A P E E R - R E V I E W E D F O RU M F O R N U R S E P R AC T I T I O N E R S
■■Dietary Cholesterol, CVD ■■Primary HPV Screening ■■No Link Between MMR Vaccine, Autism ■■IVF and Maternal Morbidity CASE STUDY
Gynecomastia in an Elderly Man LEGAL ADVISOR
RN Fired Over Social Media Post
Implementation of a Screening Questionnaire for OSA in the EMR
Inflamed, Hyperpigmented Axillary Plaque
M AY 2 01 9
The Art of Administering a Tuberculin Skin Test: Wheal Does Matter The vast majority of clinics use the Mantoux test to screen for cases of tuberculosis.
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EXPERTS If a patient has you stumped, write us and we’ll forward your query to one of our consultants and publish the response in Advisor Forum.You can also use this space to contribute a clinical pearl of your own or comment on another letter.
Advisor Forum the color of the affected area was normal, the skin CLINICAL PEARLS felt quite thick and inflexible. These skin changes stopped abruptly at the collar line, below which POISON IVY PREVENTION the skin was entirely normal. Poison ivy season is starting! I recommend that Abundant evidence of sun damage — includ- people take an old pair of knee-high tube socks ing weathering, telangiectasias, solar lentiginosis, and cut off the foot part above the heel. Pull the and numerous actinic keratoses on prominent socks over the arms up to the start of their sleeve areas of his cheeks and ears — was noted. Similar (assuming they are wearing a T-shirt) and tuck changes were noted on the dorsa of both hands into gloves. Use the socks to protect arms when but were not present on his arms and trunk working in the yard or other high-risk poison because he wore long-sleeved shirts when in the ivy areas. They can be rolled off the arms and sun. Although he had worn a wide-brimmed hat thrown away, or washed and re-used. I remind while in the sun during his adult life, he had never people to always wear gloves, and to remove worn anything, such as a bandana, on his neck. the gloves before touching anything, including Always wear The posterior neck is especially susceptible door handles. This significantly reduces the gloves to to the effects of the sun, evidence of which fre- exposure area of skin to poison ivy. —JUDITH protect the quently manifests as it did in this patient. This MCINTOSH, MSN, Kokomo, Indiana skin from condition is called cutis rhomboidalis nuchae weath- VERRUCA VULGARIS TREATMENT exposure to (CRN), which represents thickening and weath ering of the epidermis as well as solar elastosis I always recommend candida albicans skin anti- poison ivy, and of the underlying dermis caused by the sun. gen test injections for patients who are not remove them Although this condition is clear evidence of responding well to liquid nitrogen +/- paring for before touching chronic overexposure to the sun, CRN has no verruca vulgaris. A 0.1-mg injection every month anything. malignant potential, and treatment is neither for about 3 months creates an immune response required nor does it exist. against the warts. I have seen resolution of some Besides being common, CRN is unique in its recalcitrant cases that seemed most impossible! presentation, as well as in the patient population —SARAH LUP, PA-C, Chicago, Illinois it affects (eg, older patients with sun damage confined to the posterior neck), so the differen- RETHINKING PRESCRIBING tial is quite narrow. Punch biopsy would resolve DICLEGIS Diclegis is the only FDA-approved prescription any confusion. CRN puts this patient at higher risk for the medication for nausea and vomiting of pregdevelopmentThe of skin caused by sun expo- nancy that is classified as Category A (safe for se cancers are lette rssquamous sure, such asand basal cell carcinoma, cell mom and baby). Before writing a prescription, from prac successe titioconsider ners arou carcinoma, melanoma, and s,others. the price tag. Diclegis with a coupon obseThis nd the coun rvatpatient ions, andcosts approximately and others with similar histories require regular $345 try for 60 tablets. The pearls with who their to share their skin checks by a qualified dermatology provider most common dosagecolle is 2 tablets/dwan but tcan agues. We clinical chall at least once a year. Although this patient would be more. Some patients may obtain insurance invite you enges to participa be advised to protect himself from the sun, this coverage for this medication, but it will likely te. will do little to ward off any future skin cancers still cost something. Let’s break down Diclegis that will have been caused by sun overexposure CONSUL into its 2 active ingredients: doxylamine sucTAT occurring decades earlier. Application of sun- cinate IONand S pyridoxine hydrochloride (vitamin screen to his neck would prevent IRO worsening of B 6). Unless you are writing a prescription for N PILL 2. Cohen SM, Kwo PY, Lim, his CRN. a celebrity, recommend that your patients ON LIVE S AND THEIR JK. ACG clinical of abnorm Send us R ENZ al liver chemis ECT guideline: your purchase over-the-counter doxylamine YMESinsteadEFF Can takin evaluat tries. Am J Gastroe 3. Iron. ion g iron pills nterol. 2017;1 al Institute Reference letters with succinate and vitamin B 6 to take Nation at night elevate liver —AGNES 12:18-35. of Health nih.gov/Iron.h ques website. https:// enzymes? MURPHY, tm. Access for nausea. —AMBER PA-C, Bolognia JL, Jorizzo JL,tions Rapini RP. Dermatology. 1st ed. NewDEW, PCA and , Americus, livertox. ed April 3, commen 2019. Georgia Birmingham, Michigan York: Mosby, 2003;1380-1381. ts to: Liver enzym es Advisor Forum aspartate aminosuch as alanine amino , CASE FILE transfe The Clinica l Advisor, phatase are transferase (AST), and rase (ALT), S www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 45 275 7th Aven markers of alkaline phosfunction, and hepat ue, 10th CUTIS RHO should be referre ic injury, not hepat Floor, New Albumin, MBO ic York, d to as liver bilirubin, and chemistries. Contributed by Joe Monr IDALIS NY 10001 measures of prothrombin .You oe, MPAS, hepatocellu time are direct A 78-year-old may conta PA-C lar appropriately ct us heavily lined man presented characterized synthetic function and with thick e-mail at edito by skin on enzymes may are as “liver functio r@ be abnormal n tests.” Liver been present for an his posterior neck ened, clinicaladvis liver diseas that had even in patien indet or.com. Although e. The differe ts without the striking erminate period of Letters are ntial for elevat broad with time. skin chang tomatic, edited many be further define potential causative ed enzymes is insiste they were concerning es were asympfor length factors and and d that he be to his relativ d by the patien should risk factors. 1 clarity. The seen es who t’s by a medical histor The Clinical y and the patient had spent dermatology provider. Almost all Advisor’s policy nearl sun, farmi medications ng, ranching, y his whole life small risk of are associated is to print to his in elevat fishing, and the hepatotoxic 2 ed liver chemistries with at least a a histo property in rural tending author’s name Okla ity. Oral with ry homa or of witho iron skin cance . replacement with the letter r and claim He denied doses has little supplementation at typicaut good health. ed to be . liver or serum or No anony in The skin on enzyme elevati no adverse effects on l mous the patien or overdoses, the ons. However, contributio it in high doses lined and thickened t’s nuchal area was ns will of iron poison can cause acute hepato heavily . The multiple overla toxicity as a ing. be accepted. pping rhom lines joined to form result of ferrous sulfate Toxicity occurs after boidal shape ingestion of (approximat ≥3 g s. toxicity with Altho ely 10 tablets ugh aminotransf ). Severe the upper limit erases greate r overdoses and of normal typically than 25 times occurs with high initial larger serum iron dL). Mild levels to usually self-limmoderate cases of iron (>1000 ug/ whereas severe iting and resolve with poisoning are suppo KUSMIN cases become fatal rapidl 3 rtive care, SKY, PA-C y. —LAURA Referenc es
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1. Approach to the patient with abnorm and functio n tests. UptoD al liver bioche mical ate.com websit uptodate.com e. https://www. /contents/app roach-to-theabnormal-liver patient-with-biochemical -and-functionApril 2, 2019. tests. Access ed
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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 1
CONTENTS M AY 2 0 1 9
Newsline ■■No Association Between MMR Vaccine and Autism ■■USPSTF Recommendations for Ophthalmia
13 No MMR Vaccine and Autism Link
■■HRT May Increase Risk for Alzheimer Disease ■■Dietary Cholesterol Linked to Significant Increase in CVD ■■Primary Cervical Screening for HPV May Improve Detection ■■IVF May Increase Severe Maternal Morbidity, Mortality Risk
FEATURES 16 Metformin Use and Vitamin B12 Deficiency: Managing the Risks Three theoretical mechanisms of action regarding the contribution of metformin to the lowering of vitamin B12 have been postulated. 16 Vitamin B12 Screening With Metformin Use
31 Increasing Gynecomastia Awareness
22 Implementation of a Screening Questionnaire for OSA in the EMR Because of the harmful effects of untreated OSA, it is imperative that patients be diagnosed and effectively treated to prevent adverse outcomes. 28 The Art of Administering a Tuberculin Skin Test: Wheal Does Matter In light of the persistence of this curable pathogen, healthcare providers should advocate for increasing awareness and encouraging screening for tuberculosis infection in appropriate settings. Continues on page 4
47 RN’s Post Violates Patient’s Privacy
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CONTENTS M AY 2 0 1 9
Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com
A P E E R - R E V I E W E D F O RU M F O R N U R S E P R AC T I T I O N E R S
■ Dietary Cholesterol, CVD ■ Primary HPV Screening ■ No Link Between MMR Vaccine, Autism ■ IVF and Maternal Morbidity
MAAY PEER-REVIEWED 2 01 9 | www.ClinicalAdvisor.com FORUM FOR NURSE A PRACTITIONERS PEER-REVIEWED| FORUM APRIL 2FOR 019 NURSE | www.ClinicalAdvisor.com PRACTITIONERS | MARCH 2019
NEWSLINE INFECTIOUS DISEASE
■ Exercise and Cognitive Function ■ CRC Screening Outreach ■ Screen Time and Children
■ GI Illness in Older Adults ■ Physical Activity and HCC Risk ■ Maternal Hyperglycemia ■ WHO Top Health Threat
Case Clinic: AInsights 67-YearThe Art of Administering Into the Diagnosis Old Man Withand Atrial a Tuberculin Skin Treatment of OpioidFibrillation Risk FactorsConstipation Test: Wheal Does Matter Induced FEATURE
Gynecomastia in an Elderly Man
Case Study Gynecomastia in an Elderly Man
RN Fired Over Social Media Post
Dermatology Clinic ■ Inflamed and Hyperpigmented Plaque in the Axilla ■ Painful, Pruritic Rash on the Face
Dermatologic Look-Alikes Nodules on the Arm and Leg
Legal Advisor RN Fired Over Social Media Post
ADVISOR FORUM 44
Consultations Iron Pills and Their Effect on Liver Enzymes
Case Files Cutis Rhomboidalis
Clinical Pearls ■ Poison Ivy Prevention ■ Verruca Vulgaris Treatment ■ Rethinking Prescribing Diclegis
Implementation of a Screening Questionnaire for OSA in the EMR
Inflamed, Hyperpigmented Axillary Plaque
The Counseling Connection
The Healthcare Practitioner’s Guide to Atopic Dermatitis
Health Literacy and the Older Adult: A Persistent
NP Testifies in a Rape Case
Multiple Erythematous, Scaly Plaques
Lower Extremity Swelling and Rash
The vast majority of and Widespread Problem clinics use the Mantoux LEGAL ADVISOR test to screen for cases of tuberculosis. LEGAL ADVISOR Careful Note-Taking
FREE CME COURSE
FREE CME COURSE
Dietary Interventions for the Management of Obesity
Evolution of the Intestinal Microbiome
Atrial fibrillation is the most common type of cardiac arrhythmia.
Constipation is one of the most common adverse effects of chronic opioid therapy.
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EXCLUSIVE TO THE WEB AT
Hospitalization for MDD Costly, Associated With High Readmission Rates
ClinicalAdvisor.com/MeetingCoverage Implementing Pediatric Inpatient Concussion Guidelines Providing nurse practitioners with standardized order sets and education on concussions in pediatric patients promotes enhanced care.
Adult MDD-related hospitalizations are costly to patients and to the healthcare system, and rehospitalization within 30 days of discharge is common.
Preventive Pediatric Health Care Recommendations Approved by AAP The 2019 recommendations are intended for the care of children receiving competent parenting, have no significant health issues, and who are growing and developing at satisfactory rates.
Racial, Social Disparities in Services for PLWHIV Partners The prevalence of newly diagnosed HIV infection was particularly high in black partners who were gay, bisexual, men who had sex with men, and transgender individuals.
New Path for Maintaining Cardiology Board Certification A new performance test will be available every year, with each test covering approximately 20% of cardiovascular disease material.
Characteristics Associated With Perinatal Depression Onset Timing Specif ic background characteristics of mothers may explain why the onset of depression occurs at a particular stage of the perinatal period.
Analyzing Pediatric NP Job Satisfaction in a Hospital Setting Pediatric nurse practitioners at a children’s hospital expressed increased job satisfaction when working with patients and their families as well as in dynamic teams with other professionals.
FEATURES ClinicalAdvisor.com/Features Updated Guidelines for Managing Pediatric Severe TBI A multidisciplinary group of experts have released updated evidencebased guidelines for 2019 to optimize critical care and improve outcomes of critically ill children with traumatic brain injury. Counseling Patients With Dyspareunia in Menopause As dyspareunia may cause distress or interpersonal conflict between women and their partners, healthcare providers should routinely ask about discomfort during intercourse, especially in menopausal patients.
THE WAITING ROOM
Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Jeffrey Gudin, MD Benzodiazepines: Primary Care’s New Drug Problem Heightened awareness of the dangers of prescription opioids has prompted a movement to limit use of opioid therapies for patients with acute or chronic pain.
6 THE CLINICAL ADVISOR • MAY 2019 • www.ClinicalAdvisor.com
Advisor Dx Interact with your peers by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit ClinicalAdvisor.com/AdvisorDx. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues. Check out some of our latest cases below!
Lesions on the Fingers and Toes A 39-year-old man presents with a 3-year history of lesions on his fingers and toes that appear following exposure to cold temperatures. He complains of discomfort when wearing shoes, and light palpation is painful. The patient denies a history of smoking, systemic disease, or illicit drug use. Examination reveals edematous, erythematous papules of the affected areas. CAN YOU DIAGNOSE THIS CONDITION?
• Raynaud syndrome • Lupus erythematosus
• Sarcoid • Pernio
● See the full case at ClinicalAdvisor.com/DermDx_May19
In partnership with
Journal of Orthopedics for Physician Assistants
Supernumerary Digits Attached to the Small Fingers A 6-month-old infant is brought to the office by his parents who describe an extra digit over the small finger on each hand. He had a normal prenatal course and delivery and has no other known medical issues. On examination, floppy, duplicated fingers are identified on the proximal phalanges of both small fingers. The patient’s other fingers appear normal. WHICH IS THE BEST TREATMENT OPTION?
• Observation • Surgical ablation • Tie off the extra digit with suture • Proximal phalanx fusion ● See the full case at ClinicalAdvisor.com/OrthoDx_May19
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 7
Newsline ONCE AGAIN, a large study of Danish residents confirmed that the measles, mumps, rubella (MMR) vaccine is not associated with an increase in autism and does not trigger autism in children who are susceptible to the disorder. Findings from this study were published in the Annals of Internal Medicine. Researchers obtained data of children born in Denmark between January 1, 1999, and December 31, 2010. Specifically, they examined rates of autism diagnoses and associations with the MMR vaccine, other childhood vaccines, sibling history of autism, and autism risk factors. The cohort consisted of 657,461 children (mean age, 8.64 years), represented by 5,025,754 person-years of follow-up. The association between MMR vaccination and receiving an autism diagnosis was adjusted for age, birth year, sex, other childhood vaccines, sibling history of autism, and autism risk factors.
A total of 6517 children in the sample were diagnosed with autism (mean age at first autism diagnosis, 7.22 years) during the follow-up period (incidence 129.7 per 100,000 person-years). The median age at time of MMR vaccination was 1.34 years, and uptake of the vaccine was 95.19%. No difference was found between MMR-vaccinated children and those not vaccinated with MMR in terms of receiving an autism diagnosis, as determined by a fully adjusted hazard ratio (aHR) of 0.93 (95% CI, 0.85-1.02). In a subgroup analysis, receipt of the MMR vaccine was associated with reduced autism risk in girls (aHR, 0.79; 95% CI, 0.64-0.97) as well as in the 1999 through 2001 cohort (aHR, 0.84; 95% CI, 0.73-0.96). Risk factors associated with a higher risk for autism included being a boy (HR, 4.02; 95% CI, 3.78-4.28), being born in a later birth cohort (HR, 1.34; 95% CI, 1.18-1.52), having no early
© ER PRODUCTIONS LIMITED / GETTY IMAGES
No Association Between MMR Vaccine and Autism
Having no early childhood vaccinations increased the risk for autism.
childhood vaccinations (HR, 1.17; 95% CI, 0.98-1.38), and having siblings with autism at study entry (HR, 7.32; 95% CI, 5.29-10.12). In an accompanying editorial, Saad B. Omer, MBBS, MD, PhD, and InciYildirim, MD, PhD, MSc, of the Rollins School of Public Health at Emory University in Atlanta, Georgia,suggested that the myth linking the MMR vaccine with autism should be dispelled by practitioners by engaging with patients and their families using simple evidence-based education.
USPSTF Recommendations for Ophthalmia Neonatorum Prevention THE US PREVENTIVE SERVICES Task Force (USPSTF) reaffirmed its 2011 recommendation to provide prophylaxis with ocular topical medication against gonococcal ophthalmia neonatorum — which can cause corneal scarring, ocular perforation, and blindness as early as 24 hours after birth — to all newborns, according to a recommendation statement published in JAMA. The USPSTF noted that erythromycin ophthalmic ointment is currently the only drug approved by the US Food and Drug Administration for this purpose. In addition, ocular prophylaxis in newborns is standard neonatal care and required in most states. Screening for gonorrhea in all sexually active women
aged ≤24 years, older women at increased risk for infection, and pregnant women is also recommended by the USPSTF. Universal ocular topical prophylaxis for the prevention of gonococcal ophthalmia neonatorum is also recommended by the Centers for Disease Control and Prevention, American Academy of Pediatrics, American College of Obstetricians and Gynecologists, and World Health Organization. According to the USPSTF recommendation statement, “using a reaffirmation process, the USPSTF concludes with high certainty that the net benefit of topical ocular prophylaxis of all newborns to prevent gonococcal ophthalmia neonatorum is substantial.”
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 13
Newsline HRT May Increase Risk for Alzheimer Disease LONG-TERM USE of systemic hormone replacement therapy (HRT) may slightly increase the risk of developing Alzheimer disease (AD), according to study results published in BMJ. Previous studies have shown that AD is more common in women than men. Some experts pointed to estrogen deficiency in postmenopausal women as the reason for this gender difference, suggesting that estrogen treatment in early menopause may protect against AD. However, the data regarding the effect of HRT on the risk for AD are inconclusive. In a nationwide case control study, researchers investigated the use of HRT in 84,739 postmenopausal women in Finland diagnosed with AD between 1999 and 2013 and compared them with a similar number of postmenopausal women without AD. In 99% of women with AD, the diagnosis was made at age ≥60 years, with
Vaginal estrogen use was not associated with increased risk for AD.
56% >80 years at diagnosis. Of those with AD, 19% were treated with systemic HRT, including estradiol only (7%), combination estradiol and progestogen (12%), or tibolone (0.3%). At the time of AD diagnosis, only 15% of women were still using hormone therapy. In addition, 65% had stopped
treatment >3 years before diagnosis. The results indicated that the use of systemic HRT was more common in women with AD (18.6% vs 17.0%; P <.001), but the use of vaginal estradiol was more common in the control group (12.7% vs 13.2%; P =.005). Systemic HRT that contained only estradiol was associated with a 9% increased risk for developing AD, while systemic HRT that contained estrogen and progestin was associated with a 17% increased risk; the risk was similar with different mixed progestogens.This increased risk suggests that for every 10,000 HRT-treated women between the age of 70 and 80 years, 9 to 18 women would develop AD every year. The study showed no difference in the risk for AD based on the formulation of HRT, with a similar risk for patients treated with estrogen alone or with combinations of estrogen and progesterone.
Dietary Cholesterol Linked to Significant Increase in CVD and incident CVD and all-cause mortality.Among the 29,615 participants during a median follow-up of 17.5 years, 5400 incident CVD events and 6132 all-cause deaths occurred. Each additional 300 mg of dietary cholesterol consumed per day was significantly
significant after adjusting for dietary cholesterol consumption. It is important to note that among other limitations, these study findings are observational and cannot establish causality. “Among US adults, higher consumption of dietary cholesterol or eggs was
The relationship between dietary cholesterol consumption and CVD and mortality continues to be debated after years of research. associated with a higher risk for incident CVD and all-cause mortality, as was each additional half an egg consumed per day. However, the associations between egg consumption and incident CVD and all-cause mortality were no longer
14 THE CLINICAL ADVISOR • MAY 2019 • www.ClinicalAdvisor.com
significantly associated with higher risk of incident CVD and all-cause mortality in a dose-response manner,” concluded the authors. In addition, “these results should be considered in the development of dietary guidelines and updates.”
© SELVANEGRA / GETTY IMAGES
AMONG ADULTS in the United States, higher consumption of dietary cholesterol or eggs is significantly associated with a higher risk for incident cardiovascular disease (CVD) and all-cause mortality in a dose-response manner, according to a study published in JAMA. The relationship between dietary cholesterol consumption and CVD and mortality continues to be debated after years of research. Eggs are a major source of dietary cholesterol, with a large egg containing approximately 186 mg. By pooling individual participant data collected between March 25, 1985 and August 31, 2016 from 6 US prospective cohort studies, researchers sought to determine the associations between dietary cholesterol or egg consumption
IVF May Increase Severe Maternal Morbidity, Mortality Risk
© SCIENCE PHOTO LIBRARY - ZEPHYR / GETTY IMAGES
WOMEN WHO BECAME pregnant from infertility treatment, specifically in vitro fertilization, were found to be at higher risk for severe morbidity and mortality, according to a study published in the Canadian Medical Association Journal. A Canadian research team analyzed a population of women aged 18 to 60 years with a hospital delivery between April 2006 and March 2012. After propensity score matching, 11,546 pregnancies achieved with infertility treatment including ovulation induction, intrauterine insemination, or in vitro fertilization were compared with 47,553 unassisted pregnancies to assess the association of each with severe maternal morbidity and mortality. Infertility treatment was further categorized as invasive (in vitro fertilization with or without intracytoplasmic sperm injection) or noninvasive (intrauterine insemination or ovulation induction alone) to determine the relationship between treatment type and maternal morbidity indicators. Severe maternal morbidity or death that occurred between 20 weeks’ gestation and 42 days after hospital discharge after delivery was the primary outcome measure. Secondary outcomes included the most common individual indicators of severe maternal morbidity (severe
Invasive infertility treatment increased the risk for maternal morbidity.
postpartum hemorrhage, maternal admission to an intensive care unit, puerperal sepsis, hysterectomy, and cardiac conditions) and all-cause maternal mortality between 42 and 365 days postpartum. Severe maternal morbidity or death occurred in 356 treated pregnancies (30.8 per 1000) and in 1054 untreated pregnancies (22.2 per 1000). This outcome measure occurred in 121 pregnancies achieved through noninvasive treatment (21.7 per 1000) and in 235 achieved through invasive treatment (39.3 per 1000). The absolute risk for severe maternal morbidity or death in relation to the use of infertility treatment was more pronounced in those aged ≥40 years and in those with a multiple gestation. Maternal death from 20 weeks’ gestation to 42 days postpartum occurred in <6 women who used infertility treatment (≤0.5 per 1000) and in <6 women who did not (≤0.1 per 1000), and death from 42 to 365 days postpartum occurred in <6 women who received infertility treatment (≤0.5 per 1000) and in 11 women who did not (0.2 per 1000). Indicators of severe maternal morbidity were more common in pregnancies achieved through infertility treatment than in untreated pregnancies. Significant associations were found among severe postpartum hemorrhage, maternal admission to an intensive care unit, puerperal sepsis, and invasive infertility treatment, whereas no statistically significant associations were observed for noninvasive treatment. “Women whose pregnancy was achieved by infertility treatment, especially in vitro fertilization, are at a somewhat higher risk of severe maternal morbidity or death,” the authors concluded.“Further research should identify patient- and treatment-specific factors that might be modified to mitigate excess maternal risks.”
Primary Cervical Screening for HPV May Improve Detection COMPARED WITH liquid-based cytology, routine primary high-risk HPV (hrHPV) screening was found to significantly improve the detection of cervical intraepithelial neoplasia (CIN) and cervical cancer, according to an observational study published in BMJ. A team of UK-based investigators for The English Cervical Screening Programme compiled data on the prevalence and incidence of highgrade CIN among women who had routine primary hrHPV testing compared with primary liquid-based cytology screening. Participants included 578,547 women between ages 24 and 64 who underwent cervical screening in the primary care setting with follow-up in 3 years; 32% underwent screening with hrHPV testing and 68% underwent screening with liquid-based cytology. Of the women who underwent hrHPV testing, 12.7% tested positive, while 3.8% of those undergoing liquid-based cytology tested positive. Nearly one-third of those who had positive hrHPV results were HPV 16/18 positive. Compared with liquid-based cytology, hrHPV testing detected 50% more CIN grade 2 or worse, 40% more CIN grade 3 or worse, and 30% more cervical cancer. Although hrHPV testing has reduced specificity vs cytology — approximately 80% more colposcopies were needed for women with hrHPV testing — positive test results can be followed by reflex liquid-based cytology to mitigate excessive referral for a colposcopy. ■
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 15
FEATURE: PAULA PEACOCK, DNP, ARNP, FNP-BC
Metformin Use and Vitamin B12 Deficiency: Managing the Risks With the correlation between metformin use and vitamin B12 deficiency established, guidelines for vitamin B12 screening should be considered.
© PHILIPPE ROY / GETTY IMAGES
The blood test for monitoring vitamin B12 levels costs approximately $50.
etformin is the first-line medication for treatment of type 2 diabetes mellitus (T2DM).This commonly used medication has also been associated with lowering serum vitamin B12 levels. Although the British National Formulary documented this connection in the 1970s with a constellation of studies supporting this effect, recognition of this by most prescribers is lacking.1-17 Three theoretical mechanisms of action regarding the contribution of metformin to the lowering of B12, a water-soluble vitamin, have been postulated; it may be one or any combination of these that contributes to a diminished B12 level. The first posits that this is due to blocking by metformin of the calcium channels in the distal ileum that normally allow absorption of the vitamin B12intrinsic factor (B12-IF) complex by altering the membrane potential.2 The hydrophobic tail of metformin binds to the hydrocarbon core of the cell membrane, imparting a net positive charge; this, in turn, repels calcium that is necessary for transporting B12 across the ileal-lumen interface.18 The second mechanism details the modification of normal bacterial flora, resulting in bacterial overgrowth and impeded passage of B12-IF into the bloodstream.19 A third pathway describes metformin changing the B12-IF complex by binding to it structurally.19 Each of these potential influences lessens the amount of B12 that passes through the distal ileal wall.13 Continues on page 18
16 THE CLINICAL ADVISOR • MAY 2019 • www.ClinicalAdvisor.com
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Cash BD, Epstein MS, Shah SM. Patient satisfaction with IBS symptom relief using a novel peppermint oil delivery system in a randomized clinical trial and in the general population. Int J Dig. Dis. 2016;2(2). doi:10.4172/2472-1891.100027. Cash BD, Epstein MS, Shah SM. IBgard: a novel small intestine targeted delivery system of peppermint oil results in significant improvement in severe and unbearable IBS symptom intensity. Results from the U.S.-based, 4-week, randomized, placebo-controlled, multi-center IBSREST™ trial. Poster presented at DDW, May 2015. Cash BD, Epstein MS, Shah SM. A novel delivery system of peppermint oil is an effective therapy for irritable bowel syndrome symptoms. Dig Dis Sci. 2016;61(2):560-571. 4 Ford AC, Moayyedi P, Chey WD et al. American College of Gastroenterology Monograph on Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2018 Jun;113(Suppl 2):1-18. 5 Lacy BE. A Caraway Oil/l-Menthol Combination Improves Functional Dyspepsia (FD) Symptoms within 24 hours: Results of a Randomized Controlled Trial which Allowed Usual FD Treatments. Poster presented at DDW 2017. 6 Chey W. Rapid relief of functional dyspepsia symptoms with a novel formulation of caraway oil and l-Menthol: outcomes from a self-reported patient outcomes study. Presented at American College of Gastroenterology Annual Conference; 2017; Orlando, FL. 7 Micka A, et al. Effect of consumption of chicory inulin on bowel function in healthy subjects with constipation: a randomized, double-blind, placebo-controlled trial. International Journal of Food Sciences and Nutrition. Aug 2017 68:1, 82-89. 8 Lacy B, Epstein M, Shah S, Corsino P. Improved regularity with a chewable inulin fiber (CIF): results from a Patient Reported Outcomes (PRO) study. Presented at American College of Gastroenterology Annual Conference - Philadelphia, PA.; 2018. 9 Brodner DC, Shah SM. REM Absorption Kinetics Trial: A Randomized, Crossover, Pharmacokinetics Evaluation of a Novel Continuous Release and Absorption Melatonin Formulation versus a Same Strength Immediate-Release Formulation in Healthy Adults (Abstract 0396). Poster presented at: SLEEP 2017; June 3-7, 2017; Boston, MA. 10 Brodner C, Seiden DJ, Shah SM. Improvement in Sleep Maintenance and Sleep Quality with Ion Powered Pump Continuous Release and Absorption Melatonin: Results from a Self-Reported Patient Outcomes Study (Abstract 0419). Poster presented at: SLEEP 2018, June 2018, Baltimore MD. † Among gastroenterologists who recommended peppermint oil for IBS. Alpha ImpactRx ProVoice survey (September 2018). ‡ Among gastroenterologists who recommended herbal products for Functional Dyspepsia. Alpha ImpactRx ProVoice survey (June 2018). †† Among gastroenterologists who recommended a chewable prebiotic fiber brand. Alpha ImpactRx ProVoice survey (May 2018). CA_0519T § ©2019 IM HealthScience® Among primary care physicians with a certification in sleep disorders who recommended a brand of modified release melatonin. QuintilesIMS ProVoice survey (July-Sept. 2017). 1
*THESE STATEMENTS HAVE NOT BEEN EVALUATED BY THE FOOD AND DRUG ADMINISTRATION. THIS PRODUCT IS NOT INTENDED TO DIAGNOSE, TREAT, CURE, OR PREVENT ANY DISEASE.
METFORMIN USE AND VITAMIN B12 DEFICIENCY
Low vitamin B12 levels that are symptomatic cause a confounding clinical similarity to diabetic peripheral neuropathy. Though poorly understood, low vitamin B12 levels cause a diminution of the myelin that coats the peripheral nerves, perhaps through the attenuated methylation of myelin, which subsequently disrupts the transmission of action potentials. Nonhomogeneous myelin manifests as peripheral neuropathy.8 Vitamin B12 functions as a coenzyme in the transfer of a methyl group from 5-methyl-tetrahydrofolate to tetrahydrofolate, creating methionine with the enzyme methionine synthase.20 Methionine and adenosine triphosphate are essential in assembling 5-adenosyl methionine, which is the primary methyl donor in the methylation reactions involving amines, proteins, and phospholipids (including sphingomyelin) in the myelin sheath. Thus, a deficiency of B12 leads to diminished methylation in myelin and, subsequently, the development of peripheral neuropathy.20 Once this process occurs, it is extremely difficult to reverse and correct. Low vitamin B12 levels that are symptomatic exhibit a confounding clinical similarity to diabetic peripheral neuropathy.5 Vitamin B12 also functions as a coenzyme that connects lipid to carbohydrate metabolism in the mitochondria by converting methylmalonic acid to succinate through the enzyme methylmalonyl-coenzyme A mutase.20 A deficiency in vitamin B12 can therefore result in symptoms of malaise and fatigue. Coexisting factors can affect the absorption of vitamin B12 in patients with T2DM. Patients who are vegetarian are
POLL POSITION Which of the following factors does not negatively affect the absorption of vitamin B12 in patients with T2DM?
■ A vegetarian diet ■ Concomitant use of metformin and proton pump inhibitors
1.79% 7.14% 16.07%
■ Exposure to sunlight ■ Alcohol consumption
For more polls, visit ClinicalAdvisor.com/Polls.
known to be at risk for low vitamin B12 levels because of the absence of protein-bound vitamin B12 in plant-based foods.1 Additionally, the concomitant use of metformin with proton pump inhibitors and/or H2-antagonist medications can cause as much as a 65% and 25% reduction, respectively, in absorption of vitamin B12. This is due to the decrease in gastric hydrochloric acid, which is needed to cleave vitamin B12 from protein that is ingested.4 Similarly, alcohol use can deleteriously influence vitamin B12 levels.5 Until recently, no published guidelines existed regarding the monitoring and supplementation with exogenous cyanocobalamin, the manufactured form of vitamin B12, in patients with T2DM on long-term treatment with metformin.14,21 In 2018, the American Association of Clinical Endocrinologists and the American College of Endocrinology endorsed a comprehensive management algorithm for T2DM that calls for assessing the status of vitamin B12 levels in patients taking metformin and instituting supplementation if neuropathy develops.22 The recent change in reimbursement for primary care services, led by Medicare’s value-based reimbursement model, makes cost containment paramount.This new framework emphasizes focusing on early prevention measures to minimize complications, decreasing and controlling cost, potentiating patient satisfaction, and implementing a team-based approach involving healthcare providers and patients. If effective evidence-based measures are utilized, providers receive greater reimbursement and patient health is maximized. A simple screening test and/or supplementation that improves quality of life, increases overall safety in the setting of peripheral neuropathy, reduces office visits secondary to neuropathic exacerbations, and provides relief from symptoms would be desirable. The discrepancy between the cost of treating a patient with metformin-induced vitamin B12 deficiency vs treating complications from neuropathy misattributed to diabetes is substantial. The blood test for monitoring vitamin B12 levels costs approximately $50 at LabCorp and Quest Diagnostic labs.23 If a provider deems vitamin B12 supplementation medically necessary, the cost of 1000 mcg of oral vitamin B12 supplements is approximately $18 for a 150-day supply24 or about $36 per year.Additionally, a single-dose vial of injectable vitamin B12 costs <$15 per injection.25 These numbers stand in stark contrast to the cost of treating the painful symptoms that result from peripheral neuropathy with gabapentin, pregabalin, duloxetine, tramadol, or amitriptyline (Table).26
18 THE CLINICAL ADVISOR • MAY 2019 • www.ClinicalAdvisor.com
The risk of developing low vitamin B12 directly correlates with the dose of metformin and/or duration of its use. Furthermore, the cost of pharmaceuticals is the proverbial tip of the iceberg, since hospitalizations for micro- or macrovascular complications and their sequelae — such as infection, amputation, disability, etc — increase the cost of treatment exponentially and can soar into the billions. Recent research estimates the cost of care for type 1 diabetes mellitus annually at $0.3 to $1 billion and for T2DM at $4.3 to $12.7 billion, approximately 27% of which is due to medical care for peripheral neuropathy alone.27 Up to 50% of patients aged >65 years with T2DM experience diabetes-induced peripheral neuropathy and of these, 10% to 20% have unremitting pain as a primary symptom that requires medication.28 It is important to remember that the symptoms of neuropathy from B12 deficiency are correctable if diagnosed early but become irreversible, like diabetes-induced neuropathy, if this diagnosis is missed. To develop a successful standard of care with respect to treatment of metformin-induced vitamin B12 deficiency, the medical community must establish clear parameters for the normal range of values of vitamin B12 levels. The risk of developing low vitamin B12 directly correlates with the dose of metformin and/or duration of use. Patients who take >1000 mg/d for >3½ years are 10 times more at risk for vitamin B12 insufficiency than those taking <1000 mg/d for <3½ years.7 Low vitamin B12 levels improve in patients using metformin who take multivitamins daily compared with those who do not.29 TABLE. Cost of Medications to Treat Peripheral Neuropathy26 Medication
Average Retail Price
100 mg 300 mg 400 mg 600 mg 800 mg
$27.00 $95.00 $115.00 $169.00 $183.00
In summary, health benefits and improved quality of life are realized when patients being treated for chronic conditions are monitored closely. With the direct correlation between metformin use and potential consequences established, the frequency and extent of vitamin B12 screening needs to be addressed.5 Substantial support exists for monitoring at-risk patients, especially those presenting with complaints of neuropathy. It is important to educate providers and patients of this risk, monitor for symptoms of neuropathy, assess vitamin B12 levels when deemed appropriate, and consider prophylaxis when metformin is initially prescribed to thwart the development of symptoms. Implementation of a simple routine laboratory screening test in conjunction with oral or injectable supplementation of vitamin B12 would reduce the risk for metformin-induced vitamin B12 deficiency. Such shifts in the treatment paradigm would allow patients to follow a continuum of health and minimize the deleterious effects of T2DM, such as physical inactivity because of peripheral neuropathy, weight gain, depression, and poor glucose control. Proactively addressing the risk of developing low vitamin B12 levels in this patient population not only reduces potential physical and mental sequelae but also lessens the financial burden of disease, appointments, testing, loss of time from work, and reduction in wages. Efficient patient care, coupled with prudent expenditure of healthcare dollars, benefits all stakeholders, and screening and supplementation of vitamin B12 in this patient population is one example of such care. ■ Paula Peacock, ARNP, FNP-BC, MSN, is a nurse practitioner at Baptist Health, in Jacksonville, Florida. References 1. Agarwal P, Mital P, Meena VK, Mital P, Nawal CL, Goyal LK. A comparative study of levels of vitamin B12 in patients of type 2 diabetes mellitus on metformin and not on metformin at tertiary care center. Int J Adv Med. 2016;3(3):759-763. 2. Aroda VR, Edelstein SL, Goldberg RB, et al; Diabetes Prevention Program Research Group. Long-term metformin use and vitamin B12 deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab. 2016;101(4):1754-1761. 3. Chapman LE, Darling AL, Brown JE. The association between the biguanide drug metformin and vitamin B12 deficiency in diabetic patients: a systematic review. Presented at: Nutrition Society Summer Meeting; July 2014; Glasgow, Scotland.
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 19
METFORMIN USE AND VITAMIN B12 DEFICIENCY
4. Damião CP, Rodrigues AO, Pinheiro MF, et al. Prevalence of vitamin B12
22. Garber AJ, Abrahamson MJ, Barzilay JI. Consensus statement by the
deficiency in type 2 diabetic patients using metformin: a cross-sectional study.
American Association of Clinical Endocrinologists and American College of
Sao Paulo Med J. 2016;134(6):473-479.
Endocrinology on the comprehensive type 2 diabetes management algorithm
5. Ghefreh A. Metformin and vitamin B12 deficiency. http://www.diabetes.org.
– 2018 executive summary. Endocr Pract. 2018; 24(1):91-120.
23. Vitamin B12 Blood Test. RequestATest website. https://requestatest.com/
March 27, 2019.
vitamin-b12-testing. Accessed March 21, 2019.
6. Kancherla V, Garn JV, Zakai NA, et al. Multivitamin use and serum vitamin
24. Vitamin B12 1000 mcg. Amazon.com website. https://www.amazon.com/s/
B12 concentrations in older-adult metformin users in REGARDS, 2003-2007.
PLoS One. 2016;11(8):e0160802.
7. Ko SH, Ko SH, Ahn YB, et al. Association of vitamin B12 deficiency and met-
Accessed March 21, 2019.
formin use in patients with type 2 diabetes. J Korean Med Sci. 2014;29(7):965-972.
25. Cyanocobalamin. GoodRx website. https://www.goodrx.com/cyanoco-
8. Kibirige D, Mwebaze R. Vitamin B12 deficiency among patients with dia-
balamin. Accessed March 21, 2019.
betes mellitus: is routine screening and supplementation justified? J Diabetes
26. DrugPriceInfo.com website. http://www.drugpriceinfo.com. Accessed
Metab Disord. 2013;12(1):17.
March 27, 2019.
9. Kos E, Liszek MJ, Emanuele MA, Durazo-Arvizu R, Camacho P. Effect of
27. Gordois A, Scuffham P, Shearer A, Oglesby A,Tobian JA.The health care costs of
metformin therapy on vitamin D and vitamin B12 levels in patients with type
diabetic peripheral neuropathy in the U.S. Diabetes Care. 2003;26(6):1790-1795.
2 diabetes mellitus. Endocr Pract. 2012;18(2):179-184.
28. Koski RR, Rider-Becker JM. Managing the cost of chronic diabetic periph-
10. Mazokopakis EE, Starakis, IK. Recommendations for diagnosis and manage-
eral neuropathy in the elderly. US Pharm. 2009;34(1):30-38.
ment of metformin-induced vitamin B12 (Cbl) deficiency. Diabetes Res Clin
29. Holt C. Should people treated with metformin be screened for vitamin
B12 deficiency? Diabetes & Primary Care. 2012;14(4):204-212.
11. Niafar M1, Hai F, Porhomayon J, Nader ND.The role of metformin on vitamin B12 deficiency: a meta-analysis review. Intern Emerg Med. 2015;10(1):93-102. 12. Osama H, Hussein HAE, Abdelrahim MEA, Salem HF. Screening the effect of metformin on serum vitamin B12 and blood homocysteine levels in patients with type 2 diabetes mellitus. Med-Science. 2016;5(1):46-56. 13. Quereshi SA, Ainsworth A, Winocour PH. Metformin therapy and assessment for vitamin B12 deficiency: is it necessary? Pract Diabetes. 2011;28(7):302-304 14. Reinstatler L, Qi YP, Williamson RS, Garn JV, Oakley GP Jr. Association of biochemical B12 deficiency with metformin therapy and vitamin B12 supplements: the National Health and Nutrition Examination Survey, 1999-2006. Diabetes Care. 2012;35(2):327-333. 15. Sato Y, Ouchi K, Funase Y, Yamauchi K, Aizawa T. Relationship between metformin use, vitamin B12 deficiency, hyperhomocysteinemia and vascular complications in patients with type 2 diabetes. Endocr J. 2013;60(12):1275-1280. clinical neuropathy with metformin use in type 2 diabetes patients. J Postgrad Med. 2013;59(4):253-257. 17. Xu L, Huang Z, He X, Wan X, Fang D, Li Y. Adverse effect of metformin therapy on serum vitamin B12 and folate: short-term treatment causes disadvantages? Med Hypotheses. 2013;81(2):149-151. 18. Raizada N, Jyotsna VP, Sreenivas V, Tandon N. Serum vitamin B12 in type 2 diabetic patients on metformin compared to those never on metformin: a cross-sectional study. Indian J Endocrinol Metab. 2017;21(3):424-428. 19. Caspary WF, Zavada I, Reimold W, Deuticke E, Emrich D, Willms B. Alteration of bile acid metabolism and vitamin-B12-absorption in diabetics on biguanides. Diabetologia. 1977;13(3):187-193. 20. Audhya T. Role of B vitamin in biological methylation. Health Diagnostics and Research Institute. 2012;1-19. 21. Jeetendra S, Tushar B. Metformin use and vitamin B12 deficiency in patients with type-2 diabetes mellitus. MVP J Med Sci. 2016;3(1):67-70.
20 THE CLINICAL ADVISOR • MAY 2019 • www.ClinicalAdvisor.com
© The New Yorker Collection 2019 from cartoonbank.com. All Rights Reserved.
16. Singh A, Kumar A, Karmakar D, Jha R. Association of B12 deficiency and
FEATURE: SHAWNA JOHNSON, DNP, AGACNP, APRN-BC
Implementation of a Screening Questionnaire for OSA in the EMR The ESS is a validated questionnaire that can ensure easy and accurate assessment of daytime sleepiness.
© LDF / GETTY IMAGES
Daytime sleepiness leads to an increased risk for MVAs.
22 THE CLINICAL ADVISOR • MAY 2019 • www.ClinicalAdvisor.com
bstructive sleep apnea (OSA) is the most common sleep disorder affecting Americans; approximately 80% of patients who report poor sleep have undiagnosed OSA.1 Sleep apnea is consistently described as the collapse of the upper airway during sleep, which causes hypoxemia. When hypoxemia ensues, the individual awakens and sleep is fragmented.2-4 This cycle continues through the night and causes numerous problems such as daytime sleepiness from poor sleep quality, depression, motor vehicle accidents, workplace errors, and chronic conditions such as cardiovascular disease.1,3,5,6 Because of the harmful effects of untreated OSA, it is imperative that patients be diagnosed and effectively treated to prevent adverse outcomes. Patients with untreated OSA are at a 3-fold increased risk for motor vehicle accidents when driving compared with the general population.5 According to Knauert et al, if patients with OSA were diagnosed and treated with at least a 70% adherence rate, approximately 500,000 collisions could be prevented.2 This would result in approximately 1000 lives saved with a cost savings of approximately $11.1 billion. In a study by Sassani et al, more than 800,000 drivers were involved in accidents related to undiagnosed or untreated OSA in 2000.7 These collisions cost $15.9 billion, and 1400 lives were lost.7 Untreated OSA costs as much as $3.4 billion in additional medical costs each year.8 The number
not report symptoms suspicious of OSA.
of physician visits, medication use, and unemployment rates were significantly higher in patients with undiagnosed OSA vs patients without OSA or those successfully treated for it.8 Thus, OSA is a major public health problem for which treatment could benefit both the patient and the community. Patients with untreated OSA have been shown to have numerous cognitive disturbances, which can lead to poor work performance and quality of life.1 This is particularly important in safety-sensitive jobs, such as healthcare providers, public transportation drivers, and over-the-road truckers.9 In a study by Soylu et al, the number of incidents involving nurses — including medication errors, selection of incorrect surgical instruments, and needlestick injuries — was significantly increased among those with daytime sleepiness.10 Daytime sleepiness is one of the most important indicators of OSA.4 Sleep apnea also has an effect on chronic diseases. According to Maeder et al, OSA can cause sympathetic activation, oxidative stress, and systemic inflammation.3 These effects can have detrimental consequences on the cardiovascular system, including hypertension, diabetes, coronary artery disease, cardiac arrhythmias (including atrial fibrillation and sudden cardiac death), and heart failure. Other studies have found links between OSA and stroke, depression, and all-cause mortality.6,11,12 Although many studies have demonstrated the value of diagnosing and treating patients with OSA, there is a paucity of studies that address screening for OSA in all patients. Identification of individuals with symptoms of OSA can be easily captured with a screening questionnaire. This is frequently done with the Epworth Sleepiness Scale (ESS), which has been validated as a clinical indicator for excessive daytime sleepiness and can be used to determine whether referral for a sleep study is indicated.13 It is important to determine an ESS score for all patients, as OSA may be clinically unsuspected and left undiagnosed for some time, largely because symptoms of snoring and daytime sleepiness are often considered normal and frequent complaints of individuals in society today.14 The high prevalence of OSA has focused attention on finding simpler approaches to diagnosis, with an increasing trend toward diagnosis and therapy in the ambulatory setting. Quality Improvement Project
The purpose of this undertaking was to evaluate the use of the ESS before and after the tool was added to an EMR to screen all patients in an internal medicine office for daytime sleepiness. Questions explored were: What is the baseline rate of screening using the ESS, and how does it compare with rates after adding the ESS to the EMR? Will use of the ESS to screen all patients, not only those with reported
symptoms, increase the number of patients who are referred for polysomnography? Methods
This project was retrospective in design with 2 phases of review. The first phase comprised data collection 6 weeks before the addition of the ESS in the EMR (time 1) and 6 weeks after the ESS was added to the EMR (time 2). The second phase of the study included staff education on the use and interpretation of the ESS, followed by data collection 6 weeks after implementation of the ESS for all patients in the internal medicine office (time 3). Records were reviewed in a random and systematic fashion to obtain the sample most representative of patients seen on a daily basis. Participants’ approval was obtained from a university institutional review board, and the study was determined to pose minimal risk to participants. Population and Setting
Men and women between the ages of 18 and 92 years were included, and 50 participants were identified from each 6-week period, totaling 150 patients. A list of patients was obtained from the EMR, and every fifth patient was chosen until 50 participants from each time frame were selected. The project was conducted in an internal medicine office setting with 2 medical providers and an average patient load each of 10 to 20 patients per day. Office staff were responsible for preparing the patient for the office visit and examination. Staff were educated on the ESS and how to quickly and accurately complete the assessment with each patient. Instrument
The ESS is a commonly used tool to determine daytime sleepiness and is useful in alerting providers of a potential sleep disorder such as OSA.6,13 The ESS consists of 8 standard questions that can be quickly administered. Each question is framed to elicit the likelihood of dozing during different common daily activities such as watching television, sitting inactive in a public place, or being a passenger in a car. A score of 0 is given when the patient reports that they would never doze during an activity, 1 for a slight chance of dozing, 2 for a moderate chance, and 3 for a high chance.15 The ESS score is the sum of all answers and can range from 0 to 24. Scores less than 10 indicate a normal level of daytime sleepiness. A score of 10 or above is considered abnormal, and the patient should be referred for further testing.13 According to Johns, the ESS has a reliability of 0.81; extremely high sensitivity and specificity scores of 93.5% and 100%, respectively; and major advantages over other tests of daytime sleepiness.16
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 23
OBSTRUCTIVE SLEEP APNEA SCREENING
Patients with untreated OSA have been shown to have numerous cognitive disturbances, which can lead to poor work performance and quality of life. Demographic data including age, sex, height, weight, body mass index (BMI), race, and insurance were collected. The ESS numeric score was recorded and documentation was made if the patient was referred for polysomnography. Procedure
Phase I. Medical records of patients seen in the 6 weeks before adding the ESS to the EMR in 2016 were obtained. These charts were reviewed and marked as either having an ESS score calculated during the visit or an ESS score not obtained. Documentation was made for those patients for whom an ESS score was included in the medical record, for those who had a score of 10 or more, and for those who were referred for polysomnography. A second set of data was collected in the same way from the medical records of patients 6 weeks after the ESS was added to the EMR in 2016. Phase II. Staff were educated on the ESS tool and how to properly obtain and document the ESS in the EMR, and they were instructed to notify the provider if the ESS score was 10 or greater. Handouts were provided to all staff who may be assessing patients with the ESS, and contact information was provided for questions. One week of learning was provided for the staff to adjust to performing an ESS on each patient. A second meeting was held with staff for questions and comments. The ESS was then used during every patient encounter in the office. Weekly check-ins with staff using and documenting the ESS were conducted during the implementation phase. Each week during this phase, 10 medical records were randomly selected to ascertain whether the ESS was being documented correctly. When inconsistencies were noted, staff retraining and coaching was provided. Six weeks after implementation of ESS screening of all patients in the medical office, a third set of 50 medical records was identified. Every fifth medical record for patients seen in the prior 6-week period was reviewed, until a total of 50 patients were identified. Data Analysis
Demographic characteristics and clinical variables were analyzed using descriptive statistics. Means, standard deviations, and ranges were calculated for continuous variables at all 3 periods, including age, sex, race, insurance, and BMI. Sleep characteristics were analyzed using mean and standard deviations for ESS scores. After collection of the ESS scores, data were converted to either normal (ESS <10) or abnormal
(ESS ≥10), and documentation was made if the patient was referred for polysomnography. Results
Demographic characteristics of participants are displayed in Table 1. Patients at time 1 were slightly older than patients at the other 2 periods.There were nearly equal percentages of male and female patients sampled over the course of all 3 periods, with the exception being that time 3 has slightly more female patients. The sample consisted of predominantly white individuals, with Hispanics or Latinos and African Americans making up the remainder of patients sampled. The majority of patients in time 1 and time 2 had private TABLE 1. Study Demographic and Clinical Characteristics Time 2 (n=50)
Time 3 (n=50)
Age, mean/SD (range) 71±13 (19-88)
Sex, (n/%) Male Female
25 (50%) 25 (50%)
25 (50%) 25 (50%)
17 (34%) 33 (66%)
Race, (n/%) White 49 (98%) African American 0 (0%) Hispanic or Latino 1 (2%)
44 (88%) 2 (4%) 4 (8%)
48 (96%) 0 (0%) 2 (4%)
Insurance, (n/%) Private Medicare Fee-based care
26 (52%) 24 (48%) 0 (0%)
0 (0%) 0 (0%) 50 (100%)
Time 1 (n=50)
16 (32%) 34 (68%) 0 (0%)
29 ± 6 (17-42); 30 ± 6 (18-46); 28 ± 3 (26-32); n=49 n=46 n=4
TABLE 2. Study Sleep Characteristics Characteristic
Time 1 (n=50)
Time 2 (n=50)
Time 3 (n=50)
ESS score: mean/SD
ESS score ≥ 10 (n)
24 THE CLINICAL ADVISOR • MAY 2019 • www.ClinicalAdvisor.com
Approximately 80% of individuals who report poor sleep have undiagnosed and untreated OSA, indicating an imminent need for routine screening. insurance and/or Medicare; however, in time 3, 100% of patients were enrolled in a fee-based care model. Mean BMI was similar across the 3 periods. Data on sleep characteristics revealed no ESS scores documented in the EMR at times 1 and 2, despite the availability of the ESS in the EMR at time 2 (Table 2). At time 3, with screening of all patients, 10 patients had an ESS of 10 or more and were referred for polysomnography. Discussion
The key findings from this quality improvement project illustrate that daytime sleepiness, use of the ESS as a common screening tool, and referrals for polysomnography are missed opportunities to identify patients with a potential diagnosis of a highly treatable condition such as OSA. Approximately 80% of individuals who report poor sleep have undiagnosed and untreated OSA, indicating an imminent need for routine screening.17 At this time, there is limited discussion in the literature about screening every patient for OSA, regardless of risk factors.Although numerous sources cite the usefulness of the ESS as a screening tool in individuals who are suspected of having OSA, there is limited research on screening asymptomatic adults. Garbarino et al reported that screening dangerous-goods truck drivers for OSA revealed an unexpected high prevalence of sleep apnea in this population.18 The study analyzed 283 truck drivers who did not have symptoms of OSA. After screening was implemented, almost half of asymptomatic individuals were flagged as high risk. These high-risk individuals underwent polysomnography, and 35.7% of the group was confirmed with a diagnosis of OSA.18 These individuals were required to begin continuous positive airway pressure therapy, and after 2 years, the rates of motor vehicle accidents and near-miss accidents were significantly reduced.18 The US Preventive Services Task Force has issued a call for further research on screening asymptomatic adults for OSA through the use of screening questionnaires such as the ESS. At this time, the task force states that there is a critical gap in information and insufficient data to recommend routine screening. The task force also reports that only 20% of patients with sleep-related symptoms spontaneously reported their symptoms to their primary care provider; this leaves 80% of individuals who have sleep-related symptoms neither reported to their provider nor adequately assessed for OSA. Routine screening for OSA could potentially capture this remaining 80% and provide the necessary testing and treatment that
is so desperately needed. Nurse practitioners and physician assistants can play a key role in integrating screening for OSA in practice.19 The ESS is a simple, quick, and easily administered screening tool that can be used in primary care, specialty practice, and hospital settings. During this quality improvement project, office staff asked each patient the screening questions while obtaining the patient’s vital signs, which required little or no extra time with the patient. Taking a few moments to ask each patient 8 simple questions has the potential to decrease risk and safety issues related to OSA, as well as to improve patient outcomes and quality of life. Limitations
Limitations of this study included the relatively small sample size of 150 patients and limitation of the study to a single internal medicine practice. Between time 1 and time 2, the practice underwent changes in office structure, which involved moving to a direct primary care practice that included a fee for service. Because of the changes in the practice, a new EMR was implemented, and therefore BMI data were unable to be collected at time 3 for all patients. Implications for Practice
The implications of this project are noteworthy.The findings indicate that a simple intervention involving adding the ESS to the EMR can identify patients with OSA who would have otherwise been undiagnosed; this could lead to better patient outcomes by diagnosing and treating patients with OSA before adverse effects occur. After patients are flagged as high risk by the ESS tool, the clinician can then refer the patient for a sleep study, on the basis of which continuous positive airway pressure therapy may be initiated. According to the project findings, the potential exists for an entirely different group of patients to be identified at risk for OSA.This project could be expanded to other offices, as well as to the hospital setting. Recommendations for future research are to not simply add the ESS to the EMR, but to create a hard stop that requires providers to screen every patient. By implementing the ESS in the EMR with a hard-stop feature, there is a built-in system for sustainability of routine screening. In time 2, the ESS was available to the provider in the EMR; however, no ESS data were obtained or documented. Therefore, it is recommended that the ESS be used on every patient seen in the office, whether reporting symptoms of sleep-related disorders or asymptomatic.
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OBSTRUCTIVE SLEEP APNEA SCREENING
The ESS is a simple, quick, and easily administered screening tool that can be used in primary care, specialty practice, and hospital settings. Conclusion
11. Maurer RE, Im K. Obstructive sleep apnea and depression: issues
OSA is a significant health issue that often goes undiagnosed. This project evaluated the use of screening all patients in an internal medicine office, finding that screening resulted in a 20% increase in detection of patients at high risk for OSA, as indicated by an ESS score of 10 or more. This finding is significant in that more widespread screening can result in earlier diagnosis and referral for a sleep study and potentially the addition of continuous positive airway pressure therapy. This is important, as undiagnosed OSA is associated with comorbidities such as cardiovascular disease, stroke, diabetes, and depression.3,6,11,12 Clinicians are encouraged to adopt ESS screening in their practice, and to perform screening on every patient, even those who do not report symptoms suspicious of OSA. ■
for psychiatrists. Psychiatric Times. 2016;33(8):1-5. 12. Wells ME, Vaughn BV. Poor sleep challenging the health of a nation. Neurodiagn J. 2012;52(3):233-249. 13. Pahwa P, Karunanayake CP, Hagel L, et al. Prevalence of high Epworth Sleepiness Scale scores in a rural population. Can Respir J. 2012;19(2):e10-e14. 14. McNicholas WT, Luo Y, Zhong N. Sleep apnoea: a major and underrecognised public health concern. J Thorac Dis. 2015;7(8):1269-1272. 15. Johns MW. A new method for measuring daytime sleepiness: The Epworth Sleepiness Scale. Sleep. 1991;14(6):540-545. 16 Johns MW. Sensitivity and specificity of the multiple sleep latency test (MSLT), the maintenance of wakefulness test and the Epworth Sleepiness Scale: Failure of the MSLT as a gold standard. J Sleep Res. 2000;9(1):5-11. 17. Foldvary-Schaefer N. 5 surprising facts about sleep apnea. https://
Shawna Johnson, DNP,AGACNP,APRN-BC, is a nurse practitioner at Wichita Surgical Specialists, in Wichita, Kansas.
health.clevelandclinic.org/5-surprising-facts-about-sleep-apnea/. Published October 19, 2015. Accessed March 25, 2019. 18. Garbarino S, Guglielmi O, Campus C, et al. Screening, diagnosis, and
management of obstructive sleep apnea in dangerous-goods truck
1. Colten HR, Altevogt BM. Sleep disorders and sleep deprivation:
drivers: to be aware or not? Sleep Med. 2016;25:98-104.
an unmet public health problem. Washington, DC: National Academy
19. Grossman DC, Curry SJ, Davidson KW, et al; US Preventive Services
Task Force. Screening for obstructive sleep apnea in adults:
2. Knauert M, Naik S, Gillespie MB, Kryger M. Clinical consequences and
US Preventive Services Task Force Recommendation Statement. JAMA.
economic costs of untreated obstructive sleep apnea syndrome. World
J Otorhinolaryngol Head Neck Surg. 2015;1(1):17-27. 3. Maeder MT, Schoch OD, Rickli H. A clinical approach to obstructive sleep apnea as a risk factor for cardiovascular disease. Vasc Health Risk Manag. 2016;12:85-103. 4. Tamanna S, Ullah MI. Sleep apnea and cardiovascular disease. Cardiovasc J. 2016;8(2):143-148. 5. Basoglu OK, Tasbakan MS. Elevated risk of sleepiness-related motor vehicle accidents in patients with obstructive sleep apnea syndrome: a case-control study. Traffic Inj Prev. 2014;15(5):470-476. 6. Franklin KA, Lindberg E. Obstructive sleep apnea is a common disorder in the population-a review on the epidemiology of sleep apnea. J Thorac
Case Study Library
Dis. 2015;7(8):1311-1322. 7. Sassani A, Findley LJ, Kryger M, Goldlust E, George C, Davidson TM. Reducing motor-vehicle collisions, costs, and fatalities by treating obstructive sleep apnea syndrome. Sleep. 2004;27(3):453-458. 8. Leger D, Bayon V, Laaban JP, Philip P. Impact of sleep apnea on economics. Sleep Med Rev. 2012;16(5):455-462. 9. Perlman S. Sleep apnea and workplace safety. BCMJ. 2014;56(2):94-96. 10. Soylu O, Erboy F, Ornek T, et al. Prevalence of snoring and obstructive sleep apnea syndrome among nurses and resident doctors working in a university hospital. Eurasian J Pulmonol. 2014;16(2):105-109.
26 THE CLINICAL ADVISOR • MAY 2019 • www.ClinicalAdvisor.com
Check out all of our case studies in obesity, diabetes, and other important topics in primary care — along with our clinical challenges — by visiting us at: ClinicalAdvisor.com/Case-Study
FEATURE: YEOW CHYE NG, PHD, CRNP, CPC, AAHIVE; LOUISE C. O’KEEFE, PHD, CRNP
The Art of Administering a Tuberculin Skin Test: Wheal Does Matter When administered correctly, the Mantoux test can be an invaluable tool for the detection of tuberculosis.
© ISM / PR MICHEL BRAUNER / MEDICALIMAGES.COM; GABRIELLE BENENSON / CDC
Screening for tuberculosis is a primary prevention tool.
28 THE CLINICAL ADVISOR • MAY 2019 • www.ClinicalAdvisor.com
uberculosis is an airborne disease with serious medical consequences. It is caused by the bacterium Mycobacterium tuberculosis, which belongs to a group of closely related organisms in the M tuberculosis complex. Once an individual is infected with it, the disease develops primarily in the lungs. Only the active form of tuberculosis is contagious, with signs and symptoms that include fatigue, fever, night sweats, chills, loss of appetite, unintentional weight loss, hemoptysis, shortness of breath, and cough that may last ≥3 weeks.1 Approximately 13 million Americans have a latent tuberculosis infection, which usually results when immunocompetent individuals are exposed to M tuberculosis.2 These individuals are not contagious, nor do they exhibit symptoms. However, latent tuberculosis may progress into an active case.Thus, screening for tuberculosis is a primary prevention tool that should be performed regularly. During 2013 through 2015, for the first time in 23 years, the incidence of tuberculosis cases leveled off after decreasing each year.3 The same data showed that the majority of individuals infected with tuberculosis were clustered in California, Florida, NewYork, and Texas. In light of the persistence of this curable pathogen, healthcare providers should advocate for increasing awareness and encouraging screening for tuberculosis infection in appropriate settings. Presently, the vast majority of clinics use the Mantoux test to screen for cases of tuberculosis.
right-hand column like this one does at the top
Case Presentation The following scenario emphasizes the necessity of creating a wheal while administering the Mantoux test. A 46-year-old Asian man who recently immigrated to the United States was seen for routine employment screening for tuberculosis. The nurse initiated a Mantoux test on the right forearm (Figure 1). However, the test had to be repeated on the left forearm because no wheal was noted at the initial site. A small wheal was noted during the second test (Figure 2). The patient was advised to return to the clinic within 48 to 72 hours to have the results evaluated, and he returned for a TST reading 3 days later. The right forearm showed no sign of induration (Figure 3), while the left showed >10 mm of induration (Figure 4). The patient was referred for a chest radiograph that was obtained
Figure 1. Following improper PPD administration at the right antecubital fossa. The circled area shows the injection site.
Figure 2. Following proper PPD administration demonstrating wheal at the left antecubital fossa.
Proper injection technique is essential when testing for tuberculosis. The Mantoux test is administered in the intradermal layer of the volar aspect of the forearm approximately 4 inches below the antecubital area. The bevel edge of the needle should be facing up and then inserted to inject 0.1 mL of tuberculin purified protein derivative (PPD). Proper injection technique should produce a small elevation (wheal) at the injection site. A reaction occurs when both induration and erythema are present 48 to 72 hours after administration.The diameter of the induration is measured in millimeters at the widest part. Erythema without induration is not considered significant.4 A significant reaction indicates that a patient has been exposed to M tuberculosis recently or in the past, or has been vaccinated with bacilli-containing Calmette-Guerin vaccine, which is effective in up to 80% of those who receive it.5 The vaccine is routinely used in Europe and Latin America but not in the United States. A positive tuberculin skin test
during the same visit, the results of which were normal. All clinicians should review evidence-based literature especially when it is pertinent to a procedure that is done frequently. Screening individuals at risk for tuberculosis infection identifies groups that should be tested using the Mantoux TST or interferon-gamma release assays, such as QuantiFERONtuberculosis Gold In-Tube Test and T-SPOT®.4 In most cases, a positive Mantoux test signifies infection with M tuberculosis; however, it does not signify whether the disease is active or where it is located. Pulmonary tuberculosis is usually diagnosed by sputum cultures.To diagnose extrapulmonary tuberculosis, assessment of other specimens, such as cerebrospinal fluid, urine, or pleural fluid, is usually required.
Figure 3. Day 3 following improper PPD administration.
Figure 4. Day 3 following proper PPD administration.
(TST) does not mean active disease is present. Likewise, a negative TST does not exclude tuberculosis infection completely. In addition, an adequate immune response to produce a positive TST will not occur in a person who is immunocompromised. Reading of the TST should be conducted within 48 to 72 hours. The provider should palpate for induration to ensure that only induration and not injection is being measured. An induration measuring ≥15 mm in greatest diameter indicates a positive test in individuals with no known risk factors for tuberculosis, an induration ≥10 mm indicates a positive test in recent arrivals from high-risk countries, and an induration ≥5 mm represents a positive test in an individual with HIV or immunosuppression, or someone who recently has been exposed to active tuberculosis.6 For many years, the Centers for Disease Control and Prevention (CDC) has emphasized the importance of implementing proper techniques for administration of the Mantoux test. More specifically, healthcare providers are advised to repeat
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 29
ADMINISTERING A TUBERCULIN SKIN TEST
Assessment of specimens such as cerebrospinal fluid, urine, or pleural fluid is usually required to diagnose extrapulmonary tuberculosis. the Mantoux test on the opposite arm if the initial PPD does not yield a wheal at the injected site.7 Common misconceptions exist among clinicians concerning the significance of creating a wheal when administering a TST. As an example, a newly graduated nurse posted in an online nursing forum seeking validation from other forum members concerning her experience administrating a TST on a patient without a resultant wheal (Table).
spread, the mechanism of infection, diagnosis, and treatment. Tuberculosis education and training programs are available at the CDC website, as well as via other online resources. ■ Yeow Chye Ng, PhD, CRNP, CPC,AAHIVE, is assistant professor at the College of Nursing at the University of Alabama in Huntsville. Louise C. O’Keefe, PhD, CRNP, is director of the faculty/staff clinic and assistant professor at the College of Nursing at the University of Alabama in Huntsville.
When administered correctly, the Mantoux test can be an invaluable tool, leading to early detection, treatment, and containment of tuberculosis. Placement and interpretation of the TST should be performed by qualified health practitioners. An incorrectly placed or interpreted TST can contribute to a delay in identifying an index case, which could lead to an outbreak of tuberculosis either in the local community or on a greater scale. Educational programs for healthcare providers should include a basic course on TSTs that includes didactic content on the disease and epidemiology concepts. The content should include disease transmission, pathogenesis, and classification as well as global statistics and both national and local rates in the United States, especially in urban areas. The CDC and local departments of health offer resources that can be included in the course. Practical and clinical experience can be given using simulation with a reactor model arm. It is the responsibility of the healthcare provider to screen individuals correctly and recognize anyone at high risk, particularly those who work or live in high-risk areas such as prisons, hospitals, schools, and certain neighborhoods. Healthcare providers should stay up to date on how tuberculosis is
References 1. Centers for Disease Control and Prevention. TB elimination: the difference between latent TB infection and TB disease. https://www.cdc.gov/ tb/publications/factsheets/general/LTBIandActiveTB.pdf. November 2011. Accessed March 26, 2019. 2. Centers for Disease Control and Prevention. Latent tuberculosis infection: a guide for primary health care providers. https://www.cdc.gov/ tb/publications/ltbi/default.htm. Updated May 12, 2013. Accessed March 26, 2019. 3. Salinas JL, Mindra G, Haddad MB, Pratt R, Price SF, Langer AJ. Leveling of tuberculosis incidence — United States, 2013-2015. MMWR Morb Mortal Wkly Rep. 2016;65(11):273-278. 4. Centers for Disease Control and Prevention. Resources for TB programs. https://www.cdc.gov/tb/education/professional-resources.htm. Updated May 4, 2016. Accessed March 26, 2019. 5. Centers for Disease Control and Prevention. The role of BCG vaccine in the prevention and control of tuberculosis in the United States. April 26, 1996. https://www.cdc.gov/mmwr/PDF/rr/rr4504.pdf. Accessed April 2, 2019. 6. Nayak S, Acharjya B. Mantoux test and its interpretation. Indian Dermatol Online J. 2012;3(1):2-6. 7. Centers for Disease Control and Prevention. Mantoux tuberculin skin test: facilitator guide. https://www.cdc.gov/tb/education/mantoux/pdf/ mantoux.pdf. Published November 2013. Accessed March 26, 2019.
TABLE. Responses Given by Forum Members
8. Chin up. “I administered a TB skin test and it did not bubble up...”. Message posted to AllNurses web forum. June 5, 2011. https://allnurses.
“It happens sometimes. It will be fine.”8
com/i-administered-tb-skin-test-t387048/. 9. klone, MSN, RN. “I administered a TB skin test and it did not bubble up...”.
“If they have tuberculosis, it will still react. I wouldn’t worry too much. You probably just went a bit too deep.”9 “We were taught in school that results won’t be valid without a wheal. I guess what they say is true about things being different in the ‘real world’ of nursing!”10 “…Ideally you get a wheal, but if someone has tuberculosis they will react.”11
Message posted to AllNurses web forum. June 5, 2011. https://allnurses. com/i-administered-tb-skin-test-t387048/. 10. akita_mommy. “I administered a TB skin test and it did not bubble up...”. Message posted to AllNurses web forum. June 5, 2011. https://allnurses. com/i-administered-tb-skin-test-t387048/. 11. nola1202. “I administered a TB skin test and it did not bubble up...”. Message posted to AllNurses web forum. June 5, 2011. https://allnurses. com/i-administered-tb-skin-test-t387048/.
30 THE CLINICAL ADVISOR • MAY 2019 • www.ClinicalAdvisor.com
Case Study | MEN’S HEALTH HISTORY The patient had no history of breast abnormalities. He denied past injury to the breast, recent illness, hormone replacement therapy, or supplement use. He denied family history of breast or ovarian cancer. He had not noticed any nipple discharge. Medical history included hypertension and hyperlipidemia. Surgical history was significant for repair of the right meniscus 3 months ago. Medications included quinapril 10 mg/d, hydrochlorothiazide 25 mg/d, and rosuvastatin 40 mg/d. His last visit to the clinic was approximately 1 year earlier.
Gynecomastia in an Elderly Man
© HERCULES ROBINSON / MEDICAL IMAGES.COM
Gynecomastia is the most common male breast disease, occurring in up to 57% of men. CATHERINE CARRICO, DNP, APRN-NP; ELISE C. PILGER, DNP, APRN, AGNP-C
The patient’s height was 5 ft 10 in and his weight was 223 lb (body mass index, 32 kg/m2). Vital signs included a heart rate of 80 beats per minute, blood pressure of 138/70 mm Hg, respirations at 16 breaths per minute, and a temperature of 98.4°F. Upon examination, the left nipple was inverted, with redness noted at the 6 o’clock position. A firm, immobile, and painful 1×1-cm mass was palpated at the 5 o’clock position. Examination of the remainder of the left breast and the right breast was unremarkable. No axillary lymphadenopathy was noted. A left breast ultrasound was ordered and the patient was immediately sent to the radiology center. Ultrasound of the left breast revealed a 1×0.8×1-cm retroareolar/areolar complex.The area was hypoechoic with posterior shadowing and had irregular margins and increased vascular flow. These findings were noted to be suspicious for an aggressive process, and a biopsy was recommended.
A 77-year-old man presented to a primary care clinic with a complaint of pain and tenderness in his left nipple for 6 to 8 months. He had noticed recently that the areola was swollen, and his wife told him that she felt a hard area on his breast.
On the basis of the findings on ultrasound, the patient underwent a core biopsy, which revealed chronic inflammation. The mass was excised 1 week later, at which point a diagnosis of nodular gynecomastia of the breast was made.
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Case Study DISCUSSION This case demonstrates the lack of knowledge in regard to breast health that men can have. This patient had a known breast problem for up to 8 months before reporting to the clinic. Gynecomastia is the proliferation of mammary glands caused by an androgen/estrogen imbalance, resulting in dense tissue.1,2 It is the most common male breast disease, occurring in up to 57% of men.1 It is often seen in newborns, teenagers, and men aged >50 years.3 Causes include gonadal failure, testicular cancer, hyperthyroidism, renal disease, liver disease, certain tumors, and other diseases that result in androgen resistance.2 In some instances, gynecomastia can be idiopathic.2 A thorough history should be taken from the patient, including recent medications and supplements.1 Agents associated with gynecomastia include spironolactone, digoxin, cimetidine, marijuana, heroin, and amphetamines, as well as alcohol.2 In this case, the patient had no history of gynecomastia-inducing diseases or medications. Gynecomastia occurs in 3 stages: nodular, dendritic, and diffuse.4 It often presents as a subareolar mass that is palpable, firm, and mobile.3 Although characteristics of the disease are often found in both breasts, it can occur unilaterally.3 In this case, the mass was immobile, fixed, and hard.
DIAGNOSTIC IMAGING The need for diagnostic imaging is determined based on physical examination findings. If a hard, immobile mass is noted, imaging is recommended to rule out malignancy.3 Imaging studies can be performed via mammogram or ultrasound, with ultrasound the preferred recommendation for gynecomastia.1,3 Similar to this case, ultrasound of nodular gynecomastia often reveals a hypoechoic subareolar mass that may exhibit increased vascular flow.4 If imaging studies are suspicious for malignancy, fine-needle aspiration or biopsy is required.1
LABORATORY TESTING Multiple laboratory tests are recommended to determine the underlying cause of gynecomastia. Laboratory testing should be chosen according to the suspected underlying cause.3 Because of the suspicious presentation of the breast mass in this case, the patient was immediately sent for diagnostic imaging, and laboratory assessment was not conducted. If the condition is causing pain and/or distress, pharmacologic, radiologic, and surgical options are available.2 It is
important to remember that psychological distress is often reported and needs to be addressed in the management plan.3
TREATMENT Treatment for gynecomastia varies. Eliminating the cause is often the only intervention needed.1,3 For cases in which the symptoms are not causing distress or pain, the patient should be reassessed every 6 months.3 Medication therapy for gynecomastia works best if initiated <12 months after onset of symptoms.1 Gynecomastia that has been symptomatic for >12 months can result in permanent fibrous breast tissue.1 At this time, no pharmacologic treatments for gynecomastia are approved by the US Food and Drug Administration. Tamoxifen, anastrozole, and danazol have been used off-label to treat this condition.1 Radiation and surgical removal have also been used to treat gynecomastia.1 In this case, surgical removal was performed secondary to patient discomfort and psychological stress.
CONCLUSION In retrospect, this patient’s outcome could have been different. The patient’s lack of awareness regarding breast health caused him to wait before seeking medical treatment for his condition. If the patient had reported to the clinic earlier, he may have avoided the need for surgical intervention. Laboratory testing to determine the underlying cause of the patient’s gynecomastia should have been performed, as well. This case demonstrates the importance of increasing awareness of breast disease in men. Recognition by the clinician of the potential for breast disease in men, as well as patient education and instruction on performing routine self breast examinations may have prompted earlier reporting. ■ Catherine A. Carrico, DNP, APRN-NP, FNP, is an assistant professor at Creighton University College of Nursing and a family nurse practitioner at Children’s Hospital and Medical Center in Omaha, Nebraska. Elise C. Pilger, DNP, APRN, AGNP-C, is a nurse practitioner at Barnes Healthcare Management Group in Columbia, Missouri. References 1. Ladizinski B, et al. Gynecomastia: etologies, clinical presentations, diagnosis, and management. South Med J. 2014;107(1):44-49. 2. Johnson R, et al. Gynecomastia - evaluation and current treatment options. Ther Clin Risk Manag. 2011;7:145-148. 3. Dickson G. Gynecomastia. Am Fam Physician. 2012;85(7):716-722. 4. Chau A, et al. Male breast: clinical and imaging evaluation of benign and malignant entities with histologic correlation. Am J Med. 2016;129(8):776-791.
32 THE CLINICAL ADVISOR • MAY 2019 • www.ClinicalAdvisor.com
Dermatology Clinic CASE #1
Inflamed and Hyperpigmented Plaque in the Axilla ARIELLA NOORILY, BA; CHRISTOPHER RIZK, MD
A 28-year-old man presents with a complaint of lesions in his left axillary region. He has no history of skin conditions, but he notes that his father used to get similar rashes on his neck. The lesions are itchy and slightly painful and worsen when he sweats during exercise. He states that treatment with topical hydrocortisone cream resulted in minor improvement. On examination, an inflamed and hyperpigmented plaque with superimposed vesicular lesions, some of which are crusted over or weeping, is noted. What is your diagnosis? Turn to page 34
Painful, Pruritic Rash on the Face ASHLEY KWAN, PA-S
A 56-year-old woman presents to the clinic concerned about an itchy rash on her face of 2 months’ duration. She reports pruritus and pain, which is worse after exposure to sunlight and especially at night. She states that topical hydrocortisone 1% cream provided no relief. Physical examination reveals erythematous, smooth papules coalescing into edematous plaques on the forehead, nasal bridge, left mid-cheek, nasolabial folds, and chin. What is your diagnosis? Turn to page 35 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 33
Dermatology Clinic CASE #1
Hailey-Hailey disease (HHD), also known as familial benign chronic pemphigus, is a rare genetic dermatosis that causes keratinocyte acantholysis and disruption of the desmosomekeratin complexes in the suprabasal layers of the epidermis.1 Howard and Hugh Hailey first characterized it in 1939 in their case study of 2 adult brothers with a unique blistering syndrome.2 The disease is caused by an autosomal-dominant mutation in the ATP2C1 gene, which codes for a calcium ATPase that sequesters calcium in the Golgi apparatus and is highly expressed in epidermal keratinocytes.3 The dysregulation of intracellular calcium signaling is thought to affect normal keratinocyte adhesion and lead to epidermal defects. Clinically, HHD occurs as small vesicular lesions, erythematous scaly plaques and papules, or weeping and crusted erosions. Most commonly, these lesions affect the neck, groin, perineum, axillae, and other intertriginous regions of the skin. Other rare symptoms include involvement of the mouth, scalp, vulva, and esophagus, and linear white discoloration of the fingernails.4 The lesions may be painful or itchy, and symptoms are exacerbated or induced by heat, sweat, sun exposure, and friction.5 Thus, patients are often more symptomatic in the summer than in the winter and experience discomfort wearing tight clothing such as bras and shirt collars.1 In addition, some female patients experience worsening of premenstrual symptoms.6 Secondary bacterial, viral, or fungal infections are also common in affected areas.7 Histology studies of HHD show widespread separation of the suprabasal layers, vesicle formation, and presence of acantholytic cells in the epidermis. Dyskeratosis may also be present. Involvement of the dermis is unusual, although signs of lymphocytic infiltration may be present. Ninety-eight mutations in ATP2C1 have been recorded in patients with HHD, and the gene locus is on chromosome 3q21-q24.6 The worldwide prevalence of HHD is unknown, although the disease affects men and women at equal rates. No observed difference in frequency by ethnic group is noted.8 The disease is fully penetrant in adults but has variable expressivity. The area of onset and affected regions are also variable among patients.1 Patients with mild symptoms may show involvement only in the nails or may exhibit small skin lesions that resemble eczema. Other patients may have severe painful blistering that can inhibit normal physical activity, especially
if it occurs in the groin.4 The lesions may have a foul odor and are susceptible to secondary infection, which can affect lifestyle negatively.9 Although rare, squamous cell carcinoma may arise from a skin lesion of HHD.10 Symptoms usually appear during early adulthood, between the ages of 20 and 40 years, although onset can occur from early adolescence to late-middle age. After age 50, many patients experience periods of remission and alleviation of symptoms. However, complete resolution is rare. Because of the high variability of morphology, expressivity, and general phenotypic characteristics, HHD is often misdiagnosed. The differential diagnosis includes eczema,
There is no cure for HHD, and the chronic nature of the condition makes treatment challenging. cutaneous infection, pemphigus vulgaris, and Darier disease. In fact, before the discovery of the mutation in the ATP2C1 gene, many believed that HHD was a vesicular variant of Darier disease, which is also an inherited dermatosis. However, HHD includes more widespread acantholysis and occurs later in life than Darier disease.1 HHD is differentiated from pemphigus vulgaris because pemphigus vulgaris includes antidesmosomal autoantibodies, whereas HHD does not. Positive family history and a genetic test for the ATP2C1 mutation is the definitive way to diagnose HHD and differentiate it from these other conditions.3 There is no cure for HHD, and the chronic nature of the condition makes treatment challenging. However, several treatments are available, including topical creams, systemic treatments, light therapy, and surgery. In addition, the removal of triggers such as friction, heat, and sweat can help alleviate symptoms. It is important to note that most data about the efficacy of these treatments are based on case reports, not on results of controlled trials, and that the disease tends to wax and wane even without therapy.5 The goal of topical treatment is to modulate inflammation and protect against infections that may aggravate symptoms. Corticosteroid creams have been used in combination with topical antimicrobial agents with some success. However, the extended use of topical steroids may lead to skin atrophy, so this is a short-term treatment. Long-term control of inflammation has been achieved with topical calcineurin inhibitors, although at least 2 case reports describe the worsening of lesions with this therapy. Other topical agents with reported success
34 THE CLINICAL ADVISOR â€˘ MAY 2019 â€˘ www.ClinicalAdvisor.com
include calcitriol, cadexomer iodine powder, and 5-fluorouracil. Botulinum toxin type A injections are also effective for decreasing sudoresis and alleviating symptoms in intertriginous regions.5 When topical agents are ineffective or when lesions are widespread, systemic treatments may be more effective.These include oral antimicrobial, steroid, and retinoid medications. Other oral immunosuppressants, such as cyclosporine, may alleviate symptoms by decreasing levels of cytokines in the skin and regulating intracellular calcium levels.5 In patients with more severe cases of HHD, treatment with electron beam radiation therapy has shown variable levels of success.9 Finally, although surgical treatments such as dermabrasion and excision may lead to morbidity, they may be recommended for patients with debilitating disease.5 The patient underwent biopsy, which revealed suprabasal acantholysis. After discussion of the various treatment options, the patient opted for therapy with botulinum toxin type A injections and a topical calcineurin inhibitor. The reduction in axillary sweating and inflammation has resulted in significant improvement. Ariella Noorily, BA, is a medical student and Christopher Rizk, MD, is a dermatology resident at Baylor College of Medicine, in Houston,Texas. References 1. Burge SM. Hailey-Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol. 1992;126(3):275-282. 2. Hailey H, Hailey H. Familial benign chronic pemphigus. Arch Dermatol
Tumid lupus, also known as lupus erythematosus tumidus (LET), is an uncommon autoimmune disorder caused by a multitude of factors such as genetics, the environment, and hormones.1 LET is more commonly seen in men aged 41 to 50 years. Dysregulation of the immune system has been postulated as contributing to the pathophysiology of LET.2 Data show that a decrease in regulatory T cells results in lowered immune tolerance, especially in photosensitive conditions such as LET and subacute cutaneous lupus erythematosus. Environmental factors such as smoking are highly associated with LET.3 Clinically, LET presents as erythematous, indurated, nonscarring plaques on sun-exposed sites such as the face, upper back, neck, extensor aspects of arms, and shoulders.4 Histopathologic evaluation is required for diagnosis. Histology reveals well-demarcated perivascular and periadnexal lymphocytic infiltration and mucin deposition. The dermis appears edematous compared with the epidermal atrophy and basement membrane thickening seen in other types of cutaneous lupus erythematosus conditions. Direct immunofluorescence staining of skin lesions is negative for immunoglobulin or complement.
Syphilol. 1939;39(4):679-685. 3. Hu Z, Bonifas JM, Beech J, et al. Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet. 2000;24(1):61-65. 4. Dobson-Stone C, Fairclough R, Dunne E, et al. Hailey-Hailey disease: molecular and clinical characterization of novel mutations in the ATP2C1 gene. J Invest Dermatol. 2002;118(2):338-343.
Dysregulation of the immune system has been postulated as contributing to the pathophysiology of LET.
5. Arora H, Bray FN, Cervantes J, Falto Aizpurua LA. Management of familial benign chronic pemphigus. Clin Cosmet Investig Dermatol. 2016;9:281-290. 6. Warycha M, Patel R, Meehan S, Merola JF. Familial benign chronic pemphigus (Hailey-Hailey disease). Dermatol Online J. 2009;15(8):15. 7. Zhao Q-F, Hasegawa T, Komiyama E, Ikeda S. Hailey-Hailey disease: a review of clinical features in 26 cases with special reference to the secondary infections and their control. Dermatologica Sinica. 2017;35:7-11. 8. Engin B, Kutlubay Z, Çelik U, Serdaroğlu S, Tüzün Y. Hailey-Hailey disease: a fold (intertriginous) dermatosis. Clin Dermatol. 2015;33(4):452-455. 9. Graham PM, Melkonian A, Fivenson D. Familial benign chronic pemphigus (Hailey-Hailey disease) treated with electron beam radiation. JAAD Case Rep. 2016;2(2):159-161. 10. Holst VA, Fair KP, Wilson BB, Patterson JW. Squamous cell carcinoma arising in Hailey-Hailey disease. J Am Acad Dermatol. 2000;43(2 Pt 2):368-371.
Photosensitivity is a main component of LET,1 with phototesting establishing it as a photosensitivity subtype of cutaneous lupus erythematosus. More recently, LET has been classified as an intermittent subtype of chronic cutaneous lupus erythematosus.4 In vitro and in vivo studies have discussed the induction of lesions with ultraviolet (UV) irradiation in the form of UV-A and UV-B rays.4,5 No correlation between photosensitivity and anti-Sjögren-syndrome-related antigen A (SSA/AntiRo) antibodies in patients with LET is known. However, this correlation is seen in patients with subacute cutaneous lupus erythematosus.Approximately 80% of patients with LET do not test positive for antinuclear antibodies.6
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 35
Dermatology Clinic to follow vigilant sun protection protocols using sunscreen with an SPF of 30 to 50 to be reapplied every 2 hours while in the sun.The patient returned a third time reporting continued pruritus and pain of the lesions on her face. She was prescribed the same prednisone taper and halobetasol 0.05% topical ointment to be applied to the affected areas twice a day for 2 weeks, then as needed on the weekends. ■ Ashley Kwan, MMSPAS, PA-C, works as breast cancer surgery physician assistant at Breastlink in Orange, California. References 1. Foering K, Chang AY, Piette EW, Cucchiara A, Okawa J, Werth VP. Characterization of clinical photosensitivity in cutaneous lupus erythematosus. J Am Acad Dermatol. 2013;69(2):205-213. 2. Gambichler T, Pätzholz J, Schmitz L, Lahner N, Kreuter A. FOXP3+ and CD39+ regulatory T cells in subtypes of cutaneous lupus erythematosus. J Eur Acad Dermatol Venereol. 2015;29(10):1972-1977. 3. Böckle BC, Sepp NT. Smoking is highly associated with discoid lupus erythematosus and lupus erythematosus tumidus: analysis of 405 patients. Lupus. 2015;24(7):669-674. 4. Kuhn A, Bein D, Bonsmann G. The 100th anniversary of lupus erythematosus tumidus. Autoimmun Rev. 2009;8(6):441-448. 5. Kind P, Lehmann P, Plewig G. Phototesting in lupus erythematosus. J Invest Dermatol.1993;100(1):53S-57S. 6. Kuhn A, Richter-Hintz D, Oslislo C, Ruzicka T, Megahed M, Lehmann P. Lupus erythematosus tumidus--a neglected subset of cutaneous lupus erythematosus: report of 40 cases. Arch Dermatol. 2000;136(8):1033-1041. 7. Rémy-Leroux V, Léonard F, Lambert D, et al. Comparison of histopathologic– clinical characteristics of Jessner’s lymphocytic infiltration of the skin and lupus erythematosus tumidus: multicenter study of 46 cases. J Am Acad Dermatol. 2008;58(2):217-223. 8. Cinotti E, Merlo V, Kempf W, et al. Reticular erythematous mucinosis: histopathological and immunohistochemical features of 25 patients compared with 25 cases of lupus erythematosus tumidus. J Eur Acad Dermatology Venereol. 2015;29(4):689-697.
36 THE CLINICAL ADVISOR • MAY 2019 • www.ClinicalAdvisor.com
© The New Yorker Collection 2019 from cartoonbank.com. All Rights Reserved.
The differential diagnosis includes polymorphous light eruption, reticular erythematous mucinosis, and Jessner lymphocytic infiltrate of the skin.1 The latter is also a photosensitive disease but unlike LET presents with asymptomatic erythematous papules or nodules without scarring on the face or upper back.7 Polymorphous light eruption is differentiated from LET by a shorter symptomatic course; lesions resolve a few days after implementing sun protection measures.6 Reticular erythematous mucinosis presents as reticulated macular erythema or reticular-like plaques.8 Treatment of LET is based on limiting exposure to sunlight and symptomatic relief.4 Patients with LET are advised to avoid spending time in the sun, especially in the summer, and to avoid travel to regions closest to the equator where exposure is likely. Sunscreen should be applied 15 to 30 minutes before going outdoors. Approximately 50% of patients with LET have no recurrences after following sun protection measures. Studies have shown that topical corticosteroids and antimalarial medications can be used for symptomatic relief of pruritus and painful lesions in extensive disease. Chloroquine administered at a dosage of 3.5 to 4.0 mg/kg of ideal body weight per day for 4 to 6 weeks has been shown to be effective. Hydroxychloroquine administered at a dosage of 6.0 to 6.5 mg/kg of ideal body weight per day is an alternative to chloroquine. Skin punch biopsy of the forehead using a 4-mm punch tool was performed on the patient described in the case. Histopathology revealed tumid lupus. The patient was discharged after sutures were placed and proper dressing and care were discussed. She returned a few weeks later complaining of severe pruritus and pain, which was worse at night. She experienced mild benefit from application of Vaseline®.The patient was prescribed oral prednisone 20 mg to be tapered over 5 days. She was advised to apply topical triamcinolone 0.1% ointment to the lesions daily for 2 weeks for flares, then only on the weekends. Side effects such as atrophy and hypopigmentation were discussed. The patient was advised
Dermatologic Look-Alikes Nodules on the Arm and Leg CHRISTOPHER RIZK, MD; EMILY BURNS, BA; ARIELLA NOORILY, BA
A 67-year-old man presents with 2 nodules on his elbow. He has never had any skin conditions but 2 years previously was diagnosed with rheumatoid arthritis, which he manages with methotrexate and nonsteroidal antiinflammatory drugs.The nodules are uncomfortable and aesthetically displeasing, but they are not painful. On examination, 2 large, firm, skin-colored subcutaneous nodules on the elbow are noted. Biopsy is performed, revealing palisading necrobiotic granuloma and a central area of fibrin in the deep dermis.
A 23-month-old girl is brought to the clinic because of pink nodules on her leg increasing in number over the past month. The child’s mother denies trauma to her daughter’s leg, and her daughter has not experienced this condition before. On examination, several firm, nontender subcutaneous nodules <8 mm in diameter with overlying erythema and scaling are noted in the pretibial region. Biopsy reveals degeneration of collagen surrounded by palisading histiocytes and mononuclear inflammatory cells with mucin in central areas.
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 37
Dermatologic Look-Alikes CASE #1
Rheumatoid nodules (RNs) are extra-articular manifestations of rheumatoid arthritis, a chronic autoimmune disease of unknown etiology that affects primarily the joints. Rheumatoid arthritis is associated with several other extraarticular conditions, including vasculitis, atherosclerosis, anemia, SjĂśgren syndrome, and pulmonary nodules. However, RNs are the most common extra-articular manifestation, occurring in 20% to 30% of cases of rheumatoid arthritis.1,2 In patients with rheumatoid arthritis-associated Felty syndrome, the incidence of RNs rises to 75%.3 RNs can be associated with other connective tissue disorders, such as systemic lupus erythematosus.4 RNs occur more frequently in whites and are more common in men than in women.3 They usually affect those with a longer history of rheumatoid arthritis and a positive rheumatoid factor titer (90% of patients with RNs have this marker). In addition, patients with RNs may be more likely to have other systemic complications of rheumatoid arthritis.5 However, this does not definitively predict the severity of disease.6 Although rare, RNs may be the first clinical symptom of rheumatoid arthritis.4 Other variations of rheumatoid arthritis-associated RNs include rheumatoid nodulosis, which is the presence of multiple RNs in an otherwise asymptomatic patient, and accelerated rheumatoid nodulosis, which is characterized by the rapid onset of numerous small nodules following methotrexate treatment.5 The histopathology of RNs is defined by 3 stages: acute inflammation, granulation, and necrosis.The lesions develop from small areas of granulated tissue into large nodules with necrotic centers. These nodules typically contain fat, cellular fragments, immunoglobulins, lymphocytes, neutrophils, eosinophils, and fibrinoid material.2 On histology testing, RNs display palisading necrobiotic granulomas and a central area of fibrin and are usually seen in the deep dermis. The nodules have 3 characteristic layers: a central eosinophilic zone of fibrinoid necrosis, a surrounding region of palisading granulomas with high levels of human leukocyte antigen-D related (HLA-DR)-expressing macrophages, and an outer border infiltrated by inflammatory cells.5 The pathogenesis of RNs is unknown, but current theories suggest that trauma to small vessels causes a local aggregation of immune complexes, which stimulates immune cells
to release cytokines and other substances that promote the growth of these nodules.3 Evidence suggests that interleukin-17 and interleukin-23 are important for the onset of RNs.5 Patients with rheumatoid arthritis have a genetic predisposition for the development of RNs. Specifically, patients with the HLA-DR4 antigen haplotype are at higher risk for RNs, whereas patients displaying the HLA-DRw2 antigen are at lower risk.2 Clinically, these subcutaneous nodules usually occur in areas of the body that are subject to pressure or trauma, such as the elbow, upper forearm, digits, heels, and back.1 However, cases have been reported on other body sites, such as the mucosa of the mouth, penis, and vulva. In addition, nodules may develop on the visceral surfaces of the lungs, heart, throat, and liver.5 The nodules are firm, skin-colored papules that range in size from <5 mm to a few centimeters in diameter. Some are deep enough to adhere to underlying tendons or bursae, while others are epidermal and freely movable.4 Usually benign and painless, they can feel uncomfortable in certain areas of the body and are cosmetically distressing to many patients. If the skin over the nodules ruptures, possible complications include infection, ulceration, and gangrene.3 Additionally, nodules that are attached to the synovium may migrate to the skin and form a fistula, which requires treatment with synovectomy.2
Patients with rheumatoid arthritis have a genetic predisposition for the development of rheumatoid nodules. RNs can usually be diagnosed based on clinical findings, such as the location of the nodules, associated vasculitis, and history of rheumatoid arthritis or other rheumatologic diseases.When this is not sufficient, laboratory findings and histology testing provide a reliable method of diagnosis.5 Many other conditions include nodular lesions; therefore, the differential diagnosis of RNs is complex.The differential diagnosis includes subcutaneous granuloma annulare (GA), fibromas, xanthomas, nodular scleroderma, synovial cysts, and tumoral calcinomas. These are often differentiated on histology or based on clinical differences.2 RNs may look similar histologically to deep GA, which makes this differential diagnosis more challenging. Several features can simplify this diagnosis, including location, pattern, presence of interstitial mucin, and fibrosis.2 For example,
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Dermatologic Look-Alikes mucin deposition is very rare in RNs but is common in GA; this histologic difference is the most important method for differentiating these 2 nodular disorders.5 Because RNs are usually benign, treatment is not necessary. Draining, excising, or injecting the nodules may result in infection, so these methods should be avoided.The nodules will often regress with time and with typical rheumatoid arthritis treatments, such as nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, methotrexate, and cyclosporine.3 However, nodules may grow or worsen (eg, in accelerated rheumatoid nodulosis following methotrexate treatment). They may also be prone to ulceration and cause pain, discomfort, deformity, or issues with mobility, depending on location. In these cases, treatment options include corticosteroid injections into the nodules, surgical excision and grafting, and oral corticosteroid medications. These therapies have variable success.2 After a discussion of the various therapy options, the patient decided to wait and see whether the nodules would resolve over the next few months before trying a corticosteroid injection.
GA is a benign, self-limited, idiopathic dermatosis with multiple clinical presentations and shared histologic features. It was described in 1895 and named in 1902.7-9 The most widely documented clinical phenotypes of GA include localized GA, generalized GA, and subcutaneous GA. Localized GA is the most common variant of GA and is characterized by singular or multiple annular erythematous plaques seen on the extremities. Subcutaneous GA (SGA) is a less common subtype that occurs almost exclusively in children aged 1 to 14 years.7 Synonymous names include deep GA, subcutaneous palisading granuloma, pseudorheumatoid nodule, and necrobiotic granuloma.10 Patients typically have slow-growing pink, yellow, or tan nodules that can be solitary or multiple. Nodules are frequently pretibial but also may occur on hands, scalp, buttocks, and behind the ears.7,10 Despite SGA distribution, trauma is not a recognized cause. Nodules located superficial to bone have been reported to extend to the periosteum.They are typically motile on the extremities and slightly motile or nonmotile on the scalp or forehead.They are reported to be painless or
slightly tender on palpation. Atypical manifestations include pain, unusual location, and rapid enlargement.11 Patients with SGA are usually young (mean age, 4.3 years) and otherwise healthy.8 Lesions predominantly occur in girls, with a femaleto-male ratio of 1 to 2:1. Familial cases of SGA have been reported, but a relative lack of data exist on the genetics of SGA. Although an association of SGA with diabetes mellitus is speculated, it has not yet been established. Lesions of SGA in patients with diabetes mellitus are not discernibly different from lesions in patients without diabetes mellitus.10
Patients with granuloma annulare typically have slow-growing pink, yellow, or tan nodules that can be solitary or multiple. Excisional biopsy is diagnostic but not therapeutic, and recurrence after biopsy has been reported in up to 75% of children. Complications of excisional biopsy for diagnosis include scar formation and infection. Histologic examination shows that nodules occur in reticular dermis and subcutaneous layers. Lesions are characterized by degeneration of collagen as a result of ischemia, surrounded by palisading histiocytes and mononuclear inflammatory cells.7-10 Histologically, SGA resembles RNs and necrobiosis lipoidica diabeticorum (NLD) in adults. The key differentiating feature between SGA and RNs is the presence or lack of mucin in necrobiotic areas. A hematoxylin and eosin stain of SGA results in a bluish appearance of central zones because of mucin, which is not typically found in RNs. Staining with colloidal iron can confirm the presence of mucin.10 Because adults with RNs, which are histologically similar to SGA, are at significant risk for rheumatoid arthritis, efforts have been made to determine whether children with SGA are at similar risk for connective tissue disease. Two studies reviewing more than 100 cases found no association between SGA and the development of rheumatoid arthritis.8,12 Clinically, SGA and NLD are distinct, but they share histologic features. NLD is a granulomatous skin disorder that occurs in 0.3% of people with diabetes. It most commonly occurs on the legs but can also involve other areas such as the scalp, upper extremities, and abdomen. The average age of onset is 30 years.13 Central zones of degenerated collagen surrounded by palisading histiocytes are present in both conditions. SGA is distinguished histologically by smaller, rounder lesions involving only the deeper dermis and subcutis with more abundant mucin.
40 THE CLINICAL ADVISOR â€˘ MAY 2019 â€˘ www.ClinicalAdvisor.com
Subcutaneous Granuloma Annulare7-16
• Firm, skin-colored subcutaneous nodules • 5 mm to a few centimeters in diameter • Moveable or adherent to underlying tissue • Usually benign and painless
• Firm, skin-colored deep dermal or subcutaneous nodules • Usually <4 cm in size • Moveable or adherent to underlying tissue • Usually benign and painless
• Primarily associated with rheumatoid arthritis • May be associated with other rheumatologic diseases
• Possible association with type 1 diabetes mellitus
• Positive rheumatoid factor • Pathogenesis is unknown but thought to be related to the formation of immune complexes in cutaneous vasculature • Most common in white men
• Unknown etiology • Most commonly affects children
• Areas of the body exposed to pressure (eg, elbows, shoulders, back, digits, heels) • Rarely on mucosa, vulva, penis, and visceral surfaces
• Anterior lower legs, buttocks, scalp, and hands of children
• Subcutis • Characteristic palisading necrobiotic granulomas • 3 distinct layers: a central eosinophilic zone of fibrinoid necrosis, a surrounding region with high levels of HLA-DRexpressing macrophages, and an outer border infiltrated by inflammatory cells • Mucin involvement rare
• Degeneration of collagen surrounded by palisading histiocytes and mononuclear inflammatory cells • Presence of mucin in central areas
• Diagnosed based on clinical findings: location, associated vasculitis, and a history of rheumatoid arthritis or other rheumatologic diseases • Biopsy with histologic exam; positive rheumatoid factor laboratory result
• Incisional or excisional biopsy with histologic examination
• When nodules are benign and painless, no treatment is required; rheumatoid arthritis drug regimen may alleviate symptoms • Oral corticosteroids • Injection with corticosteroids • Surgical excision
• No treatment or intervention required • Topical and systemic steroids and surgical excision show limited efficacy • Spontaneous regression
Other potential diagnoses include neoplastic, infectious, or systemic disease. Hematomas, abscesses, and infectious granulomas are usually suspected on the basis of a history of trauma, laboratory abnormalities (elevated erythrocyte sedimentation rate, elevated rheumatoid factor level), and systemic symptoms such as fever.11 Sarcoidosis is a systemic granulomatous disease of unknown etiology that involves the lymph nodes, skin, spleen, eyes, liver, and lungs.Twentyfive percent of cases of sarcoidosis involve the skin and may include subcutaneous nodules.14 Sarcoidosis is confirmed histologically by noncaseating granulomas with lymphocytic infiltrates in the periphery.15
Benign and malignant tumors can be considered in the initial differential diagnosis. Leukemia and precursor B-lymphoblastic lymphoma may include the presence of cutaneous nodules. Soft-tissue tumors, such as rhabdomyosarcomas, can include masses with indistinct borders on the arms and legs.These lesions are typically painful. SGA is typically firmer than lipomas or neurofibromas. SGA can be confused with a soft tissue tumor, especially when nodules are located in the scalp. Radiographs indicating only soft tissue growth and no underlying bony involvement suggest a benign nodule. Dermatofibromas warrant consideration but typically are more yellow than SGA.These tumors lack palisading histiocytes on histologic evaluation.9
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 41
Dermatologic Look-Alikes Lesions of SGA are benign and do not require treatment or intervention. However, for patients who experience distress because of the cosmetic appearance of the nodules, certain therapies may be effective.These include topical and systemic steroids as well as surgical excision. However, there is limited evidence for the efficacy of these treatments.12 Recurrences locally or distally are common but do not warrant additional biopsy, which can result in scarring or infection.11 Fortunately for many patients, SGA typically regresses after 12 to 24 months but may recur after months or years.16 After discussing the various therapies, the patient’s mother decided to wait and see whether the nodules would regress before trying topical or systemic steroids. ■
5. Lora V, Cerroni L, Cota C. Skin manifestations of rheumatoid arthritis. G Ital Dermatol Venereol. 2018;(2):243-255. 6. Young A, Koduri G. Extra-articular manifestations and complications of rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2007;21(5):907-927. 7. Piette EW, Rosenbach M. Granuloma annulare: clinical and histologic variants, epidemiology, and genetics. J Am Acad Dermatol. 2016;75(3):457-465. 8. Felner EI, Steinberg JB, Weinberg AG. Subcutaneous granuloma annulare: a review of 47 cases. Pediatrics. 1997;100(6):965-967. 9. Whelan JP, Zembowicz A. Case records of the Massachusetts General Hospital. Case 19-2006. A 22-month-old boy with the rapid growth of subcutaneous nodules. N Engl J Med. 2006;354(25):2697-2704. 10. Grogg KL, Nascimento AG. Subcutaneous granuloma annulare in childhood: clinicopathologic features in 34 cases. Pediatrics. 2001;107(3):E42. 11. Chung S, Frush DP, Prose NS, Shea CR, Laor T, Bisset GS. Subcutaneous
Emily Burns, BA, is a medical student; Ariella Noorily, BA, is a medical student; and Christopher Rizk, MD, is a dermatology resident at Baylor School of Medicine in Houston,Texas.
granuloma annulare: MR imaging features in six children and literature review. Radiology. 1999;210(3):845-849. 12. Davids JR, Kolman BH, Billman GF, Krous HF. Subcutaneous granuloma annulare: recognition and treatment. J Pediatr Orthop. 1993;13(5):582-586.
13. Kota SK, Jammula S, Kota SK, Meher LK, Modi KD. Necrobiosis lipoidica diabetico
1. Cojocaru M, Cojocaru IM, Silosi I, Vrabie CD, Tanasescu R. Extra-articular
rum: a case-based review of literature. Indian J Endocrinol Metab. 2012;16(4):614-620.
manifestations in rheumatoid arthritis. Maedica (Buchar). 2010;5(4):286-291.
14. Mangas C, Fernández-Figueras M-T, Fité E, Fernández-Chico N, Sàbat M,
2. García-Patos V. Rheumatoid nodule. Semin Cutan Med Surg. 2007;26(2):100-107.
Ferrándiz C. Clinical spectrum and histological analysis of 32 cases of specific
3. Sayah A, English JC 3rd. Rheumatoid arthritis: a review of the cutaneous
cutaneous sarcoidosis. J Cutan Pathol. 2006;33(12):772-777.
manifestations. J Am Acad Dermatol. 2005;53(2):191-209.
15. Miida H, Ito M. Tuberculoid granulomas in cutaneous sarcoidosis: a study of
4. Albrecht J, Atzeni F, Baldini C, et al. Skin involvement and outcome
49 cases. J Cutan Pathol. 2010;37(4):504-506.
measures in systemic autoimmune diseases. Clin Exp Rheumatol. 2006;24
16. Rubin M, Lynch FW. Subcutaneous granuloma annulare: comment on
(1 Suppl 40):S52-S59.
familial granuloma annulare. Arch Dermatol. 1966;93(4):416-420.
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Advisor Forum These are letters from practitioners around the country who want to share their clinical challenges and successes, observations, and pearls with their colleagues. We invite you to participate.
2. Cohen SM, Kwo PY, Lim, JK. ACG clinical guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol. 2017;112:18-35.
Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 275 7th Avenue, 10th Floor, New York, NY 10001.You may contact us by e-mail at editor@ clinicaladvisor.com. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter. No anonymous contributions will be accepted.
IRON PILLS AND THEIR EFFECT ON LIVER ENZYMES Can taking iron pills elevate liver enzymes? —AGNES DEW, PCA, Americus, Georgia Liver enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase are markers of hepatic injury, not hepatic function, and should be referred to as liver chemistries. Albumin, bilirubin, and prothrombin time are direct measures of hepatocellular synthetic function and are appropriately characterized as “liver function tests.” Liver enzymes may be abnormal even in patients without liver disease. The differential for elevated enzymes is broad with many potential causative factors and should be further defined by the patient’s medical history and risk factors.1 Almost all medications are associated with at least a small risk of elevated liver chemistries with or without hepatotoxicity.2 Oral iron supplementation at typical replacement doses has little or no adverse effects on the liver or serum enzyme elevations. However, in high doses or overdoses, it can cause acute hepatotoxicity as a result of iron poisoning.Toxicity occurs after ingestion of ≥3 g of ferrous sulfate (approximately 10 tablets). Severe toxicity with aminotransferases greater than 25 times the upper limit of normal typically occurs with larger overdoses and high initial serum iron levels (>1000 ug/ dL). Mild to moderate cases of iron poisoning are usually self-limiting and resolve with supportive care, whereas severe cases become fatal rapidly.3—LAURA KUSMINSKY, PA-C References 1. Approach to the patient with abnormal liver biochemical and function tests. UptoDate.com website. https://www. uptodate.com/contents/approach-to-the-patient-withabnormal-liver-biochemical-and-function-tests. Accessed April 2, 2019.
44 THE CLINICAL ADVISOR • MAY 2019 • www.ClinicalAdvisor.com
3. Iron. National Institute of Health website. https://livertox. nih.gov/Iron.htm. Accessed April 3, 2019.
CASE FILES CUTIS RHOMBOIDALIS Contributed by Joe Monroe, MPAS, PA-C A 78-year-old man presented with thickened, heavily lined skin on his posterior neck that had been present for an indeterminate period of time. Although the striking skin changes were asymptomatic, they were concerning to his relatives who insisted that he be seen by a dermatology provider. The patient had spent nearly his whole life in the sun, farming, ranching, fishing, and tending to his property in rural Oklahoma. He denied a history of skin cancer and claimed to be in good health. The skin on the patient’s nuchal area was heavily lined and thickened. The lines joined to form multiple overlapping rhomboidal shapes.Although
Reference Bolognia JL, Jorizzo JL, Rapini RP. Dermatology. 1st ed. New York: Mosby, 2003;1380-1381.
CLINICAL PEARLS POISON IVY PREVENTION Poison ivy season is starting! I recommend that people take an old pair of knee-high tube socks and cut off the foot part above the heel. Pull the socks over the arms up to the start of their sleeve (assuming they are wearing a T-shirt) and tuck into gloves. Use the socks to protect arms when working in the yard or other high-risk poison ivy areas. They can be rolled off the arms and thrown away, or washed and re-used. I remind people to always wear gloves, and to remove the gloves before touching anything, including door handles. This significantly reduces the exposure area of skin to poison ivy. —JUDITH MCINTOSH, MSN, Kokomo, Indiana VERRUCA VULGARIS TREATMENT I always recommend candida albicans skin antigen test injections for patients who are not responding well to liquid nitrogen +/- paring for verruca vulgaris. A 0.1-mg injection every month for about 3 months creates an immune response against the warts. I have seen resolution of some recalcitrant cases that seemed most impossible! —SARAH LUP, PA-C, Chicago, Illinois
© JOHN SLATER / GETTY IMAGES
the color of the affected area was normal, the skin felt quite thick and inflexible. These skin changes stopped abruptly at the collar line, below which the skin was entirely normal. Abundant evidence of sun damage — including weathering, telangiectasias, solar lentiginosis, and numerous actinic keratoses on prominent areas of his cheeks and ears — was noted. Similar changes were noted on the dorsa of both hands but were not present on his arms and trunk because he wore long-sleeved shirts when in the sun. Although he had worn a wide-brimmed hat while in the sun during his adult life, he had never worn anything, such as a bandana, on his neck. The posterior neck is especially susceptible to the effects of the sun, evidence of which frequently manifests as it did in this patient. This condition is called cutis rhomboidalis nuchae (CRN), which represents thickening and weathering of the epidermis as well as solar elastosis of the underlying dermis caused by the sun. Although this condition is clear evidence of chronic overexposure to the sun, CRN has no malignant potential, and treatment is neither required nor does it exist. Besides being common, CRN is unique in its presentation, as well as in the patient population it affects (eg, older patients with sun damage confined to the posterior neck), so the differential is quite narrow. Punch biopsy would resolve any confusion. CRN puts this patient at higher risk for the development of skin cancers caused by sun exposure, such as basal cell carcinoma, squamous cell carcinoma, melanoma, and others. This patient and others with similar histories require regular skin checks by a qualified dermatology provider at least once a year. Although this patient would be advised to protect himself from the sun, this will do little to ward off any future skin cancers that will have been caused by sun overexposure occurring decades earlier. Application of sunscreen to his neck would prevent worsening of his CRN.
Always wear gloves to protect the skin from exposure to poison ivy, and remove them before touching anything.
RETHINKING PRESCRIBING DICLEGIS Diclegis is the only FDA-approved prescription medication for nausea and vomiting of pregnancy that is classified as Category A (safe for mom and baby). Before writing a prescription, consider the price tag. Diclegis with a coupon costs approximately $345 for 60 tablets. The most common dosage is 2 tablets/d but can be more. Some patients may obtain insurance coverage for this medication, but it will likely still cost something. Let’s break down Diclegis into its 2 active ingredients: doxylamine succinate and pyridoxine hydrochloride (vitamin B 6). Unless you are writing a prescription for a celebrity, recommend that your patients purchase instead over-the-counter doxylamine succinate and vitamin B 6 to take at night for nausea. —AMBER MURPHY, PA-C, Birmingham, Michigan www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 45
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LEGAL ADVISOR CASE
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RN Fired Over Social Media Post An RN’s post online violates a patient’s privacy, and she is fired. BY ANN W. LATNER, JD
Ms N could not get the toddler off her mind after she arrived home from her job as a nurse in the pediatric intensive care unit (ICU) of a local children’s hospital. The nurse had been in practice and working at the hospital for a decade and yet had never seen someone with this child’s disease — it had all but been eradicated. In fact, over the past decade, only 8 instances had occurred in the large city where Ms N worked. The disease? Measles. Ms N had always had mixed feelings about vaccinations, despite working in the healthcare field. In fact, she’d opted out of some vaccinations for her own 12-year-old son. She even belonged to some Facebook “anti-vaxxers” groups. But what she’d seen in the hospital today had really shaken her to the core. The toddler had contracted measles overseas. Although his older siblings had been vaccinated, he was too young to receive any vaccines before the trip. The child was clearly ill. He was covered in a splotchy red rash that had spread from his hairline to his feet, was in great pain, and had spiked a high fever. His eyes were red and watery, and he had developed
As a clinician, the greatest risk from committing a HIPAA violation is not being sued by a patient but losing employment.
a cough. Even a gentle touch to the child’s skin caused him to moan and cry. Ms N pulled her chair up to her home computer and signed onto Facebook. She pulled up the “Proud Parents of Unvaccinated Children” group and began typing about her experience. “For the first time in my career I saw measles this week. Actually, most of my coworkers and the ER docs saw measles for the first time as well. And honestly, it was rough. The kid was super sick—sick enough to be admitted to the ICU, and he looked miserable. You couldn’t touch him without him crying or moaning in pain. It was terrible. I think it’s easy for us nonvaxxers to make assumptions about these diseases, but most of us have never and will never see one of them.” She wrote more about the child’s experience and how it was scary enough to almost make someone change his or her antivaccination stance, Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 47
LEGAL ADVISOR but she reiterated that she had not changed her own views on vaccinations despite the severity of the child’s case. Ms N’s name and place of employment were on her Facebook profile, so anyone in the group knew which hospital she was referring to. The parent of another patient admitted to the same hospital saw Ms N’s posts and became concerned that her child may have been exposed to measles.The parent took screenshots of Ms N’s posts, which she then shared to the hospital’s Facebook page. The hospital immediately issued a statement in response. “A patient treated at [children’s hospital] tested positive for measles. This is a highly contagious, vaccine-preventable infection. We know vaccination is the best protection against measles.We work closely with public health entities to continuously monitor highly contagious diseases in our local, national, and international communities. Our Infection Control and Prevention team immediately identified other children who may have come in contact with this patient to assess their risk and provide clinical recommendations. We have contacted all of those families. We are also aware that one of our nurses posted information on social media, and we take these matters very seriously. A thorough investigation is underway.”
Keep your social life and your work life separate, and only post to social media what you’d want the whole world to see. Ms N was put on probation while the hospital launched its investigation. She was fired from her job 3 days later. The hospital determined that Ms N had breached hospital policy and that her actions were in violation of the Privacy Rule under the Health Insurance Portability and Accountability Act (HIPAA) of 1996. Legal Background
The HIPAA Privacy Rule was enacted in 2002 to protect the privacy of patients’ personal health information while simultaneously allowing the information necessary to provide quality healthcare to continue to flow through the medical system. It requires covered entities — including hospitals, health plans, and healthcare providers — to treat patient information as confidential. While much of the public mistakenly believes that an individual can be sued for a HIPAA violation, this is not the case. The Unites States Department of Health and Human Services Office for Civil Rights (OCR) is responsible for
It should go without saying that clinicians should never post about patients on social media, even in a “closed” group or on a personal “page.” Social media is the opposite of private. The city where this event took place has a very high vaccination rate of almost 95%. Less than 10 cases of measles had occurred there in the past decade.Thus, because Ms N posted the name of the disease with her place of employment listed on her profile, it was possible for the child to be identified even though his name wasn’t revealed. A person does not need to be mentioned by name in order to be potentially identified with current technology. If any personal identifiable protected health information (in this case disease, hospital, age group, and sex) is posted to social media without the consent of the patient, it is a violation of the HIPAA Privacy Rule. An interesting note is that if this case had happened in one of the areas that are currently experiencing an outbreak of measles cases, it would have been much more difficult to determine the identity of the child due to the sheer number of cases. But the combination of a high vaccination rate and extremely low incidence in the city where this took place made this easy to accomplish. Keep your social life and your work life separate, and only post to social media what you’d want (and is appropriate for) the whole world to see … because that’s exactly who may be seeing it. ■ Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, New York.
48 THE CLINICAL ADVISOR • MAY 2019 • www.ClinicalAdvisor.com