is wellknown fact that estrogens activate seizure foci and lower seizure threshold and progesterones dampen the seizure foci.7 Differential diagnosis of convulsion diagnosed for the first time during pregnancy include: eclampsia, thrombotic thrombocytopenic purpura,8 pheochromocytoma, neurofibromatosis, oxytocin infusion, water intoxication, cerebral vein thrombosis, neurocysticercosis,9 autoimmune encephalitis and

OBSTETRICS AND GYNECOLOGY anti-NMDA (N-methyl-D-aspartate) receptor encephalitis during pregnancy.10 Other metabolic and structural causes of seizures were ruled out from relevant investigations. During pregnancy, seizures presenting first time is called true gestational epilepsy.10 In our case, she did not have any past history of epilepsy and all abovementioned and possible structural and metabolic causes were ruled out. In our patient, after removal of ectopic products of conception, there were no further episodes of seizures and at follow-up till now about 6 months, no further complications occurred. So, the convulsions could be attributed to ectopic pregnancy, which is very unusual. CONCLUSION There are many causes of seizures in pregnancy. Ectopic pregnancy, autoimmune encephalitis and neurocysticercosis have to be considered as some of the important differential diagnosis after ruling out common causes of seizures in pregnancy mentioned above. Early recognition of the disease and prompt treatment of the condition will be a lifesaving and fertility preserving measure. REFERENCES

2. Autry AM. Medical treatment of ectopic pregnancy: is there something new? Obstet Gynecol. 2013;122(4): 733-4. 3. Igberase GO, Ebeigbe PN, Igbekoyi OF, Ajufoh BI. Ectopic pregnancy: an 11-year review in a tertiary centre in the Niger Delta. Trop Doct. 2005;35(3):175-7. 4. Goldner TE, Lawson HW, Xia Z, Atrash HK. Surveillance for ectopic pregnancy -United States, 1970-1989. MMWR CDC Surveill Summ. 1993;42(6):73-85. 5. Gupta R, Porwal S, Swarnkar M, Sharma N, Maheshwari P. Incidence, trends and risk factors for ectopic pregnancies in a tertiary care hospital of Rajasthan. JPBMS. 2012;16(7):1-3. 6. Ramakrishnan K, Scheid DC. Ectopic pregnancy: forget the "classic presentation" if you want to catch it sooner. J Fam Pract. 2006;55(5):388-95. 7. Gerard N Bamboo, Thomas P Duffy. Medical Complications During Pregnancy. 5th Edition, 411. 8. Kafali H, Harma M, Harma M. Pseudoeclampsia: convulsion diagnosed for the first time during pregnancy; eclampsia versus epileptic or psychogenic seizures. Artemis. 2004;5(1):70-2. 9. Suarez VR, Iannucci TA. Neurocysticercosis in pregnancy: a case initially diagnosed as eclampsia. Obstet Gynecol. 1999;93(5 Pt 2):816-8.

10. Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, et al. Anti-NMDA-receptor encephalitis: case series 1. Centers for Disease Control and Prevention (CDC). and analysis of the effects of antibodies. Lancet Neurol. Ectopic pregnancy - United States, 1990-1992. MMWR Morb Mortal Wkly Rep. 1995;44(3):46-8. 2008;7(12):1091-8. ■■■■

No Role of Oral Probiotics in Vaginal Health in Pregnancy A study, published online in the American Journal of Obstetrics and Gynecology, evaluated the impact of an oral probiotic food supplement on the maintenance or restoration of a normal vaginal microbiota during pregnancy. Oral Lactobacillus rhamnosus, GR-1® and L. reuteri, RC-14® (109 CFU) or placebo were administered for 8 weeks to women with <12 completed weeks of pregnancy. The proportion of normal vaginal microbiota decreased from 82.6% to 77.8% in the treatment group and from 79.1% to 74.3% in the placebo group, with no significant difference across groups post-intervention

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PEDIATRICS

Pierre Robin Syndrome NISHAD PATIL*, SUNIL MHASKE†, RAMESH B KOTHARI‡, SANDIP DEOKATE*, RAM SETHI*, PAVAN SURYAWANSHI*, RAHUL MASKI*, NIVRUTTI MUNDHE*, SURAJ NAIR#

ABSTRACT Pierre Robin syndrome (or sequence) is a condition present at birth, in which the infant has a smaller-than-normal lower jaw, a tongue that falls back in the throat, and has difficulty in breathing. Most infants, but not all, will also have a cleft palate, but none will have a cleft lip. This heterogeneous birth defect has prevalence of approximately 1 per 8,500 live births. The maleto-female ratio is 1:1, except in the X-linked form. Autosomal recessive inheritance is possible.

Keywords: Cleft soft palate, micrognathia, obstructive sleep apnea, otitis media

ierre Robin sequence or complex is the name given to a birth condition that involves the lower jaw which is either small in size (micrognathia) or set back from the upper jaw (retrognathia). As a result, the tongue tends to be displaced back towards the throat, where it can fall back and obstruct the airway (glossoptosis). Most infants, but not all, will also have a cleft palate, but none will have a cleft lip.

CASE REPORT A 6-month-old female child was brought to our out patient department (OPD) by mother with complaints of fever, cough and running nose since last 2 days. Fever was of gradual onset, slowly rising, intermittent, moderate grade without any chills or rigors. Cough was also of gradual onset, dry, intermittent, without any diurnal or postural variations. Parents gave history of repeated attacks of upper respiratory tract infections, associated with a single episode of otitis media in the past. Also parents gave history of disturbed sleep pattern of baby. She was fifth issue of nonconsanguineous marriage, born as a full-term, normal, hospital delivery

*Resident

†Professor ‡Assistant #Intern

Figure 1. Pierre Robin syndrome.

and Head Professor

Dept. of Pediatrics, Padmashree Dr Vithalrao Vikhe Patil Medical College and Hospital Ahmednagar, Gujarat Address for correspondence Dr Sunil Mhaske Professor and Head, Dept. of Pediatrics Padmashree Dr Vithalrao Vikhe Patil Medical College and Hospital Near Govt. Milk Dairy, Vilad Ghat, Ahmednagar - 414 111, Gujarat

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with good cry and weight at birth. The other siblings (includes two males and two females) were not having any congenital anomaly. On examination, her weight was 5.27 kg, length 61 cm, head circumference 39 cm (normal - 44 cm) and chest circumference 38 cm. All vital parameters were within normal limits as per her age. On head to toe examination, she was having high arched, U-shaped, cleft soft palate. Jaw was very small with small receding chin (Figs. 1 and 2).

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Micrognathia

Cleft palate

Figure 2. Pierre Robin syndrome.

PEDIATRICS Also jaw was far back in throat and the tongue was large compared to the jaw. There was a small opening in the roof of mouth, that caused choking. She was having congenital talipes equino varus (CTEV) of right foot. Presently, there was no earache or ear discharge. The systemic examination was not showing any abnormality. An opinion from ENT specialist was also taken to examine middle and inner ear, which stated no active otitis media as well as any hearing loss. DISCUSSION Lannelongue and Menard first described Pierre Robin syndrome in 1891 in a report on 2 patients with micrognathia, cleft palate and retro-glossoptosis. In 1926, Pierre Robin published the case of an infant with the complete syndrome. Until 1974, the triad was known as “Pierre Robin syndrome”; however, the term “syndrome” is now reserved for those errors of morphogenesis with the simultaneous presence of multiple anomalies caused by a single etiology. The term “sequence” has been introduced to include any condition that includes a series of anomalies caused by a cascade of events initiated by a single malformation. Over the years, there have been several names given to the condition, including Pierre Robin syndrome, Pierre Robin triad. Based on the varying features and causes of the condition, either “Robin sequence” or “Robin complex” may be an appropriate description for a specific patient. Pierre Robin was a French physician who first reported the combination of small lower jaw, cleft palate and tongue displacement in 1923. This heterogeneous birth defect has prevalence of approximately 1 per 8,500 live births. The maleto-female ratio is 1:1, except in the X-linked form. Autosomal recessive inheritance is possible. An X-linked variant has been reported involving cardiac malformations and clubfeet.

The alveolar overjet is the distance between the most anterior points of the upper and lower alveolar arches. The maxillary arch is the measurement between the 2 tragi via the subnasal point and the mandibular arch is the distance from the right to the left tragus passing through the pogonion. Glossoptosis is noted in 70-85% of reported cases. Macroglossia and ankyloglossia are relatively rare findings. The combination of micrognathia and glossoptosis may cause severe respiratory and feeding difficulty in the newborn. Obstructive sleep apnea may also occur. It can affect the soft and hard palate and is usually U-shaped or V-shaped (Fig. 5). Occasionally, it may present as a bifid or double uvula or as an occult submucous cleft. The most common otic anomaly is otitis media, followed by auricular anomalies. Hearing loss is mostly conductive, while external auditory canal atresia occurs in only 5% of patients. Temporal bone computerized planigraphs demonstrate inadequate pneumatization of the mastoid cavities in many patients with Pierre Robin sequence. Nasal deformities are infrequent and consist mostly of anomalies of the nasal root. Dental

Figure 3. Pierre Robin syndrome.

Otolaryngologic Manifestations Micrognathia is reported in the majority of cases (91.7%) (Figs. 3 and 4). It is characterized by retraction of the inferior dental arch 10-12 mm behind the superior arch. The mandible has a small body, obtuse genial angle and a posteriorly located condyle. The growth of the mandible catches up during the first year; however, mandibular hypoplasia resolves and the child attains a normal profile by approximately age 5-6 years. The jaw index is defined as the alveolar overjet multiplied by the maxillary arch divided by the mandibular arch. This index can be used to objectify mandibular growth.

Figure 4. Micrognathia.

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PEDIATRICS deletion 4q syndrome, rheumatoid arthropathy, hypochondroplasia, Moebius syndrome, and CHARGE association.

Pathogenesis Three pathophysiological theories exist to explain the occurrence of Pierre Robin sequence. a

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The mechanical theory: This theory is the most accepted. The initial event, mandibular hypoplasia, occurs between the 7th and 11th week of gestation. This keeps the tongue high in the oral cavity, causing a cleft in the palate by preventing the closure of the palatal shelves. This theory explains the classic inverted U-shaped cleft and the absence of an associated cleft lip. Oligohydramnios could play a role in the etiology, since the lack of amniotic fluid could cause deformation of the chin and subsequent impaction of the tongue between the palatal shelves.

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The neurological maturation theory: A delay in neurological maturation has been noted on electromyography of the tongue musculature, the pharyngeal pillars and the palate, as has a delay in hypoglossal nerve conduction. The spontaneous correction of the majority of cases with age supports this theory.

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The rhombencephalic dysneurulation theory: In this theory, the motor and regulatory organization of the rhombencephalus is related to a major problem of ontogenesis.

Figure 5. U-shaped cleft palate (a); V-shaped cleft palate (b).

and philtral malformations occur in one third of cases. Laryngomalacia occurs in approximately 10-15% of patients with Pierre Robin sequence. Gastroesophageal reflux and esophagitis has also been described. Speech defects occur frequently in patients with Pierre Robin sequence. Velopharyngeal insufficiency is usually more pronounced in these patients than in those with isolated cleft palate.

Systemic Manifestations In general, systemic anomalies can be seen in various cases. Anomalies involving the musculoskeletal system are the most frequent systemic anomalies. They include syndactyly, dysplastic phalanges, polydactyly, clinodactyly, hyperextensible joints and oligodactyly in the upper limbs. In the lower extremities, foot anomalies (clubfeet, metatarsus adductus), femoral malformations (coxa varus or valgus, short femur), hip anomalies (flexure contractures, congenital dislocation), anomalies of the knee (genu valgus, synchondrosis) and tibial abnormalities have been reported. Vertebral column deformities include scoliosis, kyphosis, lordosis, vertebral dysplasia, sacral agenesis and coccygeal sinus. Cardiovascular findings such as benign murmurs, pulmonary stenosis, patent ductus arteriosus, patent foramen ovale, atrial septal defect and pulmonary hypertension have all been documented. Central nervous system (CNS) defects such as language delay, epilepsy, neurodevelopmental delay, hypotonia and hydrocephalus may occur. Ocular anomalies are seen as per following in decreasing order of frequency: hypermetropia, myopia, astigmatism, corneal sclerosis and nasolacrimal duct stenosis. Genitourinary defects may include undescended testes, hydronephrosis and hydrocele. Associated syndromes and conditions include Stickler syndrome, trisomy 11q syndrome, trisomy 18 syndrome, velocardiofacial (Shprintzen) syndrome,

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Conservative Management ÂÂ In the majority of patients, conservative management with close observation and follow- up is successful. The natural history shows that with normal growth, airway compromise resolves without immediate surgical intervention. Isolated Pierre Robin syndrome patients usually respond more favorably to the conservative approach. ÂÂ Recently, Abel et al (2012) reported on longterm outcomes in 104 children with Pierre Robin syndrome and airway obstruction. In most children (86.5%), airway obstruction was managed by conservative measures or with a nasopharyngeal airway (NPA) for a few months. ÂÂ Prone positional therapy has proved to be highly efficient in airway management. Oral airway placement, laryngeal mask, nasopharyngeal stenting and short-term intubation (<2 week) are other options in case positioning is inadequate. Intubation is often difficult owing to the

PEDIATRICS micrognathia and should be performed by someone specialized in problematic pediatric airway management. ÂÂ

Feeding difficulties can be alleviated by upright feeding techniques, modification of the nipple for bottle feeding, temporary use of nasogastric or orogastric feeding tube and the placement of a gastrostomy. Palatal plates such as the pre-epiglottic baton plate, which have a velar extension, pull the base of the tongue forward. This can be helpful in the relief of airway obstruction, and it also facilitates the swallowing mechanism during feeds.

lengthening by gradual distraction may be used for severe mandibular hypoplasia that causes obstructive apnea. Published articles by Hong and others (2011, 2012) on the use of mandibular distraction osteogenesis in Pierre Robin syndrome patients have described significant improvements in both airway obstructive symptoms and feeding abnormalities. Patients showed clinical and objective improvements in reflux and swallowing function after surgery. ÂÂ

As the therapy of choice to correct the conductive hearing loss and prevent middle ear complications, tympanostomy tubes are usually inserted when the palatoplasty is performed.

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Surgical procedures to repair the cleft palate, details of which are not included herein, fall into 1 of 2 categories. The first category comprises all the one-stage procedures, and the second includes all multistage approaches in which the velum is initially closed and hard palate repair is delayed. The most common procedure is the single-stage palate (hard and soft) closure, performed when the child is aged 6-18 months.

Surgical Management ÂÂ

ÂÂ

Infants with pronounced micrognathia may experience severe respiratory distress or failure to thrive. Treatment is prioritized according to the severity of airway compromise followed by the extent of feeding difficulties. Lidsky et al (2008) reviewed 67 Pierre Robin syndrome patients from their multidisciplinary cleft team at a tertiary pediatric hospital. They found that delaying airway intervention may necessitate feeding assistance via a G-tube. Surgical intervention is necessary in these cases. Although many different surgical procedures have been described, tracheostomy remains the most widely used technique. Other surgical procedures, such as subperiosteal release of the floor of the mouth (Fig. 6), and different types of glossopexy, such as the Routledge procedure or other forms of tongue-lip adhesions, can be used. Any glossopexy should be released before significant dentition develops (age 9-12 months). Mandibular

BIBLIOGRAPHY 1. Abel F, Bajaj Y, Wyatt M, Wallis C. The successful use of the nasopharyngeal airway in Pierre Robin sequence: an 11-year experience. Arch Dis Child. 2012;97(4):331-4. 2. Bath AP, Bull PD. Management of upper airway obstruction in Pierre Robin sequence. J Laryngol Otol. 1997;111(12):1155-7. 3. Breugem CC, Courtemanche DJ. Robin sequence: clearing nosologic confusion. Cleft Palate Craniofac J. 2010;47(2):197-200. 4. Bronshtein M, Blazer S, Zalel Y, Zimmer EZ. Ultrasonographic diagnosis of glossoptosis in fetuses with Pierre Robin sequence in early and mid pregnancy. Am J Obstet Gynecol. 2005;193(4):1561-4. 5. Bütow KW, Hoogendijk CF, Zwahlen RA. Pierre Robin sequence: appearances and 25 years of experience with an innovative treatment protocol. J Pediatr Surg. 2009;44(11):2112-8. 6. Caouette-Laberge L, Plamondon C, Larocque Y. Subperiosteal release of the floor of the mouth in Pierre Robin sequence: experience with 12 cases. Cleft Palate Craniofac J. 1996;33(6):468-72. 7. Dionisopoulos T, Williams HB. Congenital Anomalies of the Ear, Nose and Throat. New York, NY: Oxford University Press; 1997. pp. 243-60.

Figure 6. Diagram illustrating the surgical technique for subperiosteal release of the floor of mouth in patients with Pierre Robin sequence.

8. Elliott MA, Studen-Pavlovich DA, Ranalli DN. Prevalence of selected pediatric conditions in children with Pierre Robin sequence. Pediatr Dent. 1995;17(2):106-11.

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PEDIATRICS 9. Evans AK, Rahbar R, Rogers GF, Mulliken JB, Volk MS. Robin sequence: a retrospective review of 115 patients. Int J Pediatr Otorhinolaryngol. 2006;70(6): 973-80. 10. Haapanen ML, Laitinen S, Paaso M, Ranta R. Quality of speech correlated to craniofacial characteristics of cleft palate patients with the Pierre Robin sequence. Folia Phoniatr Logop. 1996;48(5):215-22. 11. Handzic-Cuk J, Cuk V, Gluhinic M. Mastoid pneumatization and aging in children with Pierre-Robin syndrome and in the cleft palate population out of syndrome. Eur Arch Otorhinolaryngol. 1999;256(1):5-9. 12. Hong P, Brake MK, Cavanagh JP, Bezuhly M, Magit AE. Feeding and mandibular distraction osteogenesis in children with Pierre Robin sequence: a case series of functional outcomes. Int J Pediatr Otorhinolaryngol. 2012;76(3):414-8. 13. Hong P. A clinical narrative review of mandibular distraction osteogenesis in neonates with Pierre Robin sequence. Int J Pediatr Otorhinolaryngol. 2011;75(8):985-91. 14. Lehman JA, Fishman JR, Neiman GS. Treatment of cleft palate associated with Robin sequence: appraisal of risk factors. Cleft Palate Craniofac J. 1995;32(1):25-9.

16. Marques IL, Barbieri MA, Bettiol H. Etiopathogenesis of isolated Robin sequence. Cleft Palate Craniofac J. 1998;35(6):517-25. 17. Morovic CG, Monasterio L. Distraction osteogenesis for obstructive apneas in patients with congenital craniofacial malformations. Plast Reconstr Surg. 2000;105(7): 2324-30. 18. Myer CM 3rd, Reed JM, Cotton RT, Willging JP, Shott SR. Airway management in Pierre Robin sequence. Otolaryngol Head Neck Surg. 1998;118(5):630-5. 19. Pasyayan HM, Lewis MB. Clinical experience with the Robin sequence. Cleft Palate J. 1984;21(4):270-6. 20. Sheffield LJ, Reiss JA, Strohm K, Gilding M. A genetic follow-up study of 64 patients with the Pierre Robin complex. Am J Med Genet. 1987;28(1):25-36. 21. Syndromes with oral manifestation (Chap 308). In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF (Eds.). Nelson Textbook of Pediatrics. 18th Edition Philadelphia, Pa: Saunders Elsevier; 2007. 22. Tewfik TL, Teebi AS, Der Kaloustian VM. Selected syndromes and conditions. In: Tewfik TL, Der Kaloustian VM (Eds.). Congenital Anomalies of the Ear, Nose and Throat. New York, NY: Oxford University Press; 1997. pp. 516-7.

15. Lidsky ME, Lander TA, Sidman JD. Resolving feeding 23. Vegter F, Hage JJ, Mulder JW. Pierre Robin syndrome: difficulties with early airway intervention in Pierre Robin mandibular growth during the first year of life. Ann Plast Surg. 1999;42(2):154-7. Sequence. Laryngoscope. 2008;118(1):120-3. ■■■■

Revised Beighton Score to Assess Joint Hypermobility in Preschool Children In a new study, the revised Beighton score was applied to preschool children to evaluate joint hypermobility in five parts of the body. In all, 284 healthy preschool children (146 boys and 138 girls) and 26 preschool children with genetic disorders (15 boys and 11 girls) were assessed. A cut-off score >4 was used to identify hypermobility. About 7% healthy children and 89% with genetic syndromes associated with hypermobility had a score >4. The revised version of the Beighton score could help define generalized hypermobility for children up to 5 years of age. The findings are published online June 20 in the Journal of Pediatrics.

Vitamin D Supplementation in Very Low Birth Weight Preterm Neonates Vitamin D supplementation in a dose of 1,000 IU/day is more effective in maintaining serum calcium, phosphate, alkaline phosphatase (ALP), 25(OH)D and parathormone levels with lower incidence of skeletal hypomineralization and better growth among very low birth weight preterm neonates, suggests a new study published online June 19 in the Journal of Tropical Pediatrics. After 6 weeks of supplementation, the mean serum calcium and 25(OH)D levels were significantly higher and ALP and parathormone levels significantly lower in neonates receiving 1,000 IU/day vitamin D.

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PSYCHIATRY

Illness Anxiety Disorder: A Case Report PANKHURI AGGARWAL

ABSTRACT Illness anxiety disorder is characterized by a preoccupation that normal or minor physical signs and symptoms are indicators of serious illnesses, despite of contrary medical evidence. Up to 10% of visits to primary healthcare physicians might be due to illness anxiety disorder related concerns. A case of a 25-year-old male with illness anxiety disorder with panic attacks is presented, who benefited immensely from cognitive behavioral therapy, reiterating the importance of psychotherapy in such cases.

Keywords: Illness anxiety disorder, panic attacks, psychotherapy

CASE REPORT A 25-year-old single, male came with the presenting concerns of palpitation, anxiety about possibly experiencing panic attacks, and recurrent thoughts about being diagnosed with and dying from an illness since last 3-4 years. The client has approached multiple physicians in the past for complaints of backache, neck ache, irritation while urinating, stomach ache, premature ejaculation, skin disease, etc. and despite receiving negative test results from the laboratories, he either got himself retested or approached other doctors in the field. The client reports feeling physically discomforted when he hears any of his family members diagnosed with even mildest of illnesses, or when he sees an ambulance passing by. He is unable to enjoy action movies or any reality shows with highly aggressive content as he experiences severe headache and high blood pressure. The client’s second youngest sister died of jaundice when the client was 12 years old. At around the same time, he also witnessed his grandfather’s brother-inlaw struggle with an illness. The client remembers his childhood characterized by financial constraints. He was frequently hit by his father when he was young. The client also received severe physical beatings from his girlfriend’s three brothers when he was spotted

Postgradute in Applied Psychology (Specilized in Clinical Psychology) School of Human Ecology Tata Institute of Social Sciences, Mumbai, Maharashtra E-mail: pankhuri.aggarwal@gmail.com

with her outside his coaching center although no major injuries were reported. The client is currently on tablet escitalopram (10 mg), tablet alprax (0.25 mg), tablet propranolol (40 mg) and tablet olanzapine (2.5 mg). Despite the positive effect of the medicines, the client approached the psychiatrist complaining that the effects are gradually wearing off. The client was diagnosed with illness anxiety disorder (specifier care seeking type) with panic attack and was referred to the psychologist for psychotherapy. DISCUSSION Formerly referred to as hypochondriasis or health anxiety, illness anxiety disorder is characterized by preoccupation with one’s health in the absence of objective and verifiable evidence for a minimum duration of 6 months.1 Other symptoms include heightened feelings of hypervigilance about one’s or others’ health conditions, experiencing clinically significant stress in terms of impairment in personal, social and occupational functioning, etc. The genesis of the clients’ beliefs rests in their misinterpretation of physical symptoms or signs due to heightened bodily sensations. Even in cases of verifiable health conditions, the severity of the problem is minor and usually lies within normal limits. This is often followed by repeated self-examination, selfdiagnosis and unsatisfactory examination by others as these individuals are likely to doubt the test results and discard their doctors repeated assurances. In such cases, a denial to treat these clients or prescribe additional medicines for their exaggerated medical

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PSYCHIATRY concerns doesn’t help solve the dilemma. Neither does stopping of the existing consumption of medications is advised as these clients derive a sense of meaning from these medicines. These medicines give the clients a new direction and purpose in life. Even if the doctor decides not to prescribe medicines to these clients, they usually approach other doctors who they think will understand their problems better. Therefore, in such cases, clients would immensely benefit from cognitive behavioral therapy.2 Their distorted thinking patterns and irrational beliefs are brought into therapeutic limelight, and are worked upon using different psychotherapeutic tools and techniques until they become adaptive. In the present case, the client was explained the links between emotion, cognition, physical sensation and behavior. The client was further explained the plausible reasons of the emergence of his psychological disturbance. It is likely that the client had associated the aversive situations of his childhood (struggle of multiple closed ones due to various illnesses and physical beatings by father and girlfriend’s brothers) with hypervigilant health related thoughts (preoccupation) and terrifying emotions of anxiety and fear using classical conditioning.3 These behaviors were further generalized to similar situations in the outside world (passing of ambulance, watching wrestling match on television, etc.) and thus elicited the same physiological, emotional and cognitive responses from the client. His behavior of visiting doctors and getting himself tested, and consuming medicines led to a reduction in his anxiety levels and were thus reinforced through the principles of operant conditioning4 and theory of law of effect.5 He was told about the nature of anxiety using the cycle of panic, thereby helping him understand that during crisis situations, anxiety would have gradually worn off even if he did not engage in any immediate safety behaviors. Downward pyramid technique of cognition was employed to illustrate ways in which the client arrived at hasty

generalizations despite the availability of contradictory evidence. Arousal reduction technique of Jacobson’s Progressive Muscle Relaxation (JPMR) was taught to the client and practiced in each session. The client was told to include a worry period in his daily schedule, whereby he would devote 5-10 minutes thinking about all his worries. Therefore, he was told to postpone his worry thoughts from throughout the day, to the worry period of the day, freeing himself from the clutches of omnipresent anxiety. CONCLUSION A doctor’s response towards a client with illness anxiety disorder is critical. He/she should not deny the client of the only phenomena which might provide him with a sense of meaning and purpose in his life, while at the same time, the refusal to treat or prescribe medications may serve no good as the client would continue to approach different practitioners. It is advised that the client in addition to being prescribed antidepressants and selective serotonin reuptake inhibitors (SSRIs) should be referred to a clinical psychologist/counselor for psychotherapy. REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th Edition, Arlington, VA: American Psychiatric Publishing; 2013. 2. Beck AT. Depression: Clinical, experimental, and theoretical aspects. New York: Harper and Row; 1967. Republished as: Beck AT. Depression: Causes and treatment. Philadelphia: University of Pennsylvania Press; 1970. 3. Pavlov IP. Conditioned reflexes. Oxford, UK: Oxford University Press; 1927. 4. Skinner BF. About behaviourism.Vintage; 2011.

5. Thorndike EL. The elements of psychology. New York: AG Seiler; 1905. ■■■■

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SURGERY

Situs Inversus: A Preoperative Finding Not So Uncommon VENKATESH SUBBIAH*, S ASOKAN†, SOMASUNDARAM‡

ABSTRACT We present a case of abdominal pain presenting as obstructive paraumbilical hernia with situs inversus and appendicitis also. Situs inversus totalis, also called situs transversus or opposites, a rare condition causing mirror image of the thoracic and abdominal contents with frequency of about 1 in 10,000 among the normal population. The major organs within the abdomen and thorax are transposed through the sagittal plane. The heart is located on the right side of the thorax, the stomach and spleen on the right side of the abdomen and the liver and gallbladder on the left side.

Keywords: Situs inversus, dextrocardia, obstructive paraumbilical hernia, appendicitis

itus inversus totalis, also called situs transversus or opposites, is a rare condition causing mirror image of the thoracic and abdominal contents with frequency of about 1 in 10,000 among the normal population.1,2 Nearly 3-5% of the above mentioned population have congenital heart disease, while others have a structurally normal heart.3 The major organs within the abdomen and thorax are transposed through the sagittal plane. The heart is located on the right side of the thorax, the stomach and spleen on the right side of the abdomen and the liver and gallbladder on the left side. The left lung is trilobed and right lung is bilobed. The blood vessels, nerves, lymphatics and intestines are also transposed. There is usually no functional abnormality.

Patient gave history of swelling around the umbilicus for the last 2 years. Patient is premorbidly healthy. There was no previous history of hospitalization or any surgeries in the past. Her vitals were as follows: Heart rate (HR) - 102/min, blood pressure (BP) 120/80 mmHg, blood oxygen saturation (SpO2) 100% on RA, blood glucose - 98 mg/dL. Examination revealed heart sounds S1, S2 in right 5th intercostal space. Respiratory and central nervous system examination were normal. Per abdomen: A palpable mass of size 8 × 8 cm was noted in the left paraumbilical region. Abdomen had guarding rigidity. Mass was not reducible. Bowel sounds were absent. Provisional diagnosis of obstructed paraumbilical hernia was made. Preoperative investigations were done. Basic blood investigations revealed elevated total counts.

CASE REPORT

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X-ray-chest (Fig. 1).

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ECG showed right axis deviation, positive QRS complexes (upright P and T wave) in aVR, Lead I showed global negativity (inverted P, inverted T and negative QRS) (Fig. 2).

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U/S abdomen - Situs inversus totalis, a defect of 5 × 5 cm in the anterior abdominal wall. Contents found were omentum and tip of appendix.

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2D Echo - Dextrocardia with normal sized cardiac chambers and normal LV function.

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Human immunodeficiency virus (HIV) nonreactive; hepatitis B surface antigen (HBsAg) negative.

A 40-year-old lady presented to the OPD complaints of abdominal pain for the last 3 She had 3-4 episodes of vomiting. She also history of not passing stools and flatus for last 3

*Assistant Professor †Professor ‡Professor and Head Dept. of General Surgery Velammal Medical College and Hospital, Madurai, Tamil Nadu Address for correspondence Dr Venkatesh Subbiah Assistant Professor Dept. of General Surgery Velammal Medical College and Hospital, Madurai, Tamil Nadu E-mail: venkateshpims@gmail.com

with days. gave days.

PA view

showed

dextrocardia

Surgery was planned. Under spinal anesthesia, parts were prepared and draped. Pfannenstiel skin incision was made. Incision was deepened in layers

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SURGERY

Figure 1. X-ray-chest PA view - showing dextrocardia.

up to the rectus. Upper flap was raised just above the defect level. Defect was well-defined, structures within the defect were found to be omentum and tip of appendix. Omentum were pale with adhesions. Appendix, which was found in the defect, was inflamed. Omentectomy and appendicectomy were done. Remaining contents were reduced, anatomical repair was done. A mesh of appropriate size was anchored over the anterior abdominal wall using 2-0 prolene. Hemostasis was achieved, a romovac drain kept and the wound was closed in layers. Postoperatively, patient was treated with intravenous antibiotics, antacids and analgesics. Patient was discharged after a week in a stable condition with: ÂÂ

Oral antibiotics (cefixime)

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Oral analgesics (a combination of aceclofenac, paracetamol and serratiopeptidase)

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Antacids.

Patient was advised to come for review in OPD after 3 days. DISCUSSION The importance of situs inversus is in clinical diagnosis of medical conditions with pain on the opposite side of the commonly presenting site. It also helps in preventing surgical mishaps resulting from failure in recognizing the history with the clinical presentation and the reversed anatomy. The reversal of the organs may lead to some confusion as the clinical signs and symptoms will be on the reverse side. People with situs inversus can lead normal healthy lives, without any complications related to their medical condition. Most of them are unaware of their unusual anatomy until they seek medical

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Figure 2. ECG showing right axis deviation, positive QRS complexes.

attention for an unrelated condition. HM Blegen, in his paper on surgery in situs inversus says, “Although a busy surgeon, therefore, may expect to encounter this anomaly only once or twice in a lifetime, it is his responsibility, in order to protect these individuals and to avoid embarrassing errors, to familiarize himself with this anomaly and to consider it as a remote possibility in all cases of obscure abdominal pain.”4 In all, 144 cases of situs inversus were reviewed in which 158 surgical procedures were performed and approximately 45% cases had incorrect preoperative diagnosis, due to which 31% had an incorrect surgical incision made.4 CONCLUSION Magnetic resonance imaging, CT and ultrasound have played a major role in suspected diagnosis of situs inversus. Organ transplantation operations also may be complicated as donor organs will mostly come from situs solitus donors. In any patient, presenting with abdominal pain, situs inversus should be kept in mind as clinical signs and symptoms may be reversed. REFERENCES 1. Le Wald LT. Complete transposition of the viscera: a report of twenty-nine cases, with remark on etiology. JAMA. 1925;84:216-68. 2. Yokoyama T, Copeland NG, Jenkins NA, Montgomery CA, Elder FF, Overbeek PA. Reversal of left-right asymmetry: a situs inversus mutation. Science. 1993;260(5108):679-82. 3. Kulkarni PR, Inamdar VV. Situs inversus with dextrocardia associated with ventricular septal defect - a case report. J Anat Soc India. 2005;54(1) 4. Blegen HM. Surgery in situs inversus. Ann Surg. 1949;129(2):244-59.

MEDILAW

A Known Phenomenon is not Medical Negligence A patient filed a case against his treating doctor alleging that he had negligently treated him and when his line of treatment was not successful, the doctor referred him to a higher centre for treatment.

The ureteral stone migrated during surgery.

Proceed

My GP referred me to a surgeon, who failed to do a successful surgery for my ureteral stone and later referred me to a higher centre.

A known phenomenon cannot be a cause for negligence.

Lesson: In an order DMC/DC/F.14/Comp.615/2010, the Council observed that migration of ureteral stone during surgery is a known phenomenon documented in medical literature, hence, prima facie no medical negligence can be attributed on the part of the doctor.

CASE OVERVIEW Patient X filed a complaint against Dr A and Dr B with the medical council alleging medical negligence in the treatment that had been given to him at Hospital Y. The following documents were examined by the Council: Complaint filed by patient X, joint written statements of Dr A and Dr B, written statement of Dr C, Medical Superintendent of Hospital Y, medical records and other documents placed on record. COUNCIL OBSERVATIONS The Council noted that patient X was diagnosed to have ureteric stone. Therefore, a laparoscopic ureterolithotomy was planned for 29.7.2009. The stone could not be localized hence, it was decided to convert the laparoscopic procedure into an open procedure. However, owing to the difficult anatomy in the region of kidney, the surgeon was unsuccessful in removing the stone. The operation notes of the surgeon mention

this fact. The attendants of the patient were informed about this including the further plan of percutaneous nephrolithotomy (PCNL) and double J (DJ) stent removal in a higher centre, a fact that is evident from the postoperative orders documented in the medical records of the hospital. The patient was discharged from Hospital Y on 6.8.2009. The Executive Committee also observed that the discharge summary did not mention the fact that the stone has not been removed during surgery, although it did mentioned a follow-up in OPD after 6 weeks and DJ stent to be removed. The patient has probably filed this complaint because of this lack of communication. The Council noted that migration of ureteric stone during this procedure is a known phenomenon and is well-documented in medical literature. Hence, no medical negligence can be attributed on the part of Drs A and B in the treatment administered to Patient X.

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MEDILAW Council Judgement Based on its observations, the Council disposed of the complaint as it found that the concerned doctors had followed the standard surgical protocol in managing the ureteral stone in this patient. The Council; however, directed the hospital to ensure better record keeping and doctor-patient communication. REFERENCE 1. DMC/DC/F.14/Comp.615/2010/, dated 7th June, 2010.

LEGAL IMPLICATIONS OF MEDICAL RECORDS Medical records are documents that include complete details about the patient’s history, clinical findings, results of diagnostic tests, pre- and postoperative care, patient’s progress and medication/s administered. If written correctly, notes will support the doctor about the correctness of treatment.1 Hospital medical records are a documentary evidence as per the Indian Evidence Act, 1872, as amended up to August 1, 1952 & 1961. Hence, they are usually required in cases of medical negligence under the Consumer Protection Act or in criminal courts.2 The legal system relies mainly on documentary evidence in cases of medical negligence. Medical records are one of the most important aspect on which practically almost every medicolegal battle is won or lost.1 Therefore, it is essential to ensure the integrity of medical records as without them you are deprived of any means to defend the allegation of negligence or professional misconduct. Good records mean good defence, poor records mean poor defence, no records mean no defence.3 REFERENCES 1. Bali A, Bali D, Iyer N, et al. Management of medical records: facts and figures for surgeons. J Maxillofac Oral Surg. 2011;10(3):199-202. 2. Singh S, Sinha US, Sharma NK. Preservation of medical records - an essential part of health care delivery. Indian Internet Journal of Forensic Medicine & Toxicology. 2005;3(4). 3. Thomas J. Medical records and issues in negligence. Indian J Urol. 2009;25(3):384-8.

WHEN IS A PHYSICIAN LIABLE FOR NEGLIGENCE? A physician may be held liable for negligence only if he did not possess the requisite skill which he professed to have possessed or that he failed to exercise, with

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reasonable competence in the given case, the skill which he did possess.1 However, physicians cannot give a warranty of the perfection of their skill or a guarantee of cure. If a doctor has adopted a practice that is considered “proper” by a reasonable body of medical professionals who are skilled in that particular field, he or she will not be held negligent only because something went wrong.2 It is a known fact that with the best skill in the world, things sometimes went wrong in medical treatment or surgical operation. A doctor was not to be held negligent simply because something went wrong.3 In a landmark judgement in Laxman Balkrishna Joshi vs Trimbak Bapu Godbole And Anr on 2 May, 1968 AIR 1969 (SC)128, the Supreme Court of India held that “… The medical practitioner has a discretion in choosing the treatment which he proposes to give to the patient and such discretion is wider in cases of emergency, but, he must bring to his task a reasonable degree of skill and knowledge and must exercise a reasonable degree of care according to the circumstances of each case.” A doctor is not guilty of negligence if he has acted in accordance with the practice, which is accepted as proper by a reasonable body of medical professionals. The onus to prove negligence lies on the complainant. In Dr. Devendra Madan And Ors. vs Shakuntala Devi on 25 October, 2002, I (2003) CPJ 57 NC, the National Consumer Disputes Redressal observed that “…the complainant has to prove, (1) that there was a breach of duty on the part of the doctor; and (2) that the breach of duty was the real cause of the damage complained of and such damage was reasonably foreseeable.” A mere allegation of negligence will be of no help to the Complainant as was alleged in Smt. Savitri Singh v. Dr. Ranbir PD. Singh and others. 2004;(1) CPJ 25 (Bihar).3 REFERENCES 1. Yadav M, Singh H, Sharma G, et al. Recent scenario of criminal negligence in India Doctor, community & apex court. JIAFM. 2005;27(4):252-7. 2. Murthy KK. Medical negligence and the law. Indian J Med Ethics. 2007;4(3):116-8. 3. Joga Rao SV. Medical negligence liability under the consumer protection act: A review of judicial perspective. Indian J Urol. 2009;25(3):361-71.

CIVIL VS CRIMINAL NEGLIGENCE “…For negligence to amount to an offence, the element of mens rea must be shown to exist. For an act to amount to criminal negligence, the degree of negligence should be much higher i.e. gross or of a very high degree … To prosecute a medical professional for negligence

MEDILAW under criminal law it must be shown that the accused did something or failed to do something which in the given facts and circumstances no medical professional in his ordinary senses and prudence would have done or failed to do. The hazard taken by the accused doctor should be of such a nature that the injury which resulted was most likely imminent.” Jacob Mathew vs State of

Punjab and Anr: 5th day of August 2005:334/2005/SCI/ 144-145 of 2004. “… For civil liability only damages can be imposed by the court but for criminal liability the doctor can also be sent to jail (apart from damages which may be imposed on him in a civil suit or by the consumer fora)…” Martin F. D’Souza vs Mohd. Ishfaq, 3541 of 2002, dated 17.02.2009.

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CONFERENCE PROCEEDINGS

60th Annual Conference of the Indian Orthopaedic Association (IOACON 2015) FEMORAL NECK FRACTURES - FIX OR REPLACE? WHAT’S THE EVIDENCE? Dr Robert Dunbar, USA ÂÂ

Mortality: No difference.

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Revision rate: THA lowest, hemiarthroplasty intermediate, internal fixation (IF) highest by far.

Total Elbow Arthroplasty (TEA) Pearls: Discard fractured condyles, efficient surgery to reduce infection, ‘Gentle’ surgery to avoid fractures, immobilize elbow until skin heals.

Key Points ÂÂ

Nonoperative treatment has an important but limited role.

ÂÂ

Complications: IF worse than arthroplasty.

ÂÂ

Infection: THA worse than IF.

ÂÂ

ORIF successful in the majority of patients.

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Function: THA best, ORIF and hemiarthroplasty tend to degrade over time.

ÂÂ

TEA indicated for comminuted fractures in lower demand elderly patients.

ÂÂ

Satisfaction: THA best.

ÂÂ

Blood loss: More with THA.

Hemiarthroplasty may have a role when ORIF is not possible but patient too active for TEA.

ÂÂ

OR time: THA longest.

ÂÂ

Cost: IF is the most expensive.

ÂÂ

Cementing: Probably better in terms of pain control, mobility & avoidance of intraoperative complications, good for the healthy.

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Bipolar vs Unipolar: Very little to support added cost of bipolar.

EVOLVING MANAGEMENT OF DISTAL HUMERUS FRACTURES Dr Graham JW King, UK

Nonsurgical management is a good option in elderly patients. These patients behave differently than the younger patients on casts in nonoperative cases. Don’t put casts in patients with severe dementia. Union rate is 81%. In younger patients the 90-90 plates work well. ORIF Outcome ÂÂ

85% good to excellent outcome - mild impairment.

ÂÂ

Results durable over time (20 years).

ÂÂ

Most achieve union and a functional ROM.

ÂÂ

Failure higher in elderly, smokers, obesity, DM, OA.

ÂÂ

Complications 30% - neuropathy, nonunion.

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PROXIMAL FEMUR OSTEOTOMY: A FORGOTTEN ART Dr Ulrich Holz, Germany Poor reduction is the main cause of failure in a femoral head fracture. “The bifurcation operation of Lorenz is simple, of short duration, and if performed correctly leads to a relief of pain and deformity with no loss of stability and does not cause strain on the lumbar region” (McMurray in 1935). But the rules of mechanobiology are still the same and the concept of functional adaptation works very well. That is why osteotomies should not become a forgotten art. Osteotomies are good options and THR never comes too late! HIERARCHY OF EVIDENCE Dr Mohit Bhandari, Canada Evidence-based medicine (EBM) was honored as one of the top 15 Medical Discoveries in the past 166 years. EBM as an attitude of “enlightened skepticism” towards the application of diagnostic, therapeutic and prognostic technologies. It is the conscientious use of current best evidence from clinical care research in making healthcare decisions. Cornerstone of EBM practice is the Applicability to the clinical situation and integration of our clinical expertise with patients’ values and with the best available research evidence.

CONFERENCE PROCEEDINGS Randomized trials aren’t always practical or feasible. Skills are needed to practice EBM.

female. Decision-making should take into consideration the following:

To summarize, EBM is an approach to making clinical decisions based upon best available evidence, patients’ preferences and your clinical circumstances.

If restoration of posterior facet is the aim this is only possible by surgery. If age >50 years prefer conservative treatment. If patient had neuropathic limb (DM, nerve injury), bed ridden patient; better conserve.

ARTHROPLASTY FOR DIFFICULT DEVELOPMENTAL DYSPLASIA OF THE HIP IN ADULTS Dr Colin R Howie, UK

Femoral Osteotomy ÂÂ

Difficult but solves problems!

ÂÂ

Union easy bit!

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Soft tissue operation.

ÂÂ

Make the revision easy!

Key Points ÂÂ

Restore centre of rotation.

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Restore offset.

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Rim graft/fem osteotomy.

ÂÂ

Optimize joint function

ÂÂ

Don’t overlengthen

ÂÂ

Soft tissue operation.

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Cemented is “good for all”.

MINIMAL INVASIVE FIXATION OF FRACTURE CALCANIUM Dr Vinod Tiwari, Chhattisgarh Operative treatment: Conventional plating, Y plating, reconstruction plating, LCP, Titanium LCP. Advantage: Gold standard treatment, anatomic reduction, rigid fixation, early movement, early weightbearing - return to work earlier (74-100%), 61-72% good to excellent result, better motion at subtalar joint.

FEMORAL NECK FRACTURES IN YOUNG PATIENTS: EVIDENCE FOR TIMING AND TECHNIQUE Dr Theodore Miclau, USA ÂÂ

No strong evidence for current practices, particularly for: Time to fixation; open vs. closed technique; selection of implant (screw vs. CHS vs. medial buttress plating).

ÂÂ

Most accepted: Need for anatomic reduction.

ÂÂ

There is a lack of consensus.

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There is a need for clinical trials.

ORTHOPAEDIC TRAUMA ASSOCIATION Dr Theodore Miclau, USA Orthopaedic Trauma Center Study Group conceived by Edwin Bovill, Michael Chapman, and Ramon Gustilo (1977) and Orthopaedic Trauma Hospital Association founded (1983). Orthopaedic Trauma Association incorporated (1985).

Mission Statement To promote excellence in care for the injured patient, through provision of scientific forums and support of musculoskeletal research and education of orthopedic surgeons and the public. Association Membership offers Educational Opportunities, Professional Development and Meeting Discounts. Apply at www.ota.org; e-mail: miclaut@ orthosurg.ucsf.edu

Disadvantage: Not possible to reduce each fragment, rigid fixation?; neither load sharing nor weight-bearing implant; weight-bearing axis is different than plate biomechanics; subtalar arthritis; late collapse; surgery should be done before 24 hrs or after 10-14 days when wrinkle sign appears; inability to restore medial wall, height, length; extensive soft tissue dissection; more chances of wound problem; skin necrosis; LCP = ordinary low profile plate; plate may be painful and require second extensive surgery.

Locking compression plate is considered standard fixation for proximal humerus fracture in indicated cases. Fixation failure typically occurs due to varus collapse. Do not choose lateral approach and change over to deltopectoral, when 4 part fracture reduction not achieved by closed reduction and fracture dislocation.

Indication of ORIF: Young, healthy, motivated, nonsmoking, closed, displaced, intra-articular fracture,

The displaced tuberosities have not been sufficiently reduced or are inadequately fixed to the plate either

STANDARD FIXATION PROXIMAL HUMERUS: WHY THINGS GO WRONG Dr SC Goel, Varanasi

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CONFERENCE PROCEEDINGS with head screws or strong suture loops. This may cause secondary displacement or a subacromial impingement, especially if the displacement is >5 mm. To avoid problems check for proper techniques, good reduction, medial support and plate and screw positioning. VOLAR & COLUMN SPECIFIC PLATING Dr Amit Ajgaonkar ÂÂ

Radial styloid fracture - assess for the intercarpal ligament injury, later proceed to fixing the radial column.

ÂÂ

Volar plating alone does not give stability, if not executed well.

ÂÂ

Never be too rigid in choice of implant.

ÂÂ

Always mix and match plates, plan on templates.

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Approach should never be an inhibition, even dorsal is easy, in fact elevation of depressed fragments possible from dorsal.

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Volar rim and tear drop fragments should be identified.

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Radial styloid release.

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Fix in such a way, to mobilize early.

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External fixator should be the last option.

needs

buttress/brachioradialis

3D PRINTED TITANIUM TRUSS STRUT SCAFFOLDS FOR THE RECONSTRUCTION OF SEGMENTAL BONE DEFECTS

ÂÂ

Careful and objective assessment of patient, as well as your own skills.

EVIDENCE-BASED RESULTS OF SHOULDER ARTHROPLASTY: ANATOMICAL & REVERSE Dr Ashish Kumar, Lucknow ÂÂ

Isolated radiographic shoulder OA is not an indication for operative intervention in the absence of symptoms.

ÂÂ

CT scan is useful in assessing glenoid version, glenoid tilt and glenoid bone stock when planning a TSA procedure.

ÂÂ

TSA outperforms Hemi for the treatment of primary shoulder OA with low revision rates.

ÂÂ

TSA is a safe method of treatment for middle-aged active patients with primary OA of the shoulder in patients who are older than 50.

ÂÂ

Caution needs to be exercised when performing TSA in active patients who are younger than 50 years old.

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TSA has a lower rate of revision surgery especially when cemented all-polyethylene glenoid components are used.

RSA should be reserved for very disabling shoulder arthropathy with massive rotator cuff rupture, exclusively in patients over 70 years old with low functional demands. MENISCUS REPAIR

Dr Kevin Tetsworth, Australia

Segmental Bone Defects

Dr Rajat Jangir, Jaipur ÂÂ

Preparation of tear is essential step.

ÂÂ

Enhancement trephinate/clot.

ÂÂ

Reduce tear accurately and maintain reduction throughout fixator/suture placement.

ÂÂ

<3 cm (tibia) = Acute shortening.

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>4 cm (tibia) = Bone transport.

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Infected tibia = Circular ex fix.

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Infected femur = Unilateral ex fix.

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Incomplete metaphyseal lesion = Locked plate, then bone graft.

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Hybrid techniques are useful especially in deformed, displaced buckets.

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Acute tibia/femur diaphyseal = Masquelet technique.

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Soft tissue defect > bone defect? = Free flap.

Accessory portals to improve access and fixation configuration.

ÂÂ

Very large defects – Consider Masquelet technique and support with truss strut graft.

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Perpendicular placement of implants every 5 mm.

ÂÂ

Ensure that implants are not proud (intra- or extraarticular).

ÂÂ

Avoid stuffing the meniscus with stress riser inducing implants.

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Rehabilitation: Individualized.

ÂÂ

Skilled and experienced: Debridement; external fixation; lengthening/transport; IM rods; ORIF.

ÂÂ

Flexibility, imagination, perseverance.

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Calculated risks, recognize limitations.

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techniques:

Debride/abrade/

CONFERENCE PROCEEDINGS

62nd Annual Conference of Cardiological Society of India (CSI 2016) THE ARTICLES THAT STRUCK MY HEART AND HURT MY CONSCIENCE

ÂÂ

New ideas have emerged as to the meaning of mechanical discoordination (or dyssynchrony). New discoveries have demonstrated that an electromechanical substrate is required for CRT response.

ÂÂ

Mechanical discoordination (dyssynchrony) may be due to contractile heterogeneity or scar. Patients who improve dyssynchrony have better clinical outcomes. Persistent or worsening dyssynchrony is a marker for disease severity.

ÂÂ

Cardiac imaging, especially echo, has great potential to improve patient selection for CRT to identify myocardial substrate responsive to CRT and be additive to ECG alone.

Dr Anjan Lal Dutta, Kolkata ÂÂ

In COMET trial, superiority of carvedilol was proved over metoprolol, but metoprolol used here was metoprolol tartrate and not metoprolol succinate control-release, which had shown survival benefit in MERIT-HF trial. It was like punishing the namesake if you cannot catch the culprit.

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In JUPITER trial, importance of hsCRP was highlighted. The main investigator is co-owner of patent for CRP kit manufacturing.

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In PURE trial, percentage of use of statin, aspirin, β-blocker, ACEI/ARB were shown unbelievably low in India compared to other reports in India. Was it to justify and promote business of polypill? Authors of both these trials need to be reminded that a judge should not only be impartial but he or she should appear impartial.

EMERGING NOVEL APPROACHES TO TREAT HT Prof C Venkata S Ram, Hyderabad The goals for BP reduction have to be lower than previously recommended. ÂÂ

The new goal based upon the SPRINT results is to lower the BP to <140/90 mmHg in all patients irrespective of age, gender or comorbid medical conditions. Ideal BP should be 120/80 mmHg.

ÂÂ

New drugs like ARN inhibitors and the latest ARBAzilsartan are extremely effective in the treatment of HT.

STENTS VS CABG IN 2015: PRACTICE AND POLITICS Prof Dr David Taggart, UK ÂÂ

CABG is best for 80% of 3-vessel disease and twothirds of left main disease.

ÂÂ

There are unwarranted variations in the ratios of PCI:CABG throughout the world.

Azilsartan will be available in India next month and will change the management of HT in India.

ÂÂ

Patients with severe CAD should be discussed by Heart Team.

Azilsartan is a powerful ARB, which lowers the BP extremely well in all grades of HT.

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Azilsartan is the new therapeutic frontier and will be widely used to reach goal BP in Indian patients. It is an excellent molecule and will revolutionize management of HT.

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International guidelines for treatment should be mandatory.

ADVANCES IN UNDERSTANDING RESPONSE TO CRT AND PATIENT SELECTION

PCI IN NSTE-ACS: IN WHOM AND WHEN? Dr Sanjay Chugh, New Delhi

Dr John Gorcsan III, USA ÂÂ

Nonresponse remains an important issue for CRT. Although ECG criteria of QRS widening and LBBB are most highly favored, other factors can be considered.

ÂÂ

In ACS, early PCI should be done in all except the low risk cases.

ÂÂ

Risk stratification is done using the TIMI and GRACE scores.

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CONFERENCE PROCEEDINGS ÂÂ

In GRACE scoring, higher the age/heart rate/Killip class/serum creatinine and lower the BP, higher the risk scores. Cardiac arrest, ST depression, >0.5 mm, and elevated cardiac enzymes get highest scores (39/28/14, respectively).

ÂÂ

GRACE score: Low risk <109, intermediate risk 109140, high risk >140.

ÂÂ

Low risk patients have T-wave inversion in ECG, no ST changes, negative troponins, no ongoing pain, TIMI SC0RE 0/1, GRACE <109. They need stress test, ischemia-guided coronary angiogram and PCI.

ÂÂ

Patients with GRACE risk score >140 with ST depression >0.5 mm in the ECG, with raised cardiac enzymes/troponins are at high risk and should have a coronary angiogram and revascularization within 24 hours; preferably within 2 hours, just as in STEAMI.

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Those with ongoing or recurrent angina at rest/ hemodynamic compromise/HF/hypotension/VT, VF, cardiac arrest/ischemic mitral regurgitation are the highest risk and must be taken up immediately, within 2 hours. Those with GRACE score 109-140, LVEF <0.4, prior CABG/PCI (<6 m), post-infarction angina, raised serum creatinine are intermediate risk and should be dealt after prior stabilization in 2-3 days (25-72 h) because data from various RCTs was inconclusive on benefits if PCI was done early. A meta-analysis published in a recent issue of Annals of Internal Medicine, which included four randomized studies, showed less bleeding and survival benefit with transradial PCI compared to transfemoral PCI. The Wellness and Radial Intervention Society (www. waris.co.in; contactus@waris.co.in) is committed to training Cardiologists in TRI. It takes 10 years to become facile and take on all primary angioplasty transradially. The society helps shorten the learning curve for Cardiologists with fellowship programs, publications, and its conference RADIAL LIVE, held on February 6, 2015 (www.radial-live.com).

MANAGEMENT OF STABLE CAD: MEDICAL THERAPY ALONE, PCI OR CABG? Dr Samin Sharma, USA ÂÂ

186

Contrary to ACS/MI, where PCI has shown to be superior to medical management, the role of percutaneous revascularization in stable CAD has been the focus of intense debate and research in the last decade.

Indian Journal of Clinical Practice, Vol. 27, No. 2, July 2016

ÂÂ

Lesion assessment by coronary angiography has limitation of subjective interpretation and has poor predictive value for future events. FFR, which measures the gradient across the epicardial stenosis has emerged as a valuable tool in predicting future events. FFR of <0.8 has shown to be associated with higher subsequent adverse cardiac events if left on medical therapy alone and hence should undergo PCI. Lesions with FFR of >0.8 have excellent prognosis on medical therapy alone and their should be no need for PCI.

ÂÂ

Additional imaging of lesions by IVUS, OCT and NIRS adds little to overall prediction of the cardiac events.

ÂÂ

Studies comparing PCI with CABG in patients with MVD and DM have shown CABG to be superior to PCI in the long-term reducing death and MI but at a cost of higher stroke rate.

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All patients with complex CAD should have a Heart Team discussion involving the Cardiologist, Interventionalist and Cardiac Surgeon, to best approach revascularization in a particular patient. That plan then should be offered to the patient and family who can then make the final decision after being made aware of all the facts.

VENTRICULAR FIBRILLATION ABLATION Dr Samuel J, Asirvatham, USA ÂÂ

Ventricular fibrillation is by far the most common cause of death worldwide.

ÂÂ

While defibrillators have made a small but significant dent in preventing death from this cause, they do not prevent or cure the arrhythmia itself.

ÂÂ

Recent evidence has suggested that the Purkinje network may serve as both the trigger and maintaining substrate for VF.

ÂÂ

Ablation strategies that target this region of the heart, including areas related to the cardiac valves and papillary muscles, may serve for the first time as a viable method that eliminates this important cause of morbidity and mortality.

CURRENT APPROACH TO A PATIENT WITH FUNCTIONAL TR Dr Mrinalendu Das, Kolkata ÂÂ

Functional TR is caused by deformation of the valvulo-ventricular dysfunction with essentially structurally normal leaflets.

CONFERENCE PROCEEDINGS ÂÂ

Severe TR needs to be corrected during left-sided surgery; but, less severe TR needs a more detailed analysis. Special attention has to be given to cases with leaflet tethering.

ÂÂ

9.6% of NSTEMI patients had nonobstructive CAD, particularly nondiabetic and female patients.

ÂÂ

Invasive procedure may be withheld in the very elderly and frail, patients with comorbidities like dementia, severe chronic renal insufficiency, cancer patients and those at high risk of bleeding. CAD not amenable to revascularization may be kept on conservative treatment as data of ACS with severe/diffuse CAD are sparse.

ÂÂ

Overall a more aggressive stage-specific approach is recommended.

ÂÂ

An aggressive approach towards tricuspid repair during mitral surgery prevents poor outcomes due to residual/recurrent TR.

ÂÂ

Use of tricuspid annulus size as a trigger for repair rather than just the severity of TR helps us identify the patients who need concomitant tricuspid repair.

COMBINATION DIURETIC THERAPY IN HFREF

ÂÂ

Repair the tricuspid valve if: TR is severe, annulus is >70 mm or >21 mm/m2 on intraoperative measurement, annulus is ≥3.5 cm at TTE.

ÂÂ

Though loop diuretics are the mainstay of treatment to counter congestive symptoms in decompensated HF, diuretic resistance is a concern.

ÂÂ

“Ring” annuloplasty techniques yield a better longer-lasting result compared to “Non-Ring” techniques.

ÂÂ

Although repair is a preferred technique, tricuspid valve replacement is necessary when the leaflets themselves are diseased, abnormal or destroyed.

Combination of loop diuretics with thiazide diuretics may be a low cost, effective therapy in these subsets to counteract the problem of diuretic resistance.

ÂÂ

Tailored therapy: First two phases: Tricuspid annuloplasty; 3rd phase - Anterior leaflet augmentation + annuloplasty or tricuspid valve replacement.

Other combinations of loop diuretics with mineralocorticoid receptor antagonist and vaptans are options too.

ÂÂ

Further evidence from large randomized trials will be required to substantiate the role of combination diuretic therapy.

MANAGEMENT OF VALVULAR HEART DISEASE DURING PREGNANCY

NSTEACS: CONSERVATIVE TREATMENT FOR WHOM AND WHEN Dr Deepak Gupta, Ranchi ÂÂ

Controversy of conservative vs invasive treatment in unstable angina and NSTEMI (NSTEACS) has been more or less cleared.

ÂÂ

Risk stratification in NSTEACS is very important to decide the management protocol.

ÂÂ

Only low risk group needs ischemia-guided therapy; otherwise all patients need early invasive protocol.

ÂÂ

Dr Mriganka S Chaliha, Dibrugarh

Conservative treatment after coronary angio indicated for those who has normal angiogram (Takotsubo cardiomyopathy, coronary spasm and coronary microvascular disease).

Dr AN Patnaik, Hyderabad ÂÂ

Pre-pregnancy evaluation and counseling, which is a vital step for reducing the mortality and morbidity has to be encouraged in all pregnant women.

ÂÂ

A few presenting with isolated MS or AS are best managed with balloon dilatation of the valve, preferably in second trimester after 20 weeks of gestation in suitable centers.

ÂÂ

Those with mechanical valves pose special challenges. They need guideline-based advice about anticoagulation management.

ÂÂ

Management of valvular heart disease multifaceted and needs a team approach.

■■■■

Indian Journal of Clinical Practice, Vol. 27, No. 2, July 2016

187

CONFERENCE PROCEEDINGS

India Live 2016 and a large number of inappropriate PCI interventions.

MULTIDISCIPLINARY HEART TEAM-NEED OF THE HOUR Dr Naresh Trehan, Gurgaon ÂÂ

ÂÂ

There is a difference in views of a cardiologist and a cardiac surgeon. While a cardiologist says there’s no need to cut the body, a cardiac surgeon may say that the stent won’t work in your case and surgery will be required in 1 year. The rationale for Heart Team decision-making for patients with stable, complex coronary artery disease (CAD) - Multidisciplinary decision-making has gained emphasis over the recent years to select the most optimal treatment strategy for individual patients with stable complex CAD. However, the so-called ‘Heart Team’ concept has not been widely implemented. A multidisciplinary Heart Team consisting of at least a Clinical/Noninvasive Cardiologist, Interventional Cardiologist, and Cardiac Surgeon, can together better analyze and interpret the available diagnostic evidence.

ÂÂ

All TVD are not same - Variable coronary anatomy, patient age, DM, low EF, frailty.

ÂÂ

A qualitative analysis revealed that few cardiologists discussed the evidence-based benefits of angiogram and PCI for stable CAD, and some implicitly or explicitly overstated the benefits. The etiology of patient misunderstanding is likely multifactorial. Modifications to cardiologists’ approach to describing the risks and benefits of the procedure may improve patient understanding.

ÂÂ

The Medanta Heart Team, with the patient in the center, consists of Clinical Cardiologist, Interventional Cardiologist and Cardiac Surgeon.

ÂÂ

The Heart Team Approach is a multidisciplinary approach Looking at an individual in a collaborative

FFR: AN ESSENTIAL TOOL FOR ALL CATH LABS Dr Christoph Naber, Germany ÂÂ

FFR is extremely helpful for invasive decisionmaking.

ÂÂ

Yes, it should be there in every Cath Lab.

ÂÂ

It is relevant for clinical outcome of patient and is currently underused.

ÂÂ

It is important to understand the technical pitfalls and the physiology underlying the findings in complex situations.

TRANSRADIAL PRIMARY PCI Dr RK Jaswal, Chandigarh Transradial PCI is overwhelmingly preferred by patients for the comfort it offers to them. Transradial access is associated with nearly 0% access site complications like local hematomas, AV fistulas, pseudoaneurysms and local limb ischemia compared to femoral approach. At Fortis, Mohali, I introduced transradial program in 2005 and performed nearly 22,000 transradial procedures till date; >95% of my coronary interventions including complex and high risk coronary interventions as well as primary PCI are performed via transradial access. There is now robust clinical data to support that transradial access is associated with lower morbidity and significantly lower mortality associated with primary PCI especially when performed by highly experienced operator in a high volume transradial center. HOW I MANAGE CORONARY DISSECTION/ PERFORATION?

manner

Pre-treatment multidisciplinary discussion was

associated with improved survival

Forms the priority of care in current

cardiovascular treatment strategies

Absence of heart team results in most elective

PCI patients failing to understand its rationale

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Indian Journal of Clinical Practice, Vol. 27, No. 2, July 2016

Dr JS Dugal, Dr SK Malani, Pune ÂÂ

Coronary dissection is an integral part of PTCA.

ÂÂ

Perforation is an extension of this.

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Incidence varies from 0.2% to 0.6%.

ÂÂ

Causes include guide wires, devices, balloons and stents.

CONFERENCE PROCEEDINGS ÂÂ

Prompt recognition is important to avoid morbidity and mortality.

ÂÂ

Best treatment of perforations is prevention: Recognize high risk anatomy; do not use oversize balloons and stents; be particularly cautious with eccentric lesions; use devices cautiously; assess lesions with IVUS before treating.

ÂÂ

Know how to recognize and treat perforation when it occurs: Never lose wire position: Tamponade perforation with a balloon while you decide what next.

ÂÂ

Close observations: Small leaks or late tear extension can lead to sudden deterioration and the development of cardiac tamponade up to 48 hours later; pigtail pericardiocentesis must for at least 24 hours as recurrent bleed common.

ENDOVASCULAR INTERVENTIONS: EVOLUTION OF A SUBSPECIALTY Dr Raj Dave, USA ÂÂ

Endovascular interventions will save more limbs, improve quality-of-life and continue to evolve.

ÂÂ

CTO recanalization and drug elution will continue to see sophistication.

ÂÂ

In an era of cost-saving, more outpatient endovascular services will be provided.

ÂÂ

Venous diseases: In infancy; greater innovation, cosmetic patient preferences will fuel growth.

OCT: DOES CLINICAL UTILITY JUSTIFY COST? Dr Robert J van Geuns, Netherlands ÂÂ

Intravascular imaging is essential and can be accomplished in many forms.

ÂÂ

OCT for PCI guidance: Assess lesion; assess lumen dimensions and plaque distribution; decide strategy; select stent diameter; stent implantation and select landing zones.

ÂÂ

ILUMIEN I is a prospective, nonrandomized, observational study of PCI procedural practice in patients undergoing intraprocedural pre- and postPCI fractional flow reserve and OCT. The study revealed that OCT-guidance leads to modification of planned treatment in 55% patients. OCT triggered further stent optimization in 25%.

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OCT helps identify culprit lesion in ACS.

ÂÂ

OCT identifies plaque rupture and erosions.

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OCT is helpful in stent sizing and stent optimization.

MYOCARDIAL DAMAGE, INFLAMMATION AND MORTALITY IN CAD Dr Prakash Chandwani, Jaipur Numerous studies have shown an association between elevated serum troponin T (a marker of myocardial damage) and the short-term risk of death and cardiac events in patients with unstable CAD. Similarly, elevated levels of markers of inflammation, such as C-reactive protein and fibrinogen, have also been associated with an increased risk of death or MACE after an episode of unstable CAD. The usefulness or troponin T, C-reactive protein and fibrinogen levels and other indicators as predictors of the long-term risk of death from cardiac causes was evaluated using data obtained during an extension of the Fragmin during Instability in Coronary Artery Disease (FRISC) trial. The FRISC study was a prospective, randomized, multicenter trial of low-molecular-weight heparin for the treatment of unstable CAD. Complete data on troponin T, C-reactive protein, and fibrinogen levels were available in 917 of the 1,506 patients enrolled. The median age of the study population was 70 years. Mean follow-up was 3 years (range, 1.6-50.6 months). The index event at enrollment was unstable angina in 61% of patients and myocardial infarction in 39%. A total of 124 patients died during follow-up. Ninety-two of these deaths were due to cardiac causes. In a multivariate analysis, levels of troponin T and C-reactive protein were independent predictors of the risk of cardiac death. The predictive power of the model increased when both the serum markers and other clinical indicators of risk (age, diabetes, ST-segment depression at admission) were included. Elevated levels of troponin T and C-reactive protein are strongly related to the long-term risk of cardiac death in patients with unstable CAD. These markers function as independent and additive risk markers in conjunction with other clinical indicators. IN-STENT RESTENOSIS IN DES AND BVS: A SINGLE DIGIT PROBLEM Dr Ron Waksman, USA ÂÂ

Restenosis rates of second-generation DES and bioresorbable stent (BRS) are similar to single digit in the first year but hazard ratio of 0.6 yearly for DES with biodegradable polymer (BP).

ÂÂ

Post-dilatation is important to prevent underexpansion.

Indian Journal of Clinical Practice, Vol. 27, No. 2, July 2016

189

CONFERENCE PROCEEDINGS ÂÂ

With BRS device - vessel size mismatch is associated with increased restenosis and other events.

ÂÂ

Appropriate sizing is essential to avoid it.

ÂÂ

Treatment of in-stent restenosis (ISR) of DES-BP and BRS is a challenge with up to 20% recurrence irrespective of treatment modality.

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Rate of restenosis/ID-TLR of a BRS was not different from contemporary drug-eluting metallic stent. In an FIM trial, late restenosis was not associated with scaffold area reduction.

DEDICATED BIFURCATION STENTS: STILL IN INFANCY! Dr Marc Silvestri, France ÂÂ

Bifurcation dedicated stent concept: Custom design, respecting bifurcation anatomy; side branch access; single metal layer; simple use, immediate predictable results.

ÂÂ

Dedicated bifurcation DES - Nitinol self-expanding stent is the most common.

ÂÂ

In the NORDIC Bifurcation study, excellent clinical and angiographic results were obtained with percutaneous treatment of de novo coronary artery bifurcation lesions with SES. The simple stenting strategy used in the main vessel group was associated with reduced procedure and fluoroscopy times and lower rates of procedurerelated biomarker elevation. This strategy can be recommended as the routine bifurcation stenting technique.

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TRYTON trial: Provisional stenting should remain the preferred strategy for treatment of non-left main true coronary bifurcation lesions. The SB in-segment diameter stenosis among the angiographic cohort was lower in the bifurcation stent group compared with the provisional group, with no difference in binary restenosis rates at 9 months follow-up. The concept is attractive but the diversity of bifurcation lesion prevents the creation of a universal model. Dedicated bifurcation stents are limited; may prove to be of value for two stent technique and treatment of major bifurcations.

BIFURCATION LESIONS Dr Nabajit Talukdar, Gurgaon Bifurcation intervention had been a quagmire. It constitutes 20-25% of all coronary interventions. But, despite all advancements, results are often suboptimal. Point of contention is about 1 stent vs. 2 stent technique. With 1 stent or provisional strategy, about 80-90% of lesions can be tackled as seen and established by NORDIC pivotal study. Two stent strategy may be used for which MADS criteria is used. To state simply, side branch >2.5 mm diameter with >50% stenosis and >5 mm lesion length are pressing indications for 2 stents. Recently concluded NORDIC-IV study confirmed better results with 2 stents in these cases. Of note, recent developments include drugeluting balloon in side branch. With stent in main branch, dedicated bifurcation stents, etc. are in offing. Biodegradable polymer containing stents and BVS scaffolds are also newer areas of work. We must remember “We cannot cram the embryonic world of tomorrow into yesterday’s conventional cubby holes.” - Alvin Toffler – Future Shock. Newer thoughts, newer technologies may be endeavored for and improve outcomes with bifurcation lesions. OPTIMAL STRATEGIES FOR A CORONARY INTERMEDIATE LESION: LIMITATIONS OF FFR Dr Hyeon Cheol Gwon, South Korea ÂÂ

Assessment of intermediate lesion: Invasive - IVUS, FFR, CFR; noninvasive - exercise ECG test, exercise stress echo, etc.

ÂÂ

There’s a huge mismatch between IVUS and FFR.

ÂÂ

We need to consider a lot of technical issues during FFR measurement.

ÂÂ

FFR has variability too.

ÂÂ

FFR is not a test of gold standard.

ÂÂ

Clear cut-off value of FFR is a MYTH.

ÂÂ

Intermediate lesion is a benign disease. You can either deter or perform PCI without an increased risk.

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Clinical angioplasty is more important than functional angioplasty.

So, these are still in infancy! ■■■■

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Indian Journal of Clinical Practice, Vol. 27, No. 2, July 2016

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Emerging role of Cardiac MRI in Ischemic and Non-ischemic Cardiomyopathy

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Acute Renal Failure and Silent Myocardial Infarction Following Multiple Honey Bee Stings

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Superficial Brachial Artery: Its Embryological and Clinical Significance

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Glucose Tolerance in Nondiabetic Patients after First Attack of Acute Myocardial Infarction and its Outcome

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Cornary Artery Air Embolism

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AROUND THE GLOBE

News and Views FDA Approves New Drug for Secondary Hyperparathyroidism

nonserious adverse events, including mild to moderate dyspnea and nonmajor bleeding.

The US Food and Drug Administration (FDA) has approved calcifediol (Rayaldee, Opko Health, Inc) for the treatment of adults with secondary hyperparathyroidism (SHPT) associated with vitamin D insufficiency (serum total 25-hydroxyvitamin D levels <30 ng/mL) in stage 3 to 4 chronic kidney disease (CKD), according to a company news release. Calcifediol is a prohormone formulated as an extended-release capsule containing 30 μg of the medication. Calcifediol raises serum total 25-hydroxyvitamin D levels and lowers elevated intact parathyroid hormone (PTH) levels. It is not intended for use in patients with stage 5 CKD or with end-stage renal disease receiving dialysis.

These findings show that adverse events considered “nonserious” by traditional trial criteria may have an effect on quality of life and, thus, may precipitate the discontinuation of treatments and underscore the need for patient education when initiating treatment with ticagrelor, to optimize shared decision making and, when appropriate, maximize adherence and improve clinical efficacy.

Early AGA in Men can be Regarded as Phenotypic Equivalent of PCOS

A study presented June 11, 2016 at the American Diabetes Association 76th Scientific Sessions in New Orleans says that early interventions during pregnancy to improve diet and exercise lower the risk for gestational diabetes and ameliorate outcomes for women and their babies. Nutritionists, behaviorists and exercise therapists can often provide better advice and counseling than physicians.

A comparison of the hormonal profile of early androgenetic alopecia (AGA) in men with the phenotypic equivalent of polycystic ovarian syndrome in women found that men with early AGA could be considered as male phenotypic equivalents of women with PCOS. They can be at risk of developing the same complications associated with PCOS, including obesity, metabolic syndrome, IR, cardiovascular diseases and infertility. The study published online June 15, 2016 in JAMA Dermatology reported significantly increased LH, DHEAS, total testosterone and prolactin levels along with significantly decreased FSH and SHBG levels in the study participants.

Lymph Node Metastasis Predicts Survival PostSurgery in Gastroesophageal Cancer

Neurologic Signs and Symptoms Frequently Manifest in Acute HIV Infection

In patients with gastroesophageal cancer treated with perioperative chemotherapy, lymph node metastases and not pathologic response to chemotherapy was found to be the only independent predictor of survival after chemotherapy plus resection. The results of the MAGIC trial are reported in the Journal of Clinical Oncology, online June 13, 2016.

Acute HIV infection is commonly associated with mild neurologic findings that largely remit while on treatment, and may be mediated by direct viral factors. A total of 245 neurologic findings were noted, reflecting cognitive symptoms (33%), motor findings (34%), and neuropathy (11%). Almost 50% of the neurologic findings occurred at diagnosis, prior to initiation of combination antiretroviral therapy, and 90% of these remitted concurrent with 1 month on treatment. Severe neurologic manifestations are infrequent in treated acute HIV. These findings are reported June 10, 2016 in the journal Neurology.

Lifestyle Interventions in Antenatal Period Improve Pregnancy Outcomes

Many Stable Patients Discontinue Ticagrelor PostMI: PEGASUS A secondary analysis of the PEGASUS-TIMI 54 trial reported online June 15, 2016 in JAMA Cardiology says that stable patients with a history of MI are significantly more likely to stop taking ticagrelor (Brilinta, AstraZeneca) of their dual antiplatelet therapy, usually soon after they start the treatment. This early discontinuation of treatment was primarily driven by

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Indian Journal of Clinical Practice, Vol. 27, No. 2, July 2016

WHO Health advice for the Rio 2016 Olympic and Paralympic Games WHO released health advice for the Rio 2016 Olympic and Paralympic Games geared towards national health

AROUND THE GLOBE authorities and health workers, on Tuesday, 21st June, 2016. The health advice gives measures that travelers can take to be as safe as possible from any public health risk. WHO also provides advice and support to host governments preparing for mass gathering events, including major sporting, religious and cultural events. ÂÂ

Before departure, travelers should be advised about health risks in the areas they plan to visit and related preventive practices and measures to minimize the probability of acquiring diseases and of having accidents.

ÂÂ

Travellers to Brazil should consult the travel advice issued by their national authorities.

ÂÂ

A medical consultation should be scheduled as early as possible before travel but at least 4-8 weeks before departure in order to allow sufficient time for immunization schedules to be completed for both routine vaccines and vaccines indicated according to the specific destinations.

ÂÂ

Routine immunization schedules, established by national authorities, include vaccination against diphtheria, pertussis, tetanus, polio, measles, hepatitis B, Haemophilus influenzae type b and, in many countries, additional diseases such as rubella, mumps, flu, yellow fever, human papillomavirus, and rotavirus and pneumococcal diseases… (WHO)

Vice President Inaugurates International Conference on ‘Yoga for Body and Beyond’ The Vice President of India, Shri M Hamid Ansari has said that Yoga is a science, not a dogma and it helps improve the levels of fitness and the overall health profile. He was addressing the audience after inaugurating a 2-day International Conference on ‘Yoga for Body and Beyond’, on 22nd June, 2016. The Minister of State for AYUSH (I/C) and Health & Family Welfare, Shri Shripad Yesso Naik, Yoga Guru Swami Ramdev, Dr. Pranav Pandya, Swami Amrita Suryananda, Swami Chidanand Muni and Prof. HR Nagendra were also present on the occasion…The Vice President said that given the inability or unwillingness to augment public health funding in developing countries including India, the quest for complementary health approaches assumes urgency. Amongst these is Yoga, which has acquired a following worldwide, he added. He further said that these complementary approaches do not prevent or cure but certainly assist the process of retarding the degeneration of those functions of the human body that allow the diseases to make inroads… (PIB)

Surgery Preferred Treatment for Best Survival in Patients with Cushing’s Disease A multicenter, multinational, retrospective cohort study from the UK has said that patients with Cushing’s disease who have been in remission for more than 10 years still have an increased mortality risk of more than 60% compared with the general population. The risk of early death was especially higher in those with Cushing’s and who also had circulatory disease. Pituitary surgery alone is the preferred treatment to secure an optimum outcome, and should be done in a center of surgical excellence. The study was published online June 2 in The Lancet Diabetes & Endocrinology.

Ankylosing Spondylitis is a Risk Factor for CVD Events A study published June 9, 2016 in the Annals of the Rheumatic Diseases says that prevalent patients with ankylosing spondylitis are at a 30-50% increased risk of acute coronary, cerebrovascular, and thromboembolic events compared with the general population. But compared with patients with rheumatoid arthritis this level of increase was similar for stroke, but only half as high for acute coronary syndromes and thrombotic events.

Severe Obesity Increases Risk of Perioperative Complications post-CAGB Patients with class III obesity (BMI ≥40.0) undergoing CABG surgery have a higher risk of overall perioperative complications, especially infections, and their hospital length of stay is longer compared with patients with normal BMI, suggests a study published June 1, 2016 in the Journal of the American Heart Association.

CDC Best Practice Guidance for PCR to Diagnose H. influenzae and N. meningitidis Disease The Centers for Disease Control and Prevention (CDC) has directed laboratories to use polymerase chain reaction (PCR) assays capable of identifying serotype or serogroup in cases of Haemophilus influenzae (Hi) and Neisseria meningitidis (Nm). PCR allows for detection of Hi and Nm from clinical samples in which the organism cannot be detected by culture methods, such as when a patient has been treated with antibiotics before a clinical specimen is obtained for culture. Even when the organisms are nonviable following antimicrobial treatment, PCR can still detect Hi and Nm DNA if a sufficient amount is present in the specimens. PCR assays that can detect serotype and serogroup are important since determining serotype and serogroup

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AROUND THE GLOBE is crucial for identifying potential outbreaks and determining appropriate public health responses, such as chemoprophylaxis for contacts of cases.

Intestinal Calcium Absorption is Higher in Hypercalciuric Patients with Kidney Stones According to a study published in the June 2016 issue of the Clinical Journal of the American Society of Nephrology, high calcium absorption in duodenum and jejunum may expose hypercalciuric patients to the risk of stones because of increased postprandial calcium concentrations in urine and tubular fluid. The study suggest that measuring intestinal calcium absorption may help to identify individuals who are prone to develop kidney stones.

No Birth Defects Observed with Zika Infection During Third Trimester Preliminary surveillance data from Colombia suggest that maternal infection with Zika virus during the third trimester of pregnancy is not linked to structural abnormalities in the fetus, according to a study published online June 15, 2016 in the New England Journal of Medicine. The authors recommend continued caution and vigilance and further monitoring of these children will be needed to assess long-term repercussions of maternal infection with Zika virus on offspring.

Two Cutting-edge Technologies to Detect HIV in Infants Receive WHO Prequalification WHO has prequalified 2 new innovative technologies for early infant diagnosis of HIV that will allow many more infants to be diagnosed quickly and placed on life-saving treatment. The products, Alere™ q HIV1/2 Detect (made by Alere Technologies GmbH) and Xpert® HIV-1 Qual Assay (made by Cepheid AB) can be used to diagnose infants in as little as an hour, instead of sending a sample to a laboratory, which can take weeks or months to return a result. “These tests mark a significant breakthrough in our response to HIV in young children,” said Mike Ward, who leads the regulation unit of WHO’s Essential Medicines and Health Products department. “They are simpler, faster, automated platforms that do not require as much infrastructure as the conventional lab-based systems and can be used at or near the point of care.” (WHO, June 20, 2016)

Govt. Permits Premature Withdrawals from PPF for Education or Medical Treatment The Ministry of Finance has amended the Public Provident Fund Scheme 1968 to make way for premature

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withdrawal from and closure of a PPF account. According to the Provident Fund (Amendment Scheme), 2016, account holders can now withdraw money from their PPF account after it has completed at least five years, to pay for medical treatment or for the purpose of higher education. PPF accounts have a tenure of 15 years and so far, withdrawal of before maturity wasn’t allowed… (DNA India)

Contaminated Gloves may Cross Transmit Multidrug-resistant Bacteria Among Healthcare Workers An experimental study presented at the recent ASM Microbe meeting in Boston, USA showed that seven important pathogens were easily transmissible from nitrile gloves to a polypropylene surface. All tested microorganisms except K. pneumoniae and A. baumannii decreased dose- and time-dependently and were not detected on the polypropylene surface at 3 minutes after inoculation of gloves. In contrast, K. pneumoniae and A. baumannii remained approximately 10 CFU on the polypropylene surface at 3 minutes after inoculation of gloves and could be transmitted to a surface in the room, or in the next patient’s room.

Nocturnal or Day Time Antihypertensive Dosing has Almost Similar Impact on BP Results of the HARMONY (Hellenic-Anglo Research Into Morning or Night Antihypertensive Drug Delivery) study presented June 11 at the recently concluded European Society of Hypertension (ESH) 2016 Annual Meeting in Paris, France suggest that taking antihypertensive medications during evening or morning hours makes no difference when it comes to 24-hour ambulatory blood pressure monitoring (ABPM) levels in hypertensive patients. At the end of analysis, the observed difference in 24-hour SBP between morning and evening treatment delivery was 0.10 mmHg (adjusted difference 0.11; 95% CI -3.20 to 3.42). The 24-hour DBP was 77.24 vs 77.99 mmHg, respectively. The HARMONY trial is a randomized, crossover trial of 95 hypertension patients in the UK and Greece.

Study Recommends Myocardial Perfusion Imaging Even in Symptomatic Patients with Low Coronary Calcium Results of a study presented June 14, 2016 at the Society of Nuclear Medicine and Molecular Imaging 2016 Annual Meeting in San Diego, California, USA suggest that a very low calcium score alone might not be enough to rule out risk for coronary artery disease in symptomatic patients with no previously known

AROUND THE GLOBE disease. The authors suggest that “for every clinically suspected patient, no matter how low the calcium score is, perform myocardial perfusion imaging” and more conclusive management decisions, should be considered for patients with a positive myocardial perfusion.

Etanercept Effective in Hand Osteoarthritis in Patients with Erosive Symptoms Subcutaneous etanercept (Enbrel, Immunex Corp), a tumor necrosis factor (TNF) inhibitor, improves pain and structural damage in patients with osteoarthritis of the hand, provided they are symptomatic, have clear signs of inflammation and are in a pre-erosive or erosive state, says a multicentre trial from The Netherlands reported June 9, 2016 at the European League Against Rheumatism (EULAR) Congress 2016 in London, UK.

Periodically Monitor Port Wine Stains for Early Detection and Treatment of Complications A study published in the July 2016 issue of the Journal of American Academy of Dermatology concluded that portwine stains with early-onset hypertrophy are associated with a high rate of complications and a poor response to laser treatment. Odontologic problems were noted in 39.8% of cases. Other complications, including cataract, asymmetric development of the maxillary bone, and speech delay/disorders, were reported in 18.4% patients. Only 3% of study participants achieved complete or nearly complete clearance of the PWS after laser treatment.

Long Disease Duration Increases Risk of Malignancies in Patients with IBD A retrospective analysis of data from 1,026 patients from an IBD clinic at the University Hospital Zurich treated between 2007 and 2014 suggest that a long-standing disease course and immunosuppressive therapy increase the risk for developing malignancies in patients with inflammatory bowel disease. The most common malignancies were non-Hodgkin lymphoma, colorectal cancer (CRC), urothelial carcinoma, cholangiocellular carcinoma and prostate cancer. The most common tumor type in Crohn’s disease patients was lymphoma (5 cases), while in those with ulcerative colitis, the most common tumor types were cholangiocellular carcinoma

and colorectal cancer. The median latency between IBD diagnosis and first malignancy was 13 years (range 2-27 years). These findings are published in the journal Digestion June 18, 2016.

Study from South India Finds High Prevalence of Diabetes in Patients with TB Early results from the Effects of Diabetes on Tuberculosis Severity (EDOTS) study published in the June 2016 issue of the journal Chest have shown a strikingly high prevalence of glycemic disorders in South Indian patients with pulmonary TB and unexpected heterogeneity within the patient population with diabetes and TB. Out of 209 TB patients screened for diabetes, 113 (54.1%) were classified as diabetic. Forty-four (21.0%) were found to have impaired glucose tolerance, while 52 (24.9%) were normoglycemic. These results underscore the need for screening of patients with TB for diabetes and vice-versa.

AMA Supports Delayed School Start Times to Improve Adolescent Wellness As sleep deprivation continues to negatively impact the health and well-being of adolescents in the United States, the American Medical Association (AMA) has adopted policy during its Annual Meeting to encourage reasonable school start times that allow students to get sufficient sleep. The new policy specifically calls on school districts across the United States to implement middle and high school start times no earlier than 8:30 a.m. The new policy also encourages physicians to actively educate parents, school administrators, teachers and other community members about the importance of sleep for adolescent mental and physical health based on their proven biological needs… AMA Board Member William E. Kobler, M.D. said, “Scientific evidence strongly suggests that allowing adolescents more time for sleep at the appropriate hours results in improvements in health, academic performance, behavior, and general well-being. We believe delaying school start times will help ensure middle and high school students get enough sleep, and that it will improve the overall mental and physical health of our nation’s young people.”(AMA, June 14, 2016).

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LIGHTER READING

Her mother explained that each of these objects had faced the same adversity – boiling water – but each reacted differently. The carrot went in strong, hard and unrelenting. However, after being subjected to the boiling water, it softened and became weak. The egg had been fragile. Its thin outer shell had protected its liquid interior. But, after sitting through the boiling water, its inside became hardened! The ground coffee beans were unique, however. After they were in the boiling water, they had changed the water. “Which are you?” the mother asked her daughter. “When adversity knocks on your door, how do you respond? Are you a carrot, an egg, or a coffee bean?” Think of this: Which am I? Am I the carrot that seems strong but, with pain and

Indian Journal of Clinical Practice, Vol. 27, No. 2, July 2016

Are you a carrot, an egg, or a coffee bean? LOOKING DOWN AT THE DEFENDANT Looking down at the defendant, the judge said, “Mr. Riley, I’ve decided to give you a suspended sentence.” Tears pouring from his eyes, Riley cried, “Oh, thank you, Your Honor “Don’t thank me,” the judge replied. “I’m sentencing you to be hanged.”

Dr. Good and Dr. Bad SITUATION: A patient with chest pain could pinpoint his pain.

It is a classical heart attack.

It is non-cardiac chest pain.

A young woman went to her mother and told her about her life and how things were so hard for her. She did not know how she was going to make it and wanted to give up. She was tired of fighting and struggling. It seemed that, as one problem was solved, a new one arose. Her mother took her to the kitchen. She filled three pots with water and placed each on a high fire. Soon the pots came to a boil. In the first, she placed carrots, in the second she placed eggs, and in the last she placed ground coffee beans. She let them sit and boil, without saying a word. In about twenty minutes, she turned off the burners. She fished the carrots out and placed them in a bowl. She pulled the eggs out and placed them in a bowl. Then she ladled the coffee out and placed it in a bowl. Turning to her daughter, she asked, “Tell me, what do you see?” “Carrots, eggs, and coffee,” the young woman replied. The mother brought her closer and asked her to feel the carrots. She did and noted that they were soft. She then asked her to take an egg and break it. After pulling off the shell, she observed the hard–boiled egg. Finally, she asked her to sip the coffee. The daughter smiled as she tasted its rich aroma. The daughter then asked, “What does it mean, mother?”

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adversity, do I wilt and become soft and lose my strength? Am I the egg that starts with a malleable heart, but changes with the heat? Did I have a fluid spirit but, after a death, a breakup, or a financial hardship, does my shell look the same, but on the inside am I bitter and tough with a stiff spirit and a hardened heart? Or am I like the coffee bean? The bean actually changes the hot water, the very circumstance that brings the pain. When the water gets hot, it releases the fragrance and flavor. If you are like the bean, when things are at their worst, you get better and change the situation around you. When the hours are the darkest and trials are their greatest, do you elevate to another level? How do you handle adversity?

THE CARROT, THE EGG, AND THE COFFEE BEAN

HUMOR

INSPIRATIONAL STORY

Lighter Side of Medicine

LESSON: A cardiac chest pain can never be pinpointed by a finger.

Information for Authors Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767). Indian Journal of Clinical Practice strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so. The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript. Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper. Covering letter –

– –

The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper. Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors. Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.

Manuscript – Three complete sets of the manuscript should be submitted and preferably with a CD; typed double spaced throughout (including references, tables and legends to figures). –

The manuscript should be arranged as follow: Covering letter, Checklist, Title page, Abstract, Keywords (for indexing, if required), Introduction, Methods, Results, Discussion, References, Tables, Legends to Figures and Figures.

–

All pages should be numbered consecutively beginning with the title page.

Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors. Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the departments and institutions where the work was performed,

name of the corresponding authors, acknowledgment of financial support and abbreviations used. – The title should be of no more than 80 characters and should represent the major theme of the manuscript. A subtitle can be added if necessary. – A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included. – The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page. – A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text. Summary – The summary of not more than 200 words. It must convey the essential features of the paper. – It should not contain abbreviations, footnotes or references. Introduction – The introduction should state why the study was carried out and what were its specific aims/objectives. Methods – These should be described in sufficient detail to permit evaluation and duplication of the work by others. – Ethical guidelines followed by the investigations should be described. Statistics The following information should be given: – The statistical universe i.e., the population from which the sample for the study is selected. – Method of selecting the sample (cases, subjects, etc. from the statistical universe). – Method of allocating the subjects into different groups. – Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques. –

Confidence intervals for the measurements should be provided wherever appropriate.

Results – These should be concise and include only the tables and figures necessary to enhance the understanding of the text.

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Discussion –

This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.

References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses). At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution. Examples of common forms of references are: Articles Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes. Q. J. Expt. Physiol. 1955;40:89-111.

Figures – Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat. – All photomicrographs should indicate the magnification of the print. – Special features should be indicated by arrows or letters which contrast with the background. – The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen. – Color illustrations will be accepted if they make a contribution to the understanding of the article. –

Do not use clips/staples on photographs and artwork.

–

Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as “Fig.”.

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected summary, etc.)_______________________________ 2. Total number of pages ________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________

Books

5. Special requests _____________________________

Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.

6. Suggestions for reviewers (name and postal address)

Articles in Books

2.____________ 2.________________

Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.

3.____________ 3.________________

4.____________ 4.________________

Tables –

These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.

Legends – These should be typed double spaces on a separate sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text. –

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The legend must include enough information to permit interpretation of the figure without reference to the text.

Indian Journal of Clinical Practice, Vol. 27, No. 2, July 2016

Indian 1.____________Foreign 1.________________

7. All authors’ signatures________________________ 8. Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________

Online Submission Also e-Issue @ www.ijcpgroup.com For Editorial Correspondence

Dr KK Aggarwal

Group Editor-in-Chief Indian Journal of Clinical Practice E-219, Greater Kailash, Part-1 New Delhi - 110 048. Tel: 40587513 E-mail: editorial@ijcp.com Website: www.ijcpgroup.com

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