February 2016 Clinical Advisor by The Clinical Advisor

THE CLINICAL ADVISOR • FEBRUARY 2016

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NEWSLINE

■ Antibiotics guidelines ■ Constipation: an overview ■ End-of-life cancer care ALT MEDS UPDATE Marijuana

How effective is it? LEGAL ADVISOR

A violation of patient privacy

FEBRUARY 2016

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TREATING NONVALVULAR

ATRIAL FIBRILLATION Nonvalvular atrial fibrillation greatly increases the risk for stroke.

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CONTENTS FEBRUARY 2016

NEWS AND COMMENT 14 Newsline ■■CDC, ACP issue guidelines for appropriate antibiotic use for acute respiratory tract infection in adults ■■Constipation: Diagnosis and treatment overview ■■Hospice care is associated with better end-of-life cancer care ■■Scores on American Heart Association checklist may identify those likely to develop heart failure ■■Kidney stones becoming more common among youth, women, and African Americans ■■Parental education encouraged for epinephrine use for food allergies ■■Hepatitis C infections linked to higher risk of Parkinson disease ■■Tips for avoiding or reducing symptoms of nickel allergy ■■Potato consumption before pregnancy linked to diabetes risk 101 Commentary ■■ICD-10 codes may improve asthma care

36 CME/CE Hepatitis C virus infection: signs, symptoms, and screening Educating and testing high-risk populations are crucial steps in the effort to stem hepatitis C virus infections. 44 CME/CE Feature posttest

Antibiotic guidelines for ARTIs 14

DEPARTMENTS 10 Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com 52 CME/CE Dermatology Clinic n Rashes, diarrhea, and neuropsychiatric issues n Brown macules on the lips and nail changes

A violation of patient privacy 66

57 CME/CE Dermatologic Look-Alikes Growing lesions affecting the nails 61 CME/CE Dermatology posttest

FEATURES

Continues on page 8

27 Anticoagulant therapy for NV atrial fibrillation Multiple considerations come into play when choosing anticoagulant therapy for a patient with nonvalvular atrial fibrillation, a condition that increases the risk for stroke.

MAKING CONTACT

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Norovirus infection: a clinical overview 93

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Screening with HPV-Alone invites more risk into women’s lives than you may think. One out of 5 cases of cervical cancer were missed with HPV-Alone screening in a recent landmark, retrospective study—the largest ever conducted to evaluate the effectiveness of cervical cancer screening strategies in women ages 30-65.1* Additionally, screening with Pap+HPV Together™ (co-testing) identified more than 70% of those missed cancers.1 And it only requires one sample. So is HPV-Alone screening really worth the risk? Screen your patients with Pap+HPV Together. Because every woman deserves the best possible protection from cervical cancer. See more data at PapPlusHPV.com.

* A positive HPV screening result may lead to further evaluation with cytology and/or colposcopy. Reference: 1. Blatt AJ, Kennedy R, Luff RD, Austin RM, Rabin DS. Comparison of cervical cancer screening results among 256,648 women in multiple clinical practices. Cancer Cytopathol. 2015 April (Study included ThinPrep®, SurePath, Hybrid Capture 2 assay). ADS-01325-001 Rev. 001 © 2015 Hologic, Inc. All rights reserved. Hologic, Science of Sure, Pap+HPV Together, ThinPrep and associated logos are trademarks and/or registered trademarks of Hologic, Inc. and/or its subsidiaries in the United States and/or other countries. All other trademarks, registered trademarks, and product names are the property of their respective owners. This information is intended for medical professionals in the U.S. and is not intended as a product solicitation or promotion where such activities are prohibited. Because Hologic materials are distributed through websites, eBroadcasts and tradeshows, it is not always possible to control where such materials appear. For specific information on what products are available for sale in a particular country, please contact your local Hologic representative or write to diagnostic.solutions@hologic.com.

CONTENTS ADVISOR FORUM

Legal Advisor Violation of patient privacy

Clinical Challenge Markedly elevated serum transaminase levels

Your Comments ■ More reader comments on IUDs ■ Avoiding labeling patients as noncompliant ■ Contaminated water and cancer

Evidence-Based Medicine ■ In patients without CVD or diabetes, pooled cohort equations may underestimate risk for CV event if other risk factors are present. ■ In patients with a first unprovoked venous thromboembolism, adding CT to limited cancer screening may not lead to better rate of cancer detection. ■ Glasgow Coma Scale may underestimate the severity of isolated traumatic brain injury in patients aged ≥65 years.

Clinical Pearls ■ Erythromycin for facial lacerations

Case Files ■ Carcinoid appendix

Stat Consult Norovirus infection

Alternative Meds Update Marijuana

How effective is medical marijuana? 98

DEPARTMENTS, cont’d

HOW TO CONTACT US THE CLINIC ARY 2016

ALT MED Marijuana

S UPDATE

How effective

is it?

LEGAL ADV

A violation

ISOR

of patient priva cy

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• Send it by e-mail to editor@ClinicalAdvisor.com

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FEBRUARY

2016

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dvisor.com

TREATING

NONVAL VULAR

ATRIAL FIBRILL ATIO N Nonvalvu lar atrial fibrilla greatly incre tion ases the risk for stroke.

Course

HEPATITIS INFECTIONC VIRUS PAGE 36

19, NUMB ER 2

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IEWE D FORU M FOR NUR SE PRAC TITIO NERS

■ Antibiot ics guideline s ■ Constipa tion: an over view ■ End-of-lif e cancer care

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EXCLUSIVE TO THE WEB AT

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The Waiting Room

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Official Blog of The Clinical Advisor

CDC, ACP issue guidelines for appropriate antibiotic use for acute respiratory tract infection in adults Reducing inappropriate antibiotic prescribing will improve the quality of patient care, decrease healthcare costs, and preserve the effectiveness of antibiotics. Constipation: Diagnosis and treatment overview Strong evidence for efficacy has been established for stimulant and osmotic laxatives, new intestinal secretagogues, and peripherally restricted μ-opiate receptor antagonists, according to a review in JAMA.

ClinicalAdvisor.com/WaitingRoom Jillian Knowles, MMS, PA-C The importance of clinician-patient confidentiality in the emergency department When patients present with concerning behavior, an explanation of patient-provider confidentiality can help clinicians provide effective treatment more quickly. Sharon M. O’Brien, MPAS, PA-C Quantity of sleep continues to decline in Americans The use of sleep apps is growing among patients, but the data they provide may not be reliable.

Updated dietary guidelines focus on healthy eating patterns, disease prevention HHS and USDA have released the latest edition of dietary guidelines for Americans that focus on healthy eating patterns and preventing chronic diseases.

Jim Anderson, MPAS, PA-C, DFAAPA, ATC Wanted: Collaboration between the AAPA’s gun control advocates and gun-savvy PAs In the wake of multiple mass shootings occurring in the United States, the issue of gun control continues to divide the AAPA House of Delegates regarding the organization’s policies.

Multimedia ClinicalAdvisor.com/Multimedia New antibiotic prescription guidelines for acute respiratory tract infections The CDC and ACP have issued new advice for the prescription of antibiotics for adults with acute respiratory tract infections. They encourage clinicians to educate patients and avoid over-prescribing these drugs. Watch it here: ClinicalAdvisor.com/AntibioticVid New dietary guidelines call for reductions in sugar, sodium intake The 2015–2020 Dietary Guidelines for Americans have been released. They recommend that no more than 10%

MAKING CONTACT

of daily calories come from sugar, which can be difficult, as many foods have hidden added sugars. Watch it here: ClinicalAdvisor.com/DietGuideVid

USPSTF finds insufficient evidence to support full-body skin checks After a systemic review, the USPSTF has found insufficient evidence to weigh the pros and cons of full-body skin checks. Natalie Azar, MD, discusses the results of the review, stressing the importance of selfchecks for early skin cancer detection. Watch it here: ClinicalAdvisor.com/FullBodyVid

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Advisor Dx

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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.

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Elbow pain and a displaced radial neck fracture A 60-year-old woman presents with elbow pain after a fall 2 days earlier. She remembers falling on her wrist with her arm extended and has had severe pain with elbow motion since the fall. X-rays taken after the injury show a displaced radial neck fracture with more than 30 degrees of angulation. WHAT IS THE BEST TREATMENT OPTION?

• Long-arm cast for 4 to 6 weeks • Open reduction and internal fixation • Radial head replacement • Radial head excision ● See the full case at ClinicalAdvisor.com/OrthoDx_Feb16

Derm Dx Trunk dermatitis that does not fluoresce under Wood’s light An African American man, aged 38 years, presents for evaluation of an extensive rash involving his chest and back. The dermatitis began as a small patch several months ago and spread rapidly despite treatment with topical ketoconazole shampoo and triamcinolone cream. CAN YOU DIAGNOSE THE CONDITION?

• Tinea versicolor • Tinea corporis • Confluent and reticulated papillomatosis • Secondary syphilis ● See the full case at ClinicalAdvisor.com/DermDx_Feb16

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2016 11

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Newsline F E B R U A R Y 2 016

The quality of end-of-life cancer care page 16

Kidney stone prevalence increases page 17

Epinephrine, food allergies, and parents page 17

CDC, ACP issue guidelines for antibiotic use for acute respiratory tract infections

LARGE-SCALE reduction of antibiotic prescriptions requires a multidimensional approach, combining clinician, patient, and public education, according to updated clinical guidelines issued by the American College of Physicians (ACP) and the CDC and published January 19 online ahead of print in the Annals of Internal Medicine. The guidelines serve as an update to the 2001 guidelines. Following a narrative literature and evidence review relating to appropriate antibiotic use in the case of acute respiratory tract infection (ARTI) — i ncluding acute uncomplicated bronchitis, pharyngitis, rhinosinusitis, and the common cold — the researchers developed four points of HighValue Care Advice: • High-Value Care Advice 1: Clinicians should not perform testing or initiate antibiotic therapy in patients with bronchitis unless pneumonia is suspected.

Clinicians are advised not to initiate antibiotics in patients with bronchitis unless pneumonia is suspected.

• High-Value Care Advice 2: Clinicians should test patients with symptoms suggestive of group A streptococcal pharyngitis (for example, persistent fevers, anterior cervical adenitis, and tonsillopharyngeal exudates or other appropriate combination of symptoms) by rapid antigen detection test and/or culture for group A Streptococcus. Clinicians should treat patients with antibiotics only if they have confirmed streptococcal pharyngitis. • High-Value Care Advice 3: Clinicians should reserve antibiotic treatment for acute rhinosinusitis for patients with persistent symptoms for more than 10 days, onset of severe symptoms, or signs of high fever (>39°) and purulent nasal discharge or facial pain lasting at least 3 consecutive days, or onset of worsening symptoms following a typical viral illness that lasted 5 days that was initially improving (double sickening). • High-Value Care Advice 4: Clinicians should not prescribe antibiotics for patients with the common cold. Inappropriate antibiotic use for ARTI is an important contributor to antibiotic resistance — 41% of the 100 million annual antibiotic prescriptions are for such conditions. This increased antibiotic use can be directly correlated with the emergence of antibiotic-resistant

infections and a large number of medication-related adverse events. Throughout the past 2 decades, interventions targeting both physicians and patients have effectively decreased inappropriate antibiotic use. However, physician concern relating to patient satisfaction scores may limit the overall efficacy of these interventions. “A recent study showed an 85% decrease in antibiotic prescribing for ARTI and increased satisfaction ratings when providers gave advice on symptomatic therapy and explained why antibiotics were not needed for ARTI,” wrote Dr. Harris and colleagues. Clinicians are advised to consider implementing one of the following evidence-based strategies to limit antibiotic prescription while maintaining patient satisfaction: • Label acute bronchitis as a “chest cold” or “viral upper respiratory infection.” • Provide patient information sheets about appropriate antibiotic use and alternatives to antibiotics for managing symptoms. • A symptomatic prescription pad can be used to provide recommendations for management of symptoms • When it is unclear whether an antibiotic is needed, offer the possibility of future antibiotic treatment if the condition does not improve. This is known as the wait-and-see approach. n

14 THE CLINICAL ADVISOR • FEBRUARY 2016 • www.ClinicalAdvisor.com

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Newsline Constipation: diagnosis and treatment MANAGING PATIENTS with constipation, which leads to 8 million visits to clinicians each year, requires staying up-to-date on the most effective ways to diagnose and treat various types of the condition, according to a review published in the January 12 issue of JAMA. In the last 5 years, several important treatments for constipation have been developed. These include updates for laxatives and promotility agents; new treatments for opioid-induced constipation (OIC); and the identification of functional defecation disorders. Despite these advances, the treatment approach for chronic idiopathic constipation (CIC) has remained largely unchanged. Patients can experience constipation from several underlying causes, including a primary motor disorder involving the colon, a defection

disorder, an adverse reaction to a drug, or due to various diseases. A clinical evaluation of constipation should include: • Duration of symptoms • Frequency/consistency of stools • Presence of excessive straining • Feeling of incomplete evacuation • Use of manual maneuvers during defecation • Excluding any potential organic causes or adverse drug reactions There are 4 major groups of laxatives available in the United States. The 1st 3 groups are available over the counter (with the exception of lactulose), whereas the last group requires a prescription. 1. Bulk agents: psyllium, methylcelluose, calcium polycarbophil, wheat dextrin 2. Nonabsorbed substances: PEG 3350, lactulose, magnesium salts 3. Stimulants: bisacodyl, senna

Psyllium is a common overthe-counter bulk agent used as a laxative.

4. Secretory drugs: lubiprostone, linaclotide No one treatment course is effective for all patients with constipation, according to the researchers. Instead, clinicians are advised to work with their patient to adjust the treatment plan until they find which treatment (or combination of treatments) is most effective.

FAMILIES of patients who receive aggressive end-of-life medical care do not perceive the care as highquality, according to research published online ahead of print January 19 in JAMA. Lead author Alexi A. Wright, MD, MPH, interviewed 1,146 family members of patients with advanced-stage lung or colorectal cancer (median age, 76 years; male, 55.8%) who died in 2011. When patients received hospice care for longer than 3 days (58.8%), family members reported excellent end-of-life care more often,

Hospice care is linked to better end-of-life cancer care.

compared with family of patients who did not receive hospice care or received it for 3 or fewer days (43.1%). Family members of patients who did not receive hospice care or received 3 or fewer days were less likely to report that patients died in their preferred location (40%) than the family of those who received hospice care for longer than 3 days (72.8%). For patients admitted to an intensive care unit (ICU) within 30 days of death, family members reported excellent end-of-life care less often (45%), when compared with the

family of patients who were not admitted to an ICU within 30 days of death (52.3%). Family members of patients who died in the hospital were less likely to report excellent end-of-life care (42.2%) than those of patients who did not die in the hospital (57.4%). “Our study findings are a powerful argument for the importance of advance care planning,” Dr. Wright said. “The more information patients have, the more likely they are to receive the kind of medical care they want near death.”

IMAGES: © THINKSTOCK

How effective is aggressive end-of-life cancer care?

16 THE CLINICAL ADVISOR • FEBRUARY 2016 • www.ClinicalAdvisor.com

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HEALTH CAR E providers should increase efforts to show parents of children with food allergies when and how to use an epinephrine auto-injector and to provide a written action plan in the event of an emergency, according to a report published online ahead of print January 12 in the Journal of Allergy and Clinical Immunology: In Practice. Ruchi S. Gupta, MD, MPH, and colleagues studied 859 parents recr uited from the Chicago metro area who visited their children’s physicians twice a year. They found that less than 70% of parents remembered their allergists telling them when to use epinephrine and less than 40% remembered their pediatricians telling them this information. The numbers were lower for how many parents recalled being shown how to use epinephrine or being given a written emergency action plan, which describes common symptoms of a food allergy and what to do if a child has mild versus severe symptoms for all potential caregivers. Healthcare providers need to make sure patients understand when and how to use epinephrine and that they have an emergency action plan, Dr. Gupta said, adding that they should make sure the parents can repeat back the directions, as parents may not always absorb the information they are given in a short period.

Kidney stones becoming more common among youth, women, African Americans N E PH ROLI T H I A SIS h a s become a more common occurrence among young patients, with the greatest increase in incidence among individuals aged 15 to 19 years, women, and African Americans, after years of being an issue thought to affect middleaged white men, according to a report published online ahead of print January 14 in the Clinical Journal of the American Society of Nephrology. Lead author Gregory E. Tasian, MD, MSc, MSCE, and fellow investigators studied data on an at-risk population of 4,625,364 people and found that 152,925 patients received emergency, inpatient, or surgical care for nephrolithiasis. Overall, the annual incidence of kidney

The rate in African Americans increased 15% more than in whites.

stones increased 16% between 1997 and 2012. The risk of nephrolithiasis doubled during childhood regardless of gender, and there was a 45% increase in the lifetime risk for women. Considering age categories, the researchers found the greatest increase in incidence was among those aged 15 to 19 years, at 26% every 5 years. The highest rate of increase was among adolescent females, and nephrolithiasis was more common among females than males aged 10 to 24 years in every year studied. After age 25, kidney stones became more common among men, the researchers found. Among African-Americans, the incidence of nephrolithiasis increased 15% more than whites every 5 years.

AHA checklist score may predict heart failure MIDDLE-AGED adults who achieve a good score on the American Heart Association’s Life’s Simple 7 checklist may be less likely to develop heart failure, according to a study published online ahead of print December 23, 2015, in Circulation: Heart Failure. The seven steps listed in the checklist are to manage blood pressure, control cholesterol, reduce blood sugar, become physically active, eat better, lose weight, and stop smoking. Senior author Vanessa Xanthakis, PhD, and colleagues followed 3,201 individuals (average age, 59 years) for up to 12.3 years, finding that 188 developed heart failure. They found that a one-point increase in the Life’s Simple 7 checklist score was

associated with a 23% lower risk of developing heart failure. Those with scores falling in the middle third of the range had a risk of heart failure that was lower by nearly one-half, compared to those scoring in the bottom third. Those in the top third had an even lower risk of heart failure. The researchers also found an association between poor scores and cardiac remodeling (ie, changes in the heart’s structure and function), but after adjusting for cardiac remodeling, low scores still predicted heart failure. Limitations of the study were that most participants were white and of European ancestry, and scores were assessed only once at baseline, the authors said.

Epinephrine use for food allergies

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Newsline Potato consumption pre-pregnancy linked to diabetes

of potatoes with other vegetables, legumes, or whole grain foods might lower the risk.” The researchers followed a cohort of 15,632 women from the Nurses’ Health Study II from 1991 to 2001. More than 90% of the subjects were white. Over

Hepatitis C infections linked to risk of Parkinson disease PATIENTS INFECTED with hepatitis C virus (HCV) are at increased risk of developing Parkinson disease, according to research published online ahead of print December 23, 2015, in Neurology. Senior author Chia-Hung Kao, MD, and fellow investigators analyzed data from the Taiwan National Health Insurance Research Database between 2000 and 2010 on 199,868 people without a viral hepatitis infection and 49,967 patients infected with viral hepatitis (hepatitis B virus [HBV], 71%; HCV, 21%; both HBV and HCV, 8%). In Taiwan during the study period, blood transfusions were the most common cause of the hepatitis infection (in the United States, all donated blood has been screened for hepatitis since 1992). Over an average follow-up of 12 years, the researchers found that people with HCV infection were almost 30% more likely to develop Parkinson disease, when compared with those who were not infected with hepatitis. People infected with HBV or both HBV and HCV were not more or less likely to develop Parkinson disease than those who did not have hepatitis.

A high glycemic index is associated with potatoes.

10 years, there were 854 cases of gestational diabetes among 21,693 women with singleton pregnancies. The investigators found that women who consumed more potatoes before pregnancy had higher rates of developing gestational diabetes and that substituting two servings of potatoes with other vegetables, legumes, and whole grain foods each week was significantly associated with a 9% to 12% lower risk. The findings may be explained in part by the high glycemic index associated with potatoes, which can result in a sharp rise in blood sugar levels after consumption, according to the authors.

Tips for avoiding allergic reactions to nickel THE AMERICAN Academy of Dermatology (AAD) has posted a new video on ways to avoid and reduce symptoms of an allergic reaction to nickel to its website and YouTube channel as part of its “Video of the Month” series. The video, targeted at patients, offers the following tips: • Choose jewelry that is nickelfree, hypoallergenic, or made from surgical-grade stainless steel, 18-, 22-, or 24-karat yellow gold, pure sterling silver, or platinum. Wear watchbands made of leather, cloth, or plastic. • Replace belt buckles, bra hooks, and metal buttons, zippers, and snaps that contain nickel with ones that are plastic or plasticcoated. Coating these items with

clear nail polish can also work as a barrier against the skin, but the nail polish would need to be re-applied often. • Use a protective cover on electronic devices, as recent reports suggest that items such as cell phones, laptops, and tablets may contain nickel. • Use brass keys, titanium-coated or stainless steel razors, pots and pans with silicone handles, and titanium or plastic eyeglass frames instead of similar household objects containing nickel. • For those with an extremely sensitive allergic reaction, avoid foods containing nickel, such as soy products, licorice, buckwheat, cocoa powder, clams, cashews, and figs. n

EATING more potatoes, including French fries and potato chips, before pregnancy may be associated with greater risk of gestational diabetes mellitus, according to a study published online ahead of print January 12 in the British Medical Journal. Senior author Cuilin Zhang, MD, MPH, PhD, and fellow investigators suggested that patients who are trying to conceive may lower their risk of gestational diabetes by substituting potatoes with other foods. “Higher levels of potato consumption before pregnancy are associated with greater risk of gestational diabetes mellitus,” they wrote, “and substitution

24 THE CLINICAL ADVISOR • FEBRUARY 2016 • www.ClinicalAdvisor.com

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FEATURE: CHRISTY McDONALD LENAHAN, DNP, MSN, FNP-BC, AND DEEDRA HARRINGTON, DNP, MSN, APRN, ACNP-BC

Anticoagulant therapy for NV atrial fibrillation Multiple considerations come into play when choosing anticoagulant therapy for nonvalvular atrial fibrillation, a condition that increases the risk for stroke.

he American Heart Association estimates that atrial fibrillation (AF) affects approximately 2.7 million Americans.1 It is projected that cases of AF will increase to 12.1 million by the year 2030; however, there is much uncertainty within the magnitude of future trends in capturing diagnosis and morbidity of the sequela associated with AF.2 In addition to being the most common cardiac arrhythmia, AF is also classified as the most common rhythm disorder among adults aged older than 65 years living in the United States. Determining treatment for any individual with nonvalvular AF requires a balance between the risks and benefits of oral anticoagulation therapy. Individualized selection of an anticoagulant is based on stroke and bleeding risk, cost, interactions, likelihood of adherence to medication regimen, and individual patient preference related to lifestyle. Anticoagulation therapy for individuals who require more than aspirin therapy may include one of the three inhibitors of activated factor X (factor Xa), rivaroxaban, apixaban, or edoxaban; a direct thrombin inhibitor, dabigatran; or a vitaminK-dependent inhibitor, warfarin.3,4

Direct factor Xa inhibitors Colored angiogram of the brain of a 48-year-old patient after a massive stroke.

Direct factor Xa inhibitors cause selective inhibition of factor Xa, which aids in the formation of thrombin, therefore abetting the development of thrombosis.5 There are three oral direct factor Xa inhibitors approved by the US Food and Drug Administration (FDA) for www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2016 27

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ANTICOAGULANT THERAPY FOR NV ATRIAL FIBRILLATION

Perioperative care of a patient taking direct factor Xa inhibitors includes assessment of renal function 7 days prior to a scheduled procedure. the treatment of nonvalvular AF: rivaroxaban, apixaban, and edoxaban. Rivaroxaban. The recommended dosing of rivaroxaban is 20 mg daily taken with an evening meal if creatinine clearance (CrCl) is greater than 50 mL/min (Table 1).6 For patients with a CrCl between 15 and 50 mL/min, 15 mg daily taken with an evening meal is recommended.6 Rivaroxaban is not recommended for individuals with a CrCl less than 15 mL/min due to the decreased clearance of the drug through the kidneys.6 The drug should be withdrawn if the patient develops acute renal failure.6 Rivaroxaban’s plasma concentration is as high as 80% to 90%, with peak plasma levels 2 to 4 hours after dosing.6 It is primarily eliminated in the urine, approximately 36% unchanged.6 The half-life of rivaroxaban is about 5 to 9 hours.6 In individuals with renal impairment, clearance of the drug may differ. Patients with moderate to severe hepatic impairment, particularly those with coagulopathy concerns, should avoid rivaroxaban.6 Common reactions and side effects include bleeding, pruritus, and elevation of liver enzymes.5 Apixaban. The recommended dosing of apixaban is 5 mg twice daily (Table 1).7 In patients with at least two of the following characteristics, the recommended dose is 2.5 mg twice daily: age 80 years or older; body weight less than 60 kg; or serum creatinine level of 1.5 mg/dL or greater.7 Plasma protein binding of apixaban is approximately 87%; the drug has a half-life of 12 hours, and a peak effect is reached within 3 to 4 hours.7 Common side effects of apixaban include bleeding, anemia, nausea, skin rash, or a more serious allergic reaction.7

Edoxaban. Edoxaban is one of the newest Xa inhibitors that have been approved for treatment of nonvalvular AF. The recommended dose of this drug is 60 mg once daily for patients with a CrCl higher than 50 mL/min and no more than 95 mL/min; edoxaban is not recommended in patients with a CrCl higher than 95 mL/min (Table 1).8 For individuals with a CrCl of 15 to 50 mL/min, it is recommended to reduce the dose to 30 mg once daily.8 A plasma concentration of approximately 62% is observed in the peak onset period of 1 to 2 hours.8 Edoxaban is primarily excreted in the urine, and its half-life is 10 to 14 hours.8 The most common side effects are bleeding and anemia.8 Perioperative considerations. Perioperative care of a patient taking direct factor Xa inhibitors includes assessment of renal function 7 days prior to a scheduled procedure. For patients with a CrCl higher than 30 mL/min, procedures with a standard bleeding risk require that direct factor Xa inhibitors be discontinued 24 hours prior to the procedure and those with a high bleeding risk require that direct factor Xa inhibitors be discontinued 48 hours prior to the procedure (Table 2).6,7,9,10 If the patient has a CrCl of 30 mL/min or less, procedures with a standard bleeding risk require that direct factor Xa inhibitors be discontinued 48 hours prior and those with a high bleeding risk require that direct factor Xa inhibitors be discontinued 72 hours prior.6,7,9,10 After a procedure is completed, direct factor Xa inhibitors should be resumed as soon as possible, typically 12 to 24 hours after a minor procedure or 48 to 72 hours after a major procedure.6,7,9,10 In most patients taking direct

TABLE 1. Dosing for anticoagulant therapy in the treatment of nonvalvular atrial fibrillation Direct thrombin inhibitors

Vitamin K inhibitors

EDOXABAN

DABIGATRAN

WARFARIN

Direct factor Xa inhibitors Renal function

RIVAROXABAN

APIXABAN

Normal/mild impairment

20 mg daily with evening meal 5 mg twice daily (CrCl > 50 mL/min)

60 mg daily (CrCl > 50 mL/min)

150 mg twice daily (CrCl > 30 mL/min)

Dose adjusted for INR 2.0-3.0

Moderate impairment

15 mg daily with evening meal 2.5 mg twice dailya (CrCl, 15-50 mL/min)

30 mg daily (CrCl, 15-50 mL/min)

75 mg twice daily (CrCl, 15-30 mL/min)

Dose adjusted for INR 2.0-3.0

Severe impairment

Not recommended (CrCl < 15 mL/min)

Dose adjusted for INR 2.0-3.0

No recommendation

CrCl, creatinine clearance; INR, international normalized ratio. a Apixaban should be dosed at 2.5 mg twice daily if the patient meets two of the following three criteria: 1) age > 80 years; 2) body weight < 60 kg; or 3) serum creatinine > 1.5 mg/dL.

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Direct thrombin inhibitors prevent the conversion of fibrinogen into fibrin during the coagulation cascade and ultimately prevent a thrombus. factor Xa inhibitors, preoperative parenteral anticoagulation is not necessary.6,7,10 Hepatic or renal impairment. Typically, direct factor Xa inhibitors are metabolized in the kidney (approximately 25%–35%) and liver.5 Severe hepatic impairment could potentially result in accumulation of these agents to toxic levels.5 None of the Xa inhibitors have any known reversal agents at this time. There are also no current guidelines for monitoring of any of the Xa inhibitors, but there is a recommendation for prompt evaluation with any signs and symptoms of a drop in hematocrit and hemoglobin levels.6 Direct thrombin inhibitors

Direct thrombin inhibitors prevent the conversion of fibrinogen into fibrin during the coagulation cascade and ultimately prevent the development of a thrombus.11 Dabigatran etexilate was the first direct thrombin inhibitor approved by the FDA to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF, in October 2010.12 The recommended dosing of dabigatran etexilate is 150 mg orally taken twice daily if CrCl is greater than 30 mL/min (Table 1).13 For patients with a CrCl of 15 mL/min to 30 mL/min, the recommended dosage is 75 mg taken orally twice daily.13 There are no recommendations for patients with a CrCl less than 15 mL/min.13 Plasma concentrations of dabigatran etexilate peak at 1 to 3 hours; the drug has a half-life of 8 hours after a single dose and 12 to 14 hours after multiple doses.11,14 It is metabolized by the liver and excreted by the kidneys.11

Clearance of dabigatran etexilate is dependent on time and renal function. For patients with a CrCl of 50 mL/min or greater, the drug should be discontinued 24 hours prior to any procedure with a standard risk of bleeding and 48 hours prior to any procedure with high risk of bleeding.11 If a patient’s CrCl is higher than 30 mL/min but lower than 50 mL/min, discontinuation of the drug should occur 48 hours before procedures with a standard risk of bleeding and 4 days before procedures with a high risk of bleeding.11 Finally, for patients with a CrCl that is less than 30 mL/ min, discontinuation should occur 2 to 5 days before a procedure with a standard risk of bleeding and more than 5 days before a procedure with a high risk of bleeding.11 It should be noted that an antidote, idarucizumab, has recently been submitted for approval by the FDA for use in patients who require rapid reversal of the dabigatran etexilate.15 The most commonly reported serious adverse effect associated with dabigatran etexilate use is bleeding; however, heart attack, liver failure, and death have also been reported.16 There are no current recommendations by the FDA concerning monitoring of dabigatran etexilate, but some studies have suggested monitoring levels could decrease major bleeding risks by as much as 40%.17 Vitamin K inhibitors

Vitamin K inhibitors interfere with the cyclic interconversion of vitamin K, thereby inhibiting factors II, VII, IX, and X (procoagulants), as well as impairing proteins C and S, which are natural inhibitors of coagulation.18,19 Before the development of new oral anticoagulants (NOACs) that are not

TABLE 2. Perioperative considerations in anticoagulant treatment of nonvalvular atrial fibrillationa Direct factor Xa inhibitors

Direct thrombin inhibitors

STANDARD RISK OF BLEEDING

HIGH RISK OF BLEEDING

STANDARD RISK OF BLEEDING

HIGH RISK OF BLEEDING

> 50 mL/min

Discontinue 24 h prior to procedure

Discontinue 48 h prior to procedure

Discontinue 24 h prior to procedure

Discontinue 48 h prior to procedure

30–50 mL/min

Discontinue 24 h prior to procedure

Discontinue 48 h prior to procedure

Discontinue 4 d prior to procedure

< 30 mL/min

Discontinue 48 h prior to procedure

Discontinue 72 h prior to procedure

Discontinue 5 d prior to procedure

Discontinue > 5 d prior to procedure

Creatinine clearance

Warfarin is not included in this table but should be discontinued 5 to 6 days before a procedure. Consider bridge therapy in patients who are at high risk for developing blood clots.

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ANTICOAGULANT THERAPY FOR NV ATRIAL FIBRILLATION

Clinicians are advised to consider a patient's risk for bleeding and stroke and current medication regimen before prescribing any anticoagulant. vitamin K antagonists, warfarin was the only available oral anticoagulant option.20 Despite the availability of NOACs, use of warfarin for thromboembolic prevention in patients with nonvalvular AF continues to be prevalent worldwide.21 Warfarin levels are monitored by prothrombin times (PTs) and international normalized ratios (INRs). Ideal INR levels for patients with nonvalvular AF should be maintained between 2.0 and 3.0 (Table 1).22 INR level should be checked 2 to 3 days after initiation of treatment and should continue every 2 to 3 days until two consecutive INR checks fall within therapeutic range.23 Once this occurs the clinician may check the INR once every week until another two consecutive INR checks fall within therapeutic range.23 At this point, clinicians may then check INR levels once every 2 weeks until two consecutive INR checks fall within therapeutic range and then reduce to once every 4 weeks for continued monitoring.23 Any INR level that falls below 2.0 results in increased thrombosis risk, whereas any INR level that rises above 4.0 increases risk of serious bleeding.22 Warfarin can cause several adverse effects, but bleeding is the most serious. Clinicians should be prudent in assessing a patient’s risk for bleeding prior to prescribing warfarin. Many tools are available to assess a patient’s risk of bleeding; however, the HAS-BLED (Hypertension, Abnormal renal or liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly) tool has demonstrated more efficiency in predicting bleeding risk.24 Use of the HAS-BLED score requires the clinician to assign

POLL POSITION

For anticoagulation therapy in patients with nonvalvular AF who require more than aspirin, your first recommendation is: n=392

■ Rivaroxaban, apixaban, or edoxaban

33.67% 57.14%

■ Dabigatran ■ Warfarin 9.18%

For more polls, visit ClinicalAdvisor.com/Polls.

1 point for each risk factor described by the acronym.24 Scores of 3 or higher indicate an increased risk of bleeding, and clinicians should make every attempt to modify risk factors prior to beginning therapy in these patients.24 Should a patient on warfarin have serious bleeding, packed erythrocytes and fresh frozen plasma may be needed to stabilize the patient immediately.25 Vitamin K1 should also be given because it is the only effective antidote, but anticoagulation reversal may take several hours.25 For patients who are scheduled for surgery, warfarin therapy should be discontinued 5 to 6 days before the procedure.26 In patients who are at high risk for developing blood clots, the clinician may consider the use of bridge therapy. In bridge therapy, patients are usually prescribed a low–molecular-weight heparin starting 3 days before surgery with the last of these doses ending 24 hours before the procedure and beginning again 24 hours or more after surgery for 4 to 6 days; it is given concomitantly with warfarin until therapeutic levels of warfarin have been reached.26 Additional considerations in warfarin therapy include dietary intake, use of dietary supplements, and use of certain antibiotics. Patients should be made aware of foods rich in vitamin K and be informed that they may decrease the effect of warfarin.27 Rather than avoid these foods, patients should be advised not to make any drastic changes in current dietary habits, especially those that involve foods rich in vitamin K.27 Several dietary supplements, including ginger, gingko, St. John’s Wort, and vitamin E, can affect PT and INR levels, and potentially increase a patient’s risk of bleeding.27 The safest policy is to advise patients to avoid supplements unless they are absolutely necessary.27 Some antibiotics may interfere with the pharmacodynamics of warfarin; thus, clinicians should always be aware of a patient’s current medications.27 Conclusion

Although there are several medications available for nonvalvular AF, treatment should be tailored to the individual. The clinician should take into consideration a patient’s risk for bleeding and stroke and current medication regimen prior to prescribing any anticoagulant. Important socioeconomic factors, including a patient’s ability to pay for certain medications, a patient’s ability to adhere to potentially complicated medication regimens, and/or individual Continues on page 35

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ANTICOAGULANT THERAPY FOR NV ATRIAL FIBRILLATION

patient preference should also be taken into consideration when prescribing anticoagulant therapy. The number of individuals with nonvalvular AF is growing, and clinicians should make every effort to be familiar with the benefits and challenges of available treatments. n

press_releases/press_release_archive/2010/october_20_2010.html. Published October 19, 2010. 13. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2010. 14. Lee CJ, Ansell JE. Direct thrombin inhibitors. Br J Clin Pharmacol. 2011;72(4):581-592.

Christy McDonald Lenahan, DNP, MSN, FNP-BC, and Deedra Harrington, DNP, MSN, APRN, ACNP-BC, are assistant professors with the College of Nursing and Allied Health Professions of the University of Louisiana at Lafayette.

15. Boehringer Ingelheim submits applications for approval of idarucizumab*, specific reversal agent to dabigatran etexilate (Pradaxa®), to EMA, FDA and Health Canada. Boehringer-Ingelheim website. https://www. boehringer-ingelheim.com/news/news_releases/press_releases/2015/03_ march_2015_dabigatranetexilate.html. Published March 3, 2015.

References

16. Pradaxa. Drugwatch website. http://www.drugwatch.com/pradaxa.

1. Go AS, Mozaffarian D, Roger VL, et al; American Heart Association

Updated October 16, 2015.

Statistics Committee and Stroke Statistics Subcommittee. Heart disease

17. Phend C. Monitoring, dose adjustment for Pradaxa. MedPage Today

and stroke statistics—2014 update: a report from the American Heart

website. http://www.medpagetoday.com/Cardiology/Arrhythmias/46901.

Association. Circulation. 2014;129(3):e28-e292.

Published July 23, 2014.

2. Colilla S, Crow A, Petkun W, et al. Estimates of current and future

18. Hirsh J, Fuster V, Ansell J, et al. American Heart Association/American

incidence and prevalence of atrial fibrillation in the US adult population.

College of Cardiology Foundation guide to warfarin therapy. Circulation.

Am J Cardiol. 2013;112(8):1142-1147.

2003;107(12):1692-1711.

3. January CT, Wann LS, Alpert JS, et al; American College of Cardiology/

19. Hull RD, Garcia DA. Therapeutic use of warfarin and other vitamin K antag-

American Heart Association Task Force on Practice Guidelines. 2014

onists. UpToDate website. http://www.uptodate.com/contents/therapeutic-use-

AHA/ACC/HRS guideline for the management of patients with atrial fibril-

of-warfarin-and-other-vitamin-k-antagonists. Updated November 17, 2015.

lation: a report of the American College of Cardiology/American Heart

20. Wigle P, Hein B, Bloomfield HE, et al. Updated guidelines in outpatient

Association Task Force on Practice Guidelines and the Heart Rhythm

anticoagulation. Am Fam Physician. 2013;87(8):556-566.

Society. J Am Coll Cardiol. 2014; 64(21):e1-e76.

21. Agarwal S, Hachamovitch R, Menon V. Current trial-associated out-

4. Berry E, Padgett H. Management of patients with atrial fibrillation:

comes with warfarin in prevention of stroke in patients with nonvalvular

diagnosis and treatment. Nurs Stand. 2012;26(22):47-56.

atrial fibrillation: a meta-analysis. Arch Intern Med. 2012;172(8):623-631.

5. Lehne RA. Anticoagulant, antiplatelet, and thrombolytic drugs. In: Lehne

22. Warfarin. CARE Clinical Research website. https://www.careinternet.

RA, ed. Pharmacology for Nursing Care. 8th ed. St. Louis, MO: Elsevier

net/caregiver/warfarin.php. Updated May 20, 2015.

Saunders; 2013:631-661.

23. Warfarin management CPG—ambulatory appendix A: warfarin man-

6. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2011.

agement dosing tool—adult—ambulatory. UWHealth website. http://

7. Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2012.

www.uwhealth.org/files/uwhealth/docs/pdf3/Warfarin_Dosing_Protocol.

8. Savaysa [package insert]. Parsippany, NJ: Daiichi Sankyo, Inc.; 2015.

pdf. Published April 17, 2014.

9. Douketis JD, Spyropoulos AC, Spencer FA, et al; American College of

24. Lane DA, Lip GY. Use of the CHA(2)DS(2)-VASc and HAS-BLED

Chest Physicians. Perioperative management of antithrombotic therapy:

scores to aid decision making for thromboprophylaxis in nonvalvular atrial

Antithrombotic therapy and prevention of thrombosis, 9th ed: American

fibrillation. Circulation. 2012;126(7):860-865.

College of Chest Physicians evidence-based clinical practice guidelines.

25. Olson KR. Warfarin and superwarfarin toxicity medication. Medscape

Chest. 2012;141(2 Suppl):e326S-e350S.

website. http://emedicine.medscape.com/article/821038-medication.

10. Ageno W, Gallus AS, Wittkowsky A, et al; American College of

Updated December 10, 2014.

Chest Physicians. Oral anticoagulant therapy: Antithrombotic therapy

26. BRIDGE Study Investigators. Bridging anticoagulation: is it needed

and prevention of thrombosis, 9th ed: American College of Chest

when warfarin is interrupted around the time of a surgery or procedure?

Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2

Circulation. 2012;125(12):e496-e498.

Suppl):e44S-e88S.

27. Important information to know when you are taking: warfarin

11. Hankey GJ, Eikelboom JW. Dabigatran etexilate: a new oral thrombin

(coumadin) and vitamin K. National Institutes of Health website. http://

inhibitor. Circulation. 2011;123(13):1436-1450.

www.cc.nih.gov/ccc/patient_education/drug_nutrient/coumadin1.pdf.

12. FDA approves Pradaxa, marking a major milestone to reduce the

Published September 5, 2012.

risk of stroke in patients with nonvalvular atrial fibrillation. BoehringerIngelheim website. http://us.boehringer-ingelheim.com/news_events/

All electronic documents accessed January 7, 2016.

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CME CE FEATURED COURSE

n LEARNING OBJECTIVES After completing the activity, the participant should be better able to: • Discuss the current epidemiology of HCV infection in the United States and relate it to applicable screening recommendations. • Describe the natural history and course of HCV infection to include acute and subacute presentations leading ultimately to chronic liver failure. • Assess the laboratory and imaging studies used for the diagnosis of hepatitis C and delineate the abnormalities expected in chronic HCV infection. n COMPLETE THE POSTTEST: Page 44 n ADDITIONAL CME/CE CREDIT: Page 52, 57, 61

This activity is provided by Haymarket Medical Education (HME) for physician credit. This activity is jointly provided by Global Education Group and HME for nursing contact hours. Release Date: February 15, 2016 Expiration Date: February 15, 2017 Estimated time to complete the educational activity: 30 minutes Statement of Need: Primary care providers need to be aware of the recent breakthroughs in the management of HCV infection. This feature provides an update on evidence-based practices in the screening, diagnosis, and analysis of laboratory parameters, as well as research and modern therapeutics. Target Audience: This activity has been designed to meet the educational needs of primary care health care professionals who will treat patients with hepatitis C. Faculty Rebecca Wong St. John's University, Queens,, N.Y. Cynthia Russell, PA-C Arya Gastroenterology, Brooklyn, N.Y. Danielle Kruger, PA-C, MSED St. John's University, New York, N.Y. Accreditation Statements Physician Credit: HME is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Credit Designation: HME designates this enduring material for a maximum of 0.5 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nursing Credit: Global Education Group is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s COA. Credit Designation: This educational activity for 0.5 contact hours is provided by Global Education Group. Nurses should claim only the credit commensurate with the extent of their participation in the activity. American Academy of Physician Assistants (AAPA) The AAPA accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 0.5 hour of Category I credit for completing this program. Disclosure Policy In accordance with the ACCME Standards for Commercial Support, HME requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. HME resolves all conflicts of interest in an effort to ensure independence, objectivity, balance, and scientific rigor in all its educational programs. Furthermore, HME seeks to verify that all scientific research referred to, reported, or used in a CME/CE activity conforms to the generally accepted standards of experimental design, data collection, and analysis. HME is committed to providing its learners with high-quality CME/CE activities that promote improvements in health care and not those of a commercial interest.

HepatitisC_CME-feature_CA0216.indd 36

The faculty reported the following financial relationships with commercial interests whose products or services may be related to the content of this CME activity: Faculty Disclosures

Name of faculty

Reported Financial Relationship

Rebecca Wong

No relevant financial relationships

Cynthia Russell, PA-C

No relevant financial relationships

Danielle Kruger, PA-C, MSED

No relevant financial relationships

Staff/Planners’ Disclosures The planners, managers, and reviewers for this program reported the following financial relationships with commercial interests whose products or services may be related to the content of this CME activity: HME planners, managers, and reviewers have no relevant financial relationships to disclose. Global Education Group planners: Ashley Marostica, RN, MSN, Amanda Glazar, PhD, and Andrea Funk have nothing to disclose. Disclosure of Unlabeled Use: This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. HME and Global Education Group do not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Method of Participation: There are no fees for participating in and receiving CME/CE credit for this activity. During the period of February 15, 2016, through February 15, 2017, participants must: 1) read the learning objectives and faculty disclosures; 2) study the educational activity; 3) complete the posttest and submit it online (clinicians may register at www.myCME.com); and 4) complete the evaluation form online. A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed posttest with a score of 70% or better. Disclaimer: The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of HME or Global Education Group. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. The information presented in this activity is not meant to serve as a guideline for patient management.

1/28/16 5:09 PM

CME CE FEATURED COURSE: REBECCA WONG; CYNTHIA RUSSELL, PA-C; DANIELLE KRUGER, PA-C, MSED

Hepatitis C virus infection: signs, symptoms, and screening Educating and testing high-risk populations are crucial steps in the effort to stem hepatitis C virus infections.

n the wake of recent breakthroughs in the management of hepatitis C virus (HCV) infection, with several new promising medications available on the market and more being studied in clinical trials, it may now be possible to imagine a cure for this disease. Barriers and challenges, such as difficulty in reaching high-risk populations, the stigma of the disease, provider reluctance to assess risk factors, and patient reluctance to admit high-risk behaviors, may delay the identification of persons infected with HCV.1 Communication between healthcare providers and patients, including promoting awareness of HCV infection and emphasizing the screening of high-risk populations, is crucial in diagnosis. This article discusses the current epidemiology, risk factors, pathophysiology, diagnosis, management, and prognosis of HCV infection.

Epidemiology and risk factors

About 3.2 million people have chronic HCV infection, and more than half are unaware of their condition.

According to the World Health Organization (WHO), approximately 3% of the world’s population is infected with HCV, and more than 170 million chronic carriers are at risk for liver cirrhosis and hepatocellular carcinoma, which are complications of HCV infection.2 In the United States, approximately 30,000 new cases of HCV infection develop yearly; about 3.2 million individuals have chronic HCV infection, and an estimated 50% to 70% of them are unaware of their condition.1,3 Chronic HCV infection is the leading cause of liver-related death and reason for liver transplant in the United States, and it has recently eclipsed

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CME CE

FEATURED COURSE

TABLE 1. Risk factors for hepatitis C virus infection7 Blood product transfusion or solid organ transplant before 1992; hemophilia with receipt of factor concentrates made before 1987

In the 1970s and 1980s, the receipt of HCV-infected blood products or organs accounted for nearly 50% of new cases of HCV infection, but after the introduction of blood-screening tests in the early 1990s, the number of cases caused by infected blood products or organs dramatically declined.

Hemodialysis

The overall prevalence of HCV infection among patients receiving hemodialysis is 8%, nearly 5-fold higher than that in the general population, likely resulting from inadequate infection control practices.

Injection drug use

This is the most common risk factor for acquiring HCV infection in the United States, accounting for more than 50% of cases. A recent study cites this risk factor in 84% of patients with a diagnosis of acute HCV infection; from 20% to 30% became infected during their first 2 years of drug use, and the risk was greatest when needles were directly shared or drug paraphernalia was indirectly shared.

Male-to-male sex or other highrisk sexual activity

Up to 15% of cases in the United States are linked to sexual risk factors, but many of these cases also involve injection drug use. In 4 large prospective studies, long-term monogamous heterosexual couples had a 0.07% risk for sexual transmission. Most cases of HCV infection involve unprotected receptive anal intercourse with ejaculation or a high number of sexual contacts.

Vertical fetal transmission

About 5% of chronically HCV-infected pregnant women transmit HCV to the fetus; the risk is highest in women with detectable HCV-RNA during pregnancy and particularly at birth. Mothers co-infected with HIV and HCV have a 2-fold increased risk for transmitting HCV to the fetus. The risk for transmission during breastfeeding is negligible.

HCV, hepatitis C virus; HIV, human immunodeficiency virus.

human immunodeficiency virus (HIV) infection as a cause of death.4 The HCV infection mortality rate is 4.58 per 100,000 people per year, and almost 75% of deaths occur among adults aged 45 to 64 years. In the Third National Health and Nutrition Examination Survey (NHANES III), neither gender nor race/ethnicity was independently associated with HCV infection.2 There is considerable variation in the geographical distribution of the 6 HCV genotypes. Genotype 1 accounts for approximately 70% and genotypes 2 and 3 for approximately 30% of the HCV-infected population in the United States.5 Genotype 4 is typically found in Africa and the Middle East and is rare in the United States. Genotypes 5 and 6 are mostly confined to South Africa and Southeast Asia, respectively.6 Genotype is not a predictor of outcome but is important in selecting a genotype-specific therapeutic regimen, determining the duration of treatment, and predicting the likelihood of a response to treatment.5 The transmission of HCV in infected blood or body fluids via the parenteral route is associated with multiple risk factors (Table 1). Additional risk factors include intranasal cocaine use, body tattooing or piercing with unsterilized equipment, occupational exposure (eg, healthcare workers), and household exposure (eg, sharing razors or toothbrushes). Recent reports highlight a new cohort of injection drug users with HCV infection: white, urban dwellers aged 24 years or younger who have used oral prescription opiates before heroin.7 Patients who are HIV-positive are also at risk for HCV transmission, as the risks for transmitting HCV and HIV are identical. Many HCV-positive patients are unable to identify a source of infection.

Pathophysiology

HCV is a single-stranded, 9,600–base pair RNA virus of the family Flaviviridae. Its genome encodes a single polyprotein of 3,011 amino acids that are processed into 10 structural and regulatory proteins.2 HCV consists of a core protein and 2 envelope proteins (E1 and E2). In 2 regions on E2, there is a very high rate of mutation attributable to selective pressure by virus-specific antibodies.The nonstructural components consist of NS2, NS3, NS4A, NS4B, NS5A, NS5B, and p7.Their proteins function as helicase-, protease-, and RNA-dependent RNA polymerase. NS5A has an interferon sensitivity–determining region (Figure 1). These enzymes are all critical to the replication process of HCV and are promising targets for future antiviral therapy.2 Unlike HIV or HBV, HCV replicates its genome directly into RNA without a DNA intermediate, so it lacks a latent, nuclear form that defies ready immunological clearance. In order for the virus to exist, it must continuously replicate and may produce more than 10 trillion new viral particles daily.2,4 HCV is not cytopathic, and liver damage is mainly the result of immune-mediated responses. The mechanisms responsible for chronicity and liver lesions in HCV infection are not well understood. CD4+ T cells and their cytokines with inflammatory and regulatory activities may have an important function in the immunopathogenesis of chronic HCV infection. Responses of CD4+ T cells are polarized into type 1 and type 2 helper T-cell (Th1 and Th2) responses. Th1 cells secrete interleukin 2 (IL-2) and interferon gamma, which are important for the initiation of host antiviral immune responses comprising cytotoxic T-lymphocyte (CTL) generation and natural killer (NK)–cell activation. IL-4 and IL-10, produced by Th2 cells, boost the production of antibodies and downregulate the Th1 response.

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FIGURE 1. Schematic diagram of the hepatitis C virus (HCV) genome.12

5’ UTR

Protease cofactor

NS2 p7

NS4B

7601

6258

5313 5477

NS3

NS5A

NS4A

Structural proteins

9375

RNA-dependent RNA polymerase

Helicase

3420

2580 2769

1491

Envelope

915

342

Core

NS2/3 Protease

Serine protease

NS5B 3’ XR

Nonstructural proteins

The location of HCV genes (C, core; E1/2, envelope; NS2/3/4A/4B/5A/5B, nonstructural), proposed functions of gene products, and 5' and 3' untranslated regions (5' UTR and 3' XR) are shown. Numbering refers to the nucleotide portions of genes.

Disease progression and the inability to clear HCV infection may result from an imbalance between Th1 and Th2 responses. Patients who clear HCV virus develop a strong Th1 response with a weak or absent Th2 response. Patients who develop chronic HCV infection have a weak Th1 response but a strong Th2 response. Likely, the effect of Th1 cytokines is essential for protection against HCV infection, whereas Th2 cytokines may play a role in inhibiting the host immune system and contribute to the chronicity of the infection.8 The marked nucleotide variability and genetic heterogeneity of HCV (variability between different isolates of 1% to 50%, at least 6 different genotypes, and more than 90 subtypes8) also contribute to its ability to escape the host immune response. Within a genotype, different isolates can vary by 5% to 15%, and virions isolated from a single individual may differ by 1% to 5% owing to RNA-dependent RNA polymerase.6 This replication enzyme lacks proofreading capabilities and creates large quantities of mutant virus, a phenomenon termed quasispecies diversity, which may support virus chronicity.2,5,6 Prior infection with HCV does not protect against later infection with HCV of the same or a different genotype. Chronicity

The pathophysiological profile of HCV infection translates into infrequent recovery from acute infection, lack of immunization, and the rapid development of drug resistance.5,8 The rate of spontaneous clearance varies according to the virus, age of the individual at onset of infection, and other factors; approximately 15% to 25% of patients clear the virus without therapy during the first 6 months of infection. In the remaining 75% to 85%, chronic hepatitis develops (Table 2).7

Although gradual histological progression occurs, the condition is often asymptomatic over a 20- to 30-year period until the complications of advanced liver disease or cirrhosis develop.7 Persistent viremia causes variable degrees of hepatic inflammation and fibrosis, including histological changes of micro- or macrovesicular steatosis, bile duct injury, and lymphocytic follicles.9 Bridging fibrosis and regenerative nodules significantly distort the normal hepatic architecture and result in cirrhosis. In chronic HCV infection, a minimum of 50% of hepatocytes may be infected.2 Clinical manifestations

Asymptomatic disease and early progression. The progression of HCV infection to cirrhosis is often asymptomatic and clinically silent. In chronic hepatitis, the correlation of biochemical liver function test (LFT) values and virological markers with clinical manifestations and progression is poor.10 Patients may report nonspecific fatigue, anorexia, myalgia and arthralgia, symptoms of upper respiratory infection, nausea, intolerance to alcohol and fatty food, right upper quadrant abdominal pain, fever, jaundice, or night sweats. Of all the etiologic agents of viral hepatitis, HCV is the one most likely to remain subclinical. Symptoms in early progression are highly variable, and the most common presentation is either no abnormality or mild hepatomegaly.10 Patients report that their disease affects parameters of quality of life in general: mental health perception, physical and social function, and vitality. Successful clearance of HCV improves scores.10 Progression to advanced liver disease. In 15% to 20% of patients in whom chronic HCV infection develops, cirrhosis occurs within 15 to 40 years after the original infection. Among

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TABLE 2. Risk factors for the development of chronic hepatitis C virus infection7 African American race Age older than 25 years at onset of infection HIV infection or immunosuppressed condition Male gender Subclinical infection HIV, human immunodeficiency virus.

TABLE 3. Risk factors for progression of liver disease in persons with hepatitis C virus infection10 Age older than 40 years at acquisition Co-infection with HIV or HBV Heavy alcohol intake Longer duration of infection Male gender Moderate-to-severe hepatic fibrosis on baseline biopsy Obesity HBV, hepatitis B virus; HIV, human immunodeficiency virus.

TABLE 4. Differential diagnosis of liver disease and relevant laboratory tests Disease

Laboratory tests

HBV infection

HBsAg, anti-HBs, HBcAg, IgM anti-HBc, HBV-DNA

HIV infection

ELISA

Alpha1-antitrypsin deficiency

$ Alpha1-antitrypsin levels

Hemochromatosis

# Ferritin, glucose, transferrin saturation; $ FSH, LH; liver biopsy for stainable iron

Wilson disease

Liver biopsy for copper measurement, $ serum ceruloplasmin

Autoimmune hepatitis

ANA, anti-smooth muscle antibody, antimicrosomal antibody, hypergammaglobulinemia

Portal hypertension, $ Platelet count hypersplenism Hepatocellular carcinoma

# AFP

AFP, alpha fetoprotein; ANA, antinuclear antibody; anti-HBs, antibody to hepatitis B surface antigen; ELISA, enzyme-linked immunosorbent assay; FSH, follicle-stimulating hormone; HBcAg, hepatitis B core antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HIV, human immunodeficiency virus; IgM anti-HBc, immunoglobulin M antibody to hepatitis B core antigen; LH, luteinizing hormone.

those with cirrhosis, liver failure occurs in 20% to 30% and hepatocellular carcinoma in 10% to 15% over 10 years (Table 3).10 Manifestations of cirrhosis are consistent with a lack of hepatic synthetic function and include the following: hypoalbuminemia with subsequent edema, ascites, and fluid retention; increased lethargy; and coagulopathy due to decreased clotting factor production. Patients report malaise, anorexia, nausea, vomiting, and generalized pruritus resulting from bile salt irritation of the peripheral nerves. The liver may be enlarged or decreased in size with nodularity. In addition, derangement of the hepatic metabolism results in mixed hyperbilirubinemia with jaundice and increased estrogen levels, with resulting palmar erythema, spider nevi, gynecomastia, and testicular atrophy. Cirrhosis is the most common cause of portal hypertension, which leads to varices and hepatosplenomegaly. Complications of advanced liver disease and failure, which herald a poor prognosis, include spontaneous bacterial peritonitis, hepatic encephalopathy, variceal bleeding, hepatorenal syndrome, and hepatocellular carcinoma.10 Hepatic encephalopathy should be expected in a patient with a reversal of diurnal sleep patterns, forgetfulness, or inappropriate behavior. Extrahepatic manifestations. At least one extrahepatic manifestation develops in approximately 40% to 74% of patients with chronic HCV infection, most commonly affecting the skin, joints, kidneys, and nervous system.2,9,10,11 It is imperative for clinicians to consider the potential range of associated disease processes in HCV infection, particularly because there may not be any obvious manifestations of chronic liver disease in these patients.9 Awareness will facilitate a more prompt diagnosis and timely treatment. The disorder most commonly associated with HCV infection is mixed cryoglobulinemia (MC), which is a pathophysiological predecessor of many other associated disorders. HCV infection is present in 50% to 100% of patients with MC, and 10% to 50% of patients with HCV infection develop MC.9 HCV causes the chronic stimulation of lymphocytes, which induces the clonal expansion of B cells and the production of antibodies.9,11 In MC, polyclonal immunoglobulins, which are bound to complement and immune complexes containing HCV, reversibly precipitate in the serum at temperatures below 37°C. These complex immune protein particles deposit in small and medium-size blood vessels, causing vasculitis; they also deposit in other organs, including the skin, kidneys, and peripheral nerves. A variety of disorders seen in chronic HCV infection are related to MC, such as leukocytoclastic vasculitis with palpable purpura, peripheral neuropathies including mononeuritis multiplex, renal disease (27%–60%9,11) and nephrotic syndrome, sicca syndrome, and non-Hodgkin lymphoma9,11;

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however, these conditions may also occur in HCV infection in the absence of MC. MC is diagnosed through history and the presence of the following: palpable purpura/organ involvement, low levels of complement, circulating cryoglobulins and rheumatoid factor, and vasculitis on histology.9,11 Membranoproliferative glomerulonephritis (MPGN) is the most common HCV-related nephropathy, resulting from the deposition of cryoglobulins in the mesangium and glomerular capillaries. Porphyria cutanea tarda and lichen planus are two skin disorders strongly associated with HCV infection. In 40% to 65% of patients with HCV-infection, HCVmediated B-cell clonal expansion results in the production of antibodies associated with autoimmune disorders. These include the following: antinuclear antibody (ANA); rheumatoid factor (RF); anticardiolipin; anti-smooth muscle; anti-liver, kidney, and microsomal antibodies; anti-thyroid peroxidase; and anti-mitochondrial and/or anti–double-stranded DNA.11,12 In a consideration of autoimmune disorders as the cause of extrahepatic manifestations of HCV infection, it should be noted that the titers of these antibodies will be low, there is no gender predominance, and there is no association with specific HLA-DR genes.11 Arthralgia, fatigue, and fibromyalgia are more common in patients with HCV infection. Diagnosis and differential diagnosis

The Centers for Disease Control (CDC) recommends screening for exposure with HCV antibody (anti-HCV) and follow-up with HCV-RNA testing. About 70% to 86% of patients with positive results of anti-HCV testing are subsequently determined to be chronically infected with HCV.1 All adults born from 1945 through 1965 should be tested once regardless of risk factor status, and anti-HCV testing is also recommended for any patient with persistently high alanine aminotransferase levels or the recognized exposures/ risk factors highlighted previously. Anti-HCV test results will be positive a few weeks following the exposing event; window periods may last up to 6 months. A positive antiHCV test result does not distinguish patients who have cleared the virus from those with chronic infection. HCV recombinant immunoblot assay (RIBA) is an additional test that is highly specific for confirming the presence of anti-HCV antibodies. This test confirms exposure to HCV (positive RIBA) or a false-positive anti-HCV screen (negative RIBA). Polymerase chain reaction (PCR) is used to detect HCV-RNA; the result can be reported as a qualitative level (detects the presence of HCV), which can be used to distinguish someone with chronic HCV infection from a person who has cleared HCV either spontaneously or during treatment, or as a

quantitative level (measures the viral load). Patients who have cleared the virus will continue to have positive results of the anti-HCV test and RIBA but will be negative for HCV-RNA. Additional laboratory investigations may be indicated based on clinical assessment to rule out various entities in the differential diagnosis (Table 4). Abdominal ultrasound may be used to assess the liver, gallbladder, and biliary tree and to screen for hepatocellular carcinoma or ascites, but a normal ultrasound result does not rule out cirrhosis. A triple-phase helical computed tomographic scan of the liver with contrast improves the detection of hepatomas smaller than 3 cm in diameter. Liver biopsy is no longer required before treatment of HCV infection with pegylated interferon and ribavirin but does remain the definitive test for staging liver disease and is still important

Case Study A 47-year-old African-American man presents to the clinic for follow-up of elevated liver function test results. He was seen in the clinic 1 week earlier with persistent malaise, fatigue, and joint pain of 1 to 2 months’ duration. On abdominal examination, he is found to have mild right upper quadrant tenderness, and the liver edge is palpable 1 cm below the right costophrenic margin. There is no splenomegaly, rash, or jaundice. The remainder of the examination is noncontributory. The patient reports some illicit intravenous drug use more than 20 years ago and states that he used to drink alcohol but stopped more than 15 years ago. He is taking no medications and has no other past medical or family history. The remainder of the review of symptoms is normal. His laboratory values are as follows: • CBC and serum electrolytes: within normal limits • AST, ALT: 2.5 times the upper limit of normal • HCV-RNA: 5.8-log10 copies/mL (equivalent to 630,957 copies/mL) • HCV genotype 1a • Albumin: 4.2 g/dL • Total bilirubin: 1.1 mg/dL • Alpha fetoprotein: within normal limits • HIV antibody screen: negative The result of an abdominal ultrasound is normal. After consultation with a gastroenterologist, the patient is determined to be naïve to treatment, non-cirrhotic with an HCV PCR count of under 6 million, therefore the patient is managed on Harvoni (ledipasvir, 90 mg + sofosbuvir, 400 mg) for 8 weeks and achieves an SVR.

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TABLE 5. Pharmacological therapy for chronic hepatitis C virus infection16 Drug

Mechanism of action Notes

Adverse drug reactions

Peginterferon Synthetic interferon alfa-2a alfa assists in cellular (Pegasys, Genentech) communication (ie, blocks viral protein/ RNA synthesis, enhances immune response and antigen removal)

• In persons >5 years, treats genotypes 1, 4, 5, and 6 • Used in combination with ribavirin alone, ribavirin and simeprevir, or with ribavirin and sofosbuvir depending on genotype and other factors • Dose adjustments for renal impairment • Contraindicated in autoimmune hepatitis • Psychiatric evaluation in patient with depression or mood disorder • Pregnancy category C

• Most common side effects: fatigue, weakness, fever, myalgia, headache (40%) • Psychiatric symptoms (including suicide and hallucinations) • Worsening cardiac or liver function • GI disease (peptic ulcers, pancreatitis, cholangitis, colitis) • Autoimmune disease • Pulmonary embolism

Peginterferon alfa-2b (PegIntron, Merck)

Covalent conjugate of recombinant alfa-2b interferon with monomethoxy polyethylene glycol, induces the innate antiviral immune response

• Used as part of a combination regimen in HCV infection in patients with compensated liver disease in genotypes, 1,4 5, and 6 • Used in combination with ribavirin alone, ribavirin and simeprevir, or with ribavirin and sofosbuvir depending on genotype and other factors • Dose adjustments for renal impairment • Contraindicated in autoimmune hepatitis • Psychiatric evaluation in patient with depression or mood disorder • Pregnancy category C

Dizziness, fatigue, headache, joint or muscle pains, nausea, dry mouth, loss of appetite, weight loss, insomnia, injection site reaction, worsening depression, suicidal thoughts

Ribavirin (Copegus, Genentech; Moderiba, AbbVie; Rebetol, Merck; Ribasphere, Kadmon)

Nucleoside analog inhibits 5' cap of viral mRNA and viral RNA polymerase, inducing destructive mutation; potentiates effects of interferon

• In persons age ≥5 years, treats genotypes 1–6 • Used in combination with peginterferon, with sofosbuvir or simeprevir +/− peginterferon, and with ombitasvir/paritaprevir/ritonavir/dasabuvir depending on genotype and other factors • Contraindicated in autoimmune hepatitis, hepatic decompensation • Not to be used with didanosine • Psychiatric evaluation in patient with depression or mood disorder • Pregnancy category X • Weight-based

• Pancreatitis, GI symptoms, severe allergic reactions, vision loss or blindness, worsening liver function • Depression, suicidal thoughts and attempts • Effects on growth in children • Hemolytic anemia, worsened cardiac function, myocardial infarction

GI, gastrointestinal; HCV, hepatitis C virus.

for assessing the prognosis and guiding therapy.10 Liver biopsies are evaluated in terms of grade and stage. As an alternative to liver biopsy, the HCV FibroSure test (FibroTest–ActiTest) has been validated for the initial diagnosis of fibrosis and for the monitoring of patients with HCV infection. This noninvasive biomarker test uses the results of 6 serum levels plus the age and gender of the patient to generate a score that correlates with the degree of liver damage and converts to a histological classification. Additional laboratory assessments before the initiation of treatment for HCV infection should include liver function tests: measurement of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total/direct bilirubin, and albumin. Complete blood cell count (CBC), international normalized ratio (INR), thyroid-stimulating hormone (TSH) level, and calculated glomerular filtration rate (GFR) should also be obtained.13 ALT levels may be normal despite progressive liver disease and are often normal in advanced cirrhosis. Patients with chronic HCV infection who have consistently normal ALT levels are at low risk for progression to cirrhosis. Albumin level is a strong prognostic measure; rates of progression to the complications of liver disease are higher with levels below 35 g/L.10

Treatment

Pharmacological treatment is recommended for patients with chronic HCV infection, advanced fibrosis, compensated cirrhosis, liver transplant, severe extrahepatic manifestations, HIV co-infection, or mixed cryoglobulinemia with end-organ manifestations.13 The key to successful treatment is achieving a sustained virological response (SVR). An SVR is an undetectable HCV-RNA level 24 weeks after the completion of therapy, although the time varies per study. An SVR correlates with decreases in liver fibrosis, necrosis, and cirrhosis and a 70% reduction in the risk for liver cancer.13 In patients who achieved an SVR, the risk for death was 62% to 84% lower, the risk for hepatocellular carcinoma was 68% to 79% lower, and the risk for requiring a liver transplant was 90% lower than in patients who did not achieve an SVR.14 These studies were primarily of treatment with peginterferon alfa-2a and ribavirin, and the analyses will require repetition for the study of directly acting antivirals. Treatment recommendations and length of treatment are guided by HCV genotype, viral load, patient comorbidities, the presence of cirrhosis, and previous treatment (i.e., treatmentnaïve or experienced). Current FDA-approved medications

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Drug Simeprevir (Olysio, Janssen Pharmaceuticals)

Mechanism of action Second-generation NS3/4A HCV protease inhibitor

Notes • Treats HCV genotype 1 • Used in combination with peginterferon and ribavirin, or with sofosbuvir • Contraindicated in severe hepatic impairment • Pregnancy category C Sofosbuvir Nucleoside analog poly• Treats HCV genotypes 1–4 (Sovaldi, Gilead merase inhibitor; incorpo- • Not used as monotherapy; used in combination with ribavirin +/− Sciences) rates itself into HCV RNA peginterferon, with simeprevir, or with daclatasvir depending on by using NS5B polymerase; genotype and other factors terminates chain • Pregnancy category X Sofosbuvir + ledipasvir Ledipasvir inhibits HCV • Treats HCV genotypes 1, 4, 5, 6 (Harvoni, Gilead Sciences) NS5A, protein for viral • No well-controlled pregnancy studies replication Ombitasvir + pantaprevir Triple targeted design with • Treats HCV genotype 1 + ritonavir + dasabuvir three distinct direct-acting • Used in combination with ribavirin (Viekira Pak, AbbVie) antivirals (DAAs) • No ribavirin needed in HCV genotype 1b patients without cirrhosis (treatment experienced or naïve) • Contraindicated in moderate to severe hepatic impairment • Pregnancy category B Ombitasvir + Includes HCV NS5A • Treats HCV genotype 4 patients without cirrhosis paritaprevir + ritonavir inhibitor (ombitasvir), HCV • Used in combination with ribavirin (Technivie, AbbVie) NS3/4A protease inhibitor • Contraindicated in patients with moderate to severe hepatic (paritaprevir) and a CYP3A impairment inhibitor (ritonavir) • Pregnancy category B Daclatasvir NS5A inhibitor that blocks • Treats HCV genotype 3 with or without cirrhosis (Daklinza, Bristol-Myers both RNA replication and • Used in combination with sofosbuvir Squibb) virion assembly • No data in pregnant women available to inform a drug-associated risk

Adverse drug reactions Most common side effects: rash (including serious photosensitivity rash), pruritus, nausea • With ribavirin: fatigue, headache • With peginterferon and ribavirin: nausea, difficulty sleeping, anemia Most common side effects: fatigue, malaise, headache Most common side effects: • With ribavirin fatigue, nausea, pruritus and other skin reaction, insomnia, asthenia • Without ribavirin nausea, pruritus, insomnia Most common side effects: fatigue, weakness, nausea, sleep problems

Most common side effects: headache, fatigue, nausea, diarrhea

GI, gastrointestinal; HCV, hepatitis C virus.

are listed in Table 5. The guidelines for HCV treatment in adults are rapidly changing with the advent of new therapies and other developments. Updated guidelines are published through the Infectious Diseases Society of America (IDSA), the American Association for the Study of Liver Diseases, and the European Association for the Study of the Liver. A full medication history must be elicited before treatment, as many of these drugs interact with P-glycoprotein inducers (i.e., rifampin, St. John’s wort), anticonvulsants, and antiretrovirals. Patients should be counseled to avoid alcohol and other toxic substances to prevent disease progression and to consult their clinician before taking any prescriptions or over-thecounter medications, supplements, or vitamins. A healthful diet, weight loss in case of obesity, and control of diabetes and other comorbidities are linked to improved liver health. During treatment, the quantitative HCV viral load, CBC, creatinine level, GFR, and liver function test values should be monitored monthly. At 12 weeks, the TSH should be measured.13 The quantitative HCV viral load is analyzed at the completion of treatment and at variable intervals after treatment. It is welldocumented that host factors (age, gender, ethnicity, genetic polymorphisms) may influence the outcome of treatment.

Conclusion

HCV infection is the leading cause of liver cirrhosis and the most common reason for liver transplant in the United States. No vaccination is yet available; as such, it is crucial to screen patients at high risk for this disease. It is also important to provide patient education about ways to prevent HCV transmission. Several treatment options that can lead to an SVR are helping to improve patients’ quality and duration of life. In just the last year, several advances in medications and treatment guidelines for HCV have been reported. It is particularly important for clinicians to stay current with guidelines and to follow the results of clinical trials. More advances are on the horizon. n Rebecca Wong, is a student in the Physician Assistant, Bachelor of Science program at St. John’s University College of Pharmacy and Health Sciences in Queens, NY; Cynthia Russell, PA-C, is a physician assistant with Arya Gastroenterology Associates, P.C., in Brooklyn NY; and Danielle Kruger, PA-C, MSEd, is an associate professor in the Physician Assistant, Bachelor of Science program at St. John’s University College of Pharmacy and Health Sciences and a physician assistant practicing emergency medicine and Director of Physician Assistant Development at Coney Island Hospital in Brooklyn, NY.

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References 1. Stockman LJ, Guilfoye SM, Benoit AL, et al; Centers for Disease Control and Prevention (CDC). Rapid hepatitis C testing among persons at increased risk for infection–Wisconsin, 2012-2013. MMWR Morb Mortal

CME CE

Wkly Rep. 2014;63(14):309-311.

Expiration date: February 15, 2017

2. Dhawan VK. Hepatitis C. Medscape. http://emedicine.medscape.com/ article/177792-overview. Updated August 3, 2015. Accessed January 5, 2016.

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3. Hepatitis C. New York State Department of Health Web site. https://

CREDITS: 0.5

www.health.ny.gov/diseases/communicable/hepatitis/hepatitis_c. Updated November 2015. Accessed January 5, 2016.

POSTTEST

For more credit information, please turn to p. 36.

4. HC Hepatitis Central. http://www.hepatitiscentral.com. Accessed January 5, 2016. 5. Rutherford A, Dienstag JL. Viral hepatitis. In: Greenberger NJ, Blumberg RS, Burakoff R. Current Diagnosis and Treatment: Gastroenterology, Hepatology and Endoscopy. 3rd ed. New York, NY: McGraw-Hill; 2009:434-443. 6. Hoofnagle JH. Chronic hepatitis. In: Goldman L, Ausiello D, Arend WP, et al, eds. Cecil Medicine. 23rd ed. Philadelphia, PA: Saunders Elsevier; 2008:1108-1116. 7. Spach DH. Core concepts. HCV epidemiology in the United States. Hepatitis C Online. http://www.hepatitisc.uw.edu/go/screening-diagnosis/epidemiologyus/core-concept/all. Updated June 16, 2014. Accessed January 5, 2016. 8. Boyer N, Marcellin P. Pathogenesis, diagnosis, and management of hepatitis C. J Hepatol. 2000;32(suppl 1):98-112. 9. Fox RK. Core concepts. Extrahepatic conditions related to hepatitis C. Hepatitis C Online. http://www.hepatitisc.uw.edu/go/evaluation-staging-monitoring/extrahepatic-conditions/core-concept/all. Updated July 22, 2013. Accessed January 5, 2016.

1. What is the most common risk factor for acquiring HCV infection in the United States? a. Intravenous drug use b. Vertical fetal transmission c. Blood transfusion or organ transplant before 1992 d. High-risk sexual behaviors 2. Which of the following extrahepatic manifestations has no association with hepatitis C? a. Non-Hodgkin lymphoma b. Mixed cryoglobulinemia c. Lichen planus d. All are associated.

10. Sim M, Cheng W, Dore G, Beers K. Signs and symptoms of chronic viral hepatitis. In: HIV, Viral Hepatitis and STIs: A Guide for Primary Care. Surry Hills, Australia: Australasian Society for HIV, Viral Hepatitis, and Sexual Health Medicine; 2008:71-79. http://testingportal.ashm.org.au/ resources/HCV/HIV_viral_hep_Chapter_7.pdf. Accessed January 5, 2016. 11. Galossi A, Guarisco R, Bellis L, Puoti C. Extrahepatic manifestations of chronic HCV infection. J Gastrointestin Liver Dis. 2007;16(1):65-73. 12. Freeman AJ, Marinos G, French RA, Lloyd AR. Immunopathogenesis of hepatitis C virus infection. Immunol Cell Biol. 2001;79:515-536. 13. American Association for the Study of Liver Disease/Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed January 5, 2016. 14. Boschert S. Achieving sustained response key to successful HCV treatment.

3. A 55-year-old man requests testing for hepatitis C. His ex-wife was recently given a diagnosis of liver impairment due to chronic HCV infection, and he is concerned that she was infected during their marriage. The patient denies any medical complaint, has no past medical history, and takes no medication. Results of a physical examination are normal. He has no hepatomegaly, edema, jaundice, or skin changes. What is the most appropriate next step in the assessment? a. Quantitative HCV viral load (PCR) b. Recombinant immunoblot assay (RIBA) c. HCV antibody test (ELISA) d. Qualitative HCV test (PCR)

Clinician Reviews. www.clinicianreviews.com/?id=26596&tx_ttnews[tt_news]=3 11185&cHash=3d8313f051b71602264694d3fb24239d. 15. Gilead Sciences. Highlights of prescribing information. Harvoni. https:// www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf. Updated November 2015. Accessed January 4, 2016. 16. American Association for the Study of Liver Disease/Infectious Diseases Society of America. Initial treatment box. Summary of recommendations

4. What medication indicated for the treatment of chronic HCV infection is an NS5B polymerase inhibitor? a. Ribavirin b. Sofosbuvir c. Peginterferon alfa-2a d. Simeprevir

for patients who are initiating therapy for HCV infection by HCV genotype. http://www.hcvguidelines.org/full-report/initial-treatment-box-summaryrecommendations-patients-who-are-initiating-therapy-hcv. Updated August 7, 2015. Accessed January 4, 2016.

TO TAKE THE POSTTEST please go to: myCME.com/Feb16CAfeature

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Advisor Forum These are letters from practitioners around the country who want to share their clinical problems and successes, observations, and pearls with their colleagues. Responding consultants are identified below. We invite you to participate.

YOUR COMMENTS MORE READER COMMENTS ON ETHICAL ISSUES REGARDING USE OF IUDS Regarding “The IUD rumor mill: common misconceptions” [Nov. 2015, p. 32], conception takes place in the fallopian tube near the ovary and then continues its journey to the uterus. The IUD makes the surface of the uterus such that a fertilized ovum cannot attach itself and continue growing and surviving until birth. Therefore, the fertilized ovum cannot survive and is expelled from the mother’s body. In my estimation, this is yet another form of abortion.—JEAN LUCK, LVN, PA, Green Valley Lake, Calif. (208-2) The LNG-IUS also prevents conception. While the progestin affects the endometrium, making it inhospitable to a fertilized egg, it also thickens the cervical mucous—in the words of a lecturer I heard, “turns it into cement.” Thus, the Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001. You may contact us by e-mail at editor@ clinicaladvisor.com. If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. 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.

LNG-IUS also is a barrier method, blocking the entrance of sperm into the uterus.—SUSANNA LEVIN, WHNP, New Rochelle, N.Y. (208-3) The copper IUD also works by disruption of the endometrium and implantation. A previous commenter stated that it works by preventing fertilization. Both are possible, but neither action is acceptable according to certain belief systems.—NANCY SANDROCK, CNM, Weslaco, Texas (208-1)

AVOIDING LABELING PATIENTS AS NONCOMPLIANT Sam Mbugua, MD, wrote about using analogies for education [Advisor Forum, Dec. 2015, p. 54]. I agree that teaching requires visual aids and any other method of teaching and learning that can be used to convey a point of understanding. However, he starts his comment with the word “noncompliance.” Really? I was told in my masters program in the 1980s to never label a patient as noncompliant. My professors said that use of that word only indicates that you do not know why the patient is making the decision that he or she is making. I work hard to educate patients, friends, and families, but if education, lecturing, and pushing information toward people changed behavior, we would not have any overweight healthcare personnel. All physicians and nurses would be

OUR CONSULTANTS

Philip R. Cohen, MD,

is clinical associate professor of dermatology, University of Texas Medical Center, Houston.

Deborah L. Cross, MPH, CRNP, ANP-BC, is associate program

director, Gerontology NP Program, University of Pennsylvania School of Nursing, Philadelphia.

Abimbola Farinde, PhD, PharmD,

is a professor at Columbia Southern University in Orange Beach, Ala.

Laura A. Foster, CRNP, FNP,

Abby A. Jacobson, PA-C,

practices family medicine with Palmetto Primary Care Physicians in Charleston, S.C.

is a physician assistant at Delaware Valley Dermatology Group in Wilmington, Del.

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exercising and eating their fruits and vegetables. Instead, the first question one should ask is why has the patient made the choice that he or she made. Current research on various models of healthcare beliefs, behavioral changes, and motivational interviewing can determine if lack of understanding is the true reason for the choices that the patient has made.—BETH LANDIS, RN, MSN, Salt Lake City, Utah (208-4)

CONTAMINATED WATER AND CANCER I really liked the article, “Cervical cancer screening: why less is best” [ Jan. p. 24], and the comments made in reference to the number of partners that not only the patient has had, but how many that his or her partners have had. In this neck of the woods, the Pacific Northwest, families who live near the Hanford nuclear station in Washington state have had a high incidence of birth defects, spontaneous abortions, and thyroid cancer among members who were born and grew up there, especially along the waterway, the Columbia River. Thank goodness for proactive people who decided to study and investigate and found irradiation from the water source as the offending agent.—BARB TROXEL, ANP, BC, Portland, Ore. (208-5) FLU VACCINE IN PREGNANT WOMEN In “Managing patient perceptions of the influenza vaccine” [Dec. 2015], I am concerned because the article says the flu vaccine is cautioned/contraindicated in pregnant women (Table 2 and page 43). This is incorrect. According to the CDC recommendations, all pregnant women or those planning to become pregnant should have the flu vaccine. I think the article is misleading with these facts and could cause confusion.—MELANIE BEST, CRNP, Seneca, Pa. (208-6)

Debra August King, PhD, PA,

is senior physician assistant at New York-Presbyterian Hospital, New York City.

Mary Newberry, CNM, MSN,

provides well-woman gynecologic care as a midwife with Prima Medical Group, Greenbrae, Calif.

CLINICAL PEARLS ERYTHROMYCIN FOR FACIAL LACERATIONS Erythromycin is used for the treatment of patients with conjunctivitis and hordeolums, but there is an untapped use. When I suture the faces of kids or those with special needs or perform a facial laceration repair, I prescribe erythromycin ointment. It is safe for the eyes (where bacitracin is not) and surrounding tissue, so I educate my patients that if it happens to get into the eye, it is okay. Parents and family members are happy!— DARIA CANALE, MSN, FNP-BC, CRNP, Philadelphia, Pa. (208-7)

CASE FILES CARCINOID APPENDIX A 24-year-old thin Caucasian female with a very vague stated history of “some kind of tumor in my appendix when they took it out,” says she did not go back for any follow-up. Upon receipt of the patient’s prior records, I saw that the pathology on her diseased appendix noted an incidental finding of an 11-mm carcinoid tumor. These are classified as neuroendocrine tumors because they are capable of releasing hormones into the bloodstream. This is usually only seen in metastatic disease. They are most often found unexpectedly during other abdominal or pelvic surgeries. They are small and slow-growing with a very low rate of metastasis. Primary treatment is surgical removal, and then nuclear imaging, usually an octreoscan, is performed. Subsequent treatment is graded by size, with tumors less than 1 cm in diameter being considered cured. (208-8) n Contributed by Sherril Sego, FNP-C, DNP (See photo at bottom of this page for more information about Dr. Sego.)

Claire O’Connell, MPH, PA-C,

Katherine Pereira, DNP, FNP,

teaches in the PA Program at the New Jersey Medical School and Rutgers University, Piscataway, N.J.

is assistant professor, Duke University School of Nursing, Durham, N.C.

Sherril Sego, FNP-C, DNP,

is an independent consultant in Kansas City, Mo.

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CME CE DERMATOLOGY COURSES

n LEARNING OBJECTIVES After completing the activity, the participant should be better able to:

For Dermatology Clinic

• Examine the etiology and clinical presentation of pellagra and Laugier–Hunziker syndrome • Formulate diagnostic procedures and treatment protocols for patients presenting with pellagra and Laugier–Hunziker syndrome

For Dermatologic Look-Alikes

• Differentiate between skin manifestations of periungual warts and subungual exostosis while considering their underlying cause • Demonstrate proficiency in identifying and treating periungual warts and subungual exostosis n COMPLETE THE POSTTEST: Page 61 n ADDITIONAL CME/CE CREDIT: Page 36

The faculty reported the following financial relationships with commercial interests whose products or services may be related to the content of this CME activity: Faculty Disclosures

Expiration Date: February 15, 2017

Name of faculty

Reported Financial Relationship

Estimated time to complete the educational activity: 30 minutes

Julie Nguyen, BS

No relevant financial relationships

Amelia Bush, BS

No relevant financial relationships

Kelly Stiegel, BS

No relevant financial relationships

Maura Holcomb, MD

No relevant financial relationships

Statement of Need: Undertraining in dermatology for primary-care providers is a common phenomenon. Thus, primary-care clinicians need additional educational outlets devoted to the diagnosis and treatment of specific dermatologic conditions. For clinicians out of training, CME becomes the most accessible route. Target Audience: This activity has been designed to meet the educational needs of primary-care health-care professionals who treat patients with various dermatologic conditions. Faculty Julie Nguyen, BS, Baylor College of Medicine, Houston Amelia Bush, BS, Baylor College of Medicine, Houston Kelly Stiegel, BS, Baylor College of Medicine, Houston Maura Holcomb, MD, Baylor College of Medicine, Houston Accreditation Statements Physician Credit: HME is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Credit Designation: HME designates this enduring material for a maximum of 0.5 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nursing Credit: Global Education Group is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. Credit Designation: This educational activity for 0.5 contact hours is provided by Global Education Group. Nurses should claim only the credit commensurate with the extent of their participation in the activity. American Academy of Physician Assistants (AAPA) The AAPA accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 0.5 hour of Category I credit for completing this program. Disclosure Policy In accordance with the ACCME Standards for Commercial Support, HME requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. HME resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational programs.

Staff/Planners’ Disclosures The planners, managers, and reviewers for this program reported the following financial relationships with commercial interests whose products or services may be related to the content of this CME activity: HME planners, managers, and reviewers have no relevant financial relationships to disclose. Global Education Group planners, Ashley Marostica, RN, MSN, Amanda Glazar, PhD, and Andrea Funk, have nothing to disclose. Disclosure of Unlabeled Use: This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. HME and Global Education Group do not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Method of Participation: There are no fees for participating in and receiving CME/CE credit for this activity. During the period of February 15, 2016, through February 15, 2017, participants must: 1) read the learning objectives and faculty disclosures; 2) study the educational activity; 3) complete the posttest and submit it online (clinicians may register at www.myCME.com); and 4) complete the evaluation form online. A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed posttest with a score of 70% or better. Disclaimer: The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of HME or Global Education Group. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. The information presented in this activity is not meant to serve as a guideline for patient management.

Furthermore, HME seeks to verify that all scientific research referred to, reported, or used in a CME/CE activity conforms to the generally accepted standards of experimental design, data collection, and analysis. HME is committed to providing its learners with high-quality CME/CE activities that promote improvements in health care and not those of a commercial interest.

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Dermatology Clinic

CME CE DERMATOLOGY COURSES

CASE #1

Rashes, diarrhea, and neuropsychiatric issues JULIE NGUYEN, BS, AND MAURA HOLCOMB, MD

A man, aged 42 years, presents with a 6-month history of a painful, scaly skin rash. The eruption is symmetrically distributed over photosensitive areas, affecting his face, neck, upper back, forearms, and hands. The dorsal surfaces of his hands and forearms exhibit a dusky brown coloration over rough and cracked skin. He complains of itching and burning and reports intermittent vomiting and diarrhea. He admits to heavy alcohol intake for the last 2 decades and denies taking any medications. Neuropsychiatric evaluation reveals short-term memory loss, speech problems, and poor concentration. What is your diagnosis? Turn to page 54.

CASE #2

Brown macules on the lips and nail changes AMELIA BUSH, BS, AND MAURA HOLCOMB, MD

An elderly man presents with asymptomatic hyperpigmented, confluent, brown macules on his upper and lower lips, along with hyperpigmented macules on his hands. He also has diffuse blue-black bilateral melanonychia with nail dystrophy on his toenails, and his fingernails contain longitudinal melanonychia with hyperpigmentation of the proximal nail beds. He denies any family history of mucocutaneous pigmentation or gastrointestinal or systemic symptoms. In the last 5 years, results of a colonoscopy, upper gastrointestinal endoscopy, and blood work have all been within normal limits. What is your diagnosis? Turn to page 55. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2016 53

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CME CE

CASE #1

Dermatology Clinic

Pellagra

Pellagra is a systemic disease observed in chronic severe def iciency of niacin (also known as nicotinic acid or vitamin B3). Pellagra means rough skin and is a clinical syndrome characterized by symmetric photosensitive rashes, gastrointestinal symptoms, and neuropsychiatric disturbances.1,2 It is traditionally described by the “four Ds”: dermatitis, diarrhea, dementia, and death, if left untreated. Niacin can be synthesized from tryptophan or obtained from food sources such as meat, poultry, dry beans, nuts, and dairy products. Pellagra develops as soon as 60 days in someone on a niacin-deficient diet.2,3 Niacin is a constituent of coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which function in essential oxidation-reduction reactions; NAD is involved in cell signaling and macronutrient catabolism, and NADP functions in anabolic processes.2 Manifestations of pellagra result from the insufficiency of these coenzymes, which are found throughout the body, which in turn explains the multisystem involvement. Tissues with high-energy requirements (brain) or high turnover rates (skin and gut) are most affected by the impaired cellular energy transfer reactions.2 Although the exact incidence of pellagra is unknown, in developed countries, it is a rare condition that is confined to groups at risk for malnutrition, such as alcoholics and psychiatric patients.4 Pellagra remains endemic in povertystricken areas of Africa and Asia where the staple diet primarily consists of corn or maize, which contain bound niacin that cannot be absorbed; an exception is the maize prepared in Mexico, where the limewater washing process liberates bound niacin.1,2,4 Pellagra has no sex or race predilection and occurs infrequently in children.4 Pellagra may arise secondary to underlying conditions that interfere with niacin absorption and processing. Patients with gastrointestinal disorders are predisposed to pellagra due to impaired absorption of tryptophan and niacin; examples include Crohn disease, gastrectomy, severe ulcerative colitis, and jejunoileitis.1 Metabolic disorders such as Hartnup disease, in which pellagra-like symptoms develop in childhood, and carcinoid syndrome, may lead to pellagra. Drugs that are known to interfere with niacin metabolism include isoniazid, pyrazinamide, 6-mercaptopurine, 5-fluorouracil,

phenytoin, azathioprine, and chloramphenicol.1 Chronic alcoholics are at risk for pellagra due to a combination of poor diet, malabsorption, liver cirrhosis, and hepatic cell injury.3 The dermatitis seen in pellagra begins as painful, erythematous, pruritic patches in a bilaterally symmetrical eruption in areas exposed to sunlight, heat, and friction.1,5 Initially, the affected skin resembles an acute sunburn with erythema and progressively becomes more edematous; it may develop vesicles and bullae, which can rupture and leave crusted erosions, or develop into a hyperpigmented scaly rash.4,5 Patients may complain of a burning sensation and exacerbation following exposure to sunlight. Photosensitivity is thought to be caused by a deficiency of urocanic acid or cutaneous accumulation of kynurenic acid, which induces phototoxic changes.2

Pellagra is traditionally described by the “four Ds”: dermatitis, diarrhea, dementia, and death, if left untreated. The dorsal surfaces of the hands are the most commonly affected sites (observed in up to 97% of cases); when the rash extends proximally to the radial aspects of the forearms, it forms the characteristic gauntlet of pellagra.1,4,5 An eruption localized to the upper central portion of the chest and neck is known as Casal necklace or Casal collar.1 Typically, a sharply demarcated border between affected and normal skin is evident. Over time, the skin thickens into hyperkeratotic and parchment-like plaques that are dry and scaly, giving rise to the term goose skin.1,5 A symmetric butterfly eruption with fine scaling over the malar area is frequently observed.1 Onethird of patients have oral mucous membrane involvement, manifesting as cheilitis, angular stomatitis, and glossitis.5 The pathologic changes of hyperkeratosis, parakeratosis, and acanthosis in pellagrous skin are nonspecific. Possible histologic findings include epidermal atrophy overlying dermal fibrosis, vacuolar change, sebaceous gland atrophy, and a lymphocytic perivascular infiltrate.2,5 Although the characteristic dermatitis of pellagra is the key to diagnosis, the earliest manifestation of the disease is gastrointestinal disturbance. Patients often report decreased appetite, epigastric discomfort, abdominal pain, vomiting, and watery diarrhea.1,5 Signs of neurologic damage occur late in the disease. Common complaints include insomnia, fatigue, anxiety, and depression. Neuropsychiatric examination may reveal impaired memory, poor concentration,

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irritability, apathy, sensorimotor neuropathy, tremor, and ataxia.2,5 As pellagra advances, patients become increasingly disoriented and delirious, ultimately slipping into a coma.5 The diagnosis of pellagra is based on clinical presentation, with focus on the first three Ds and localization of skin lesions, and rapid response to oral vitamin supplementation.1,5 There are no tests that definitively diagnose pellagra, but measurements of low serum niacin and low urinary niacin metabolites may provide supportive evidence.1,5 The differential diagnosis should include phototoxic and photoallergic skin reactions, polymorphous light eruption, porphyria, and lupus erythematosus. If pellagra is diagnosed and treated appropriately, the prognosis for recovery is excellent. However, untreated pellagra will progressively worsen as neurologic function declines, leading to death within 4 to 5 years.5 The treatment of pellagra consists of oral nicotinamide or niacin (100–300 mg daily in 3–4 separate doses) until resolution of the major symptoms.2,5 Nicotinamide is preferred because it does not cause the headache and flushing associated with niacin.1,2 Severe cases may require parenteral niacin. For secondary pellagra, the underlying pathology must be addressed and offending drugs removed. Most patients require concomitant administration of riboflavin, pyridoxine, zinc, and magnesium, and a protein-rich diet for a full recovery.2 Neuropsychiatric symptoms disappear after 1 to 2 days, whereas skin lesions take 3 to 4 weeks to resolve.1,2 Topical emollients for the dermatitis may reduce discomfort.5 In our case, the patient was treated with oral niacin supplementation for 1 week, at which point his symptoms completely resolved. The patient was advised to avoid sun exposure during treatment and received alcohol counseling as well. Julie Nguyen, BS, is a medical student and Maura Holcomb, MD, is a dermatology resident at Baylor College of Medicine in Houston. References 1. Jen M, Yan AC. Cutaneous changes in nutritional disease. In: Goldsmith L, Katz S, Gilchrest B, Paller A, Leffell D, Wolff K, eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw-Hill, 2012:1499-1524. 2. Karthikeyan K, Thappa DM. Pellagra and skin. Int J Dermatol. 2002;41(8):476-481. 3. Oldham MA, Ivkovic A. Pellagrous encephalopathy presenting as alcohol withdrawal delirium: a case series and literature review. Addict Sci Clin Pract. 2012;7:12. 4. Wan P, Moat S, Anstey A. Pellagra: a review with emphasis on photosensitivity. Br J Dermatol. 2011;164(6):1188-1200. 5. Hegyi J, Schwartz RA, Hegyi V. Pellagra: dermatitis, dementia, and diarrhea. Int J Dermatol. 2004;43(1):1-5.

CASE #2

Laugier–Hunziker syndrome

Laugier–Hunziker syndrome (LHS) is a rare, benign, acquired disease with unknown pathogenesis that was first described in the 1970s by Laugier and Hunziker.1 The asymptomatic hyperpigmentation of LHS presents spontaneously on the skin, lips, or mucosa as gray, dark brown, or blue-black lenticulate or linear macules that are typically less than 5 mm in diameter.2 Histologically, the macules have a collection of pigmentation in the basal layer of the epidermis due to increased synthesis of melanosomes. Approximately 50% of patients have melanonychia with a variety of longitudinal striata that typically occur in the fingernails.2 Partial or complete nail pigmentation may also be present. Hutchinson sign, a pigmentation of the proximal nail folds, is also seen in some patients.3 Typically, LHS develops in middle-aged adults with mean onset at age 50; it is more prevalent in women and individuals of French or Italian origin.4 LHS is a rare disorder; diagnosis is based on clinical presentation with the exclusion of other systemic disease. Although LHS is a benign disease with no risk of malignant transformation, it is important to rule out other diseases of diffuse mucocutaneous and nail pigmentation that warrant further investigation or action by conducting a thorough medical history. Symptoms such as fatigue, weight loss, gastrointestinal or cardiovascular diseases, history of drug use, and abnormal laboratory values could suggest systemic conditions, including Peutz–Jeghers syndrome, Bandler syndrome, McCune–Albright syndrome, subungual melanoma, racial pigmentation, acquired immunodeficiency syndrome, and primary adrenal insufficiency.2 Peutz–Jeghers syndrome often presents with pigmentation of the lips and oral mucosa. However, intestinal polyps are also seen with Peutz–Jeghers syndrome; therefore, this disease can be ruled out with a normal colonoscopy and upper gastrointestinal endoscopy. Bandler syndrome includes hyperpigmented macules of

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CME CE

Dermatology Clinic

the hands, fingernails, and oral mucosa that occur during infancy. This syndrome also includes vascular malformations in the intestine, which can cause significant bleeding. McCune–Albright syndrome includes precocious puberty and fibrous dysplasia. The condition may present with labial or genital pigmentation, but does not affect the nails. Subungual melanoma or skin cancer should be ruled out with a punch biopsy. Racial pigmentation occurs more commonly in the g ingiva and is seen in populations such

Cosmetic treatment options for Laugier–Hunziker syndrome include laser or cryotherapy. as Asians and African Americans. Drug-induced pigmentation can occur with the use of certain medications, but this condition reverses after the patient discontinues the offending drugs.2 The patient in our case had an atypical presentation with involvement of not only his fingernails but also his toenails. There have been previous case reports of longitudinal striate on the toenails, including one report of a 77-year-old man with bilateral fingernail and toenail striate, macules on the proximal nail folds, and confluent brown hyperpigmented

macules on the lips and mucosa that developed asymptomatically over 4 years.2,5,6 This patient had complete melanonychia of some of his toenails, along with longitudinal striate, demonstrating the importance of considering the breadth and variety of nail pigmentation in LHS.2 Some patients with LHS may seek cosmetic treatment options, although there is no requirement for further medical treatment. Cosmetic treatment options include laser or cryotherapy. In one report, 22 Chinese patients received Q-switched alexandrite laser treatment; approximately 81% had excellent clearing of oral pigmentation after one treatment session.7 Although positive response to laser treatment has been reported, there is one reported case of the reoccurrence of lesions on the lips of a patient with LHS 12 months after erbium:yttrium-aluminum-garnet (Er:YAG) laser treatment.8 Further studies are needed to evaluate the efficacy of lasers in the treatment of LHS. In our case, once testing ruled out other disorders, the patient was diagnosed with LHS. He was not concerned with the appearance of the hyperpigmentation and therefore elected not to pursue treatment. n Amelia Bush, BS, is a medical student and Maura Holcomb, MD, is a dermatology resident at Baylor College of Medicine in Houston. References 1. Laugier P, Hunziker N. Essential lenticular melanic pigmentation of the lips and cheek mucosa [in French]. Arch Belg Dermatol Syphiligr.

TABLE 1: Differential diagnosis of mucocutaneous and/or nail pigmentation Acquired immunodeficiency syndrome Bandler syndrome Drug-induced pigmentation Laugier–Hunziker syndrome McCune–Albright syndrome

1970;26(3):391-399. 2. Rangwala S, Doherty CB, Khatta R. Laugier–Hunziker syndrome: a case report and review of the literature. Dermatol Online J. 2010;16(12):9. 3. Siponen M, Salo T. Idiopathic lenticular mucocutaneous pigmentation (Laugier–Hunziker syndrome): a report of a case. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;96(3):288-292. 4. Pereira PM, Rodrigues CA, Lima LL, et al. Do you know this syndrome? An Bras Dermatol. 2010;85(5):751-753. 5. Lampe AK, Hampton PJ, Woodford-Richens K, et al. Laugier–Hunziker syndrome: an important differential diagnosis for Peutz–Jeghers syndrome. J Med Genet. 2003;40(6):e77. 6. Wang WM, Wang X, Duan N, et al. Laugier–Hunziker syn-

Peutz–Jeghers syndrome

drome: a report of three cases and literature review. Int J Oral Sci.

Primary adrenal insufficiency

7. Zuo YG, Ma DL, Jin HZ, et al. Treatment of Laugier–Hunziker syn-

Racial pigmentation

Dermatol Res. 2010;302(2):125-130.

Subungual melanoma

associated with Laugier–Hunziker syndrome following Er:YAG laser treat-

2012;4(4):226-230. drome with the Q-switched alexandrite laser in 22 Chinese patients. Arch 8. Ergun S, Saruhanoğlu A, Migliari DA, et al. Refractory pigmentation ment. Case Rep Dent. 2013;2013:561040.

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Dermatologic Look-Alikes

CME CE DERMATOLOGY COURSES

Growing lesions affecting the nails KELLY STIEGEL, BS, AND MAURA HOLCOMB, MD

CASE #1

CASE #2

A woman, aged 42 years, presents with periungual lesions of the second and third fingers of her right hand. The patient reports that the lesions have been present for 4 months, and she says they appeared to be increasing in size over that time. She also reports that the lesions cause pain and swelling of the lateral nail folds. It is noted that the periungual skin is thickened and discolored. The patient has had similar symptoms in the past, but she states that those symptoms resolved without treatment after a few months.

A woman, aged 23 years, presents with a 2-month history of a lesion involving the nail of her right fourth toe. The patient experienced pain in the affected toe and noticed her toenail was becoming deformed, with a mild yellowish discoloration as the lesion progressed over time. The skin distal to her toenail is ulcerated, and the nail is slightly separated from the nail bed in some areas. The patient often wears high heels with a pointed toe and believes these shoes pinch her fourth and fifth toes and cause them to ache occasionally.

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CME CE

CASE #1

Dermatologic Look-Alikes

Periungual warts

Cutaneous viral warts (verruca vulgaris) are caused by the human papillomavirus (HPV) and can appear on the hands, feet, and mucous membranes of the oral, anal, and genital cavities.1 HPV infects these epithelial surfaces and results in a warty papule or plaque.2 There are more than 100 types of HPV, all of which are DNA viruses that infect epithelial cells.3 Certain strains of HPV (2, 4, 27, and 29) favor areas of the body with temperatures below core temperature, such as the hands and feet.1,2 A study of more than 2,000 adults revealed an overall prevalence of warts of 3.3%.3 Rates in children are much higher, with approximately 33% of 3- to 12 year-olds affected and 3.9% to 4.7% of 11- to 16-year-olds affected.3 Certain occupations are associated with a higher incidence of hand warts, such as butchers, fishmongers, and others who handle meat.3 Immunosuppression from medications or disease can also predispose individuals to HPV infection.3

Periungual verrucae may grow to a size of 10 mm to 20 mm in diameter and are usually oval in appearance. Other cutaneous lesions can resemble warts clinically, including actinic keratosis, lichen planus, prurigo nodularis, molluscum contagiosum, seborrheic keratosis, and squamous cell carcinoma.3 A history of pruritus suggests a diagnosis of prurigo nodularis or lichen planus over verruca vulgaris. Actinic keratosis and squamous cell carcinoma are more likely in light-skinned patients with a long-term history of sun exposure. Infection with molluscum contagiosum is characterized by multiple (6–11) lesions grouped together, whereas cutaneous warts are often solitary lesions. Up to two-thirds of warts resolve spontaneously within 2 years of their appearance.2 Verrucae that are not susceptible to the body’s natural immunity may persist for years and contribute to HPV infection in the general population.2 Additionally, warts can be painful and embarrassing to the patient, and treatment is generally undertaken to remove them.2

Current treatment modalities for verrucae include physical destruction (liquid nitrogen cryotherapy, surgical removal, carbon dioxide laser), chemical destruction (salicylic acid, podophyllin, cantharidin, glutaraldehyde, bleomycin), and immunomodulation (interferons, contact immunotherapy, and retinoid compounds).1,4 Administration of the quadrivalent HPV vaccine has been shown to cause regression of some common warts, possibly due to antigenic epitope cross-reactivity between the vaccine’s HPV types and those responsible for common warts.2 Periungual verrucae may grow to a size of 10 mm to 20 mm in diameter and are usually oval in appearance.5 When located under the proximal nail fold, they can cause a swelling that mimics chronic paronychia.5 Transillumination is a quick and easy tool that can determine the subungual extent of a periungual wart.6 It is especially useful in patients with thicker nail plates in whom visualization of the extent of the wart is difficult under normal light.6 In transillumination, the lights in the clinic room should be turned off, and a small flashlight is turned on under the distal portion of the finger with the light facing upward.6 A major advantage of transillumination is that it can reduce the need for nail avulsion surgery.6 Limitations include differences in light intensity transmitted through individual nails due to keratosis of palmar or plantar skin, as well as skin color.6 Treatment of periungual verrucae may differ from that of warts in other locations. Electrosurgery should be avoided in the nail region, as it can lead to keloid formation.5 Bleopuncture is useful for periungual warts: after a local anesthetic block, a drop of bleomycin solution (1 U / m L) is placed on the wart and pricked into the lesion by multiple punctures with a vaccination needle.7 Potential risks of this technique include a transient or even permanent Raynaud phenomenon.7 Pulsed dye laser is associated with a low incidence of pain and scarring and may be performed without anesthesia.7 However, periungual warts are less responsive to pulsed dye laser than are palmar or common warts; complete elimination is achieved in one-third of patients.7 In our case, clinical presentation was consistent with periungual verruca vulgaris. The location of the lesions on her fingertips helped differentiate them from subungual exostoses, as these are primarily located distally on the toes. Clinical appearance, duration of symptoms, and lack of pruritus helped differentiate it from other lesions that can mimic verruca vulgaris. The patient was treated with three rounds of liquid nitrogen cryotherapy administered at 2- to 3-week intervals. The patient achieved aesthetic and symptomatic relief from her warts after treatment.

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CASE #2

Subungual exostosis

Subungual exostosis is a benign tumor of the bone located on the distal phalanx of the digit, either beneath or adjacent to the nail.8 They are relatively uncommon tumors, first described by Dupuytren in 1847.8 The most common location for a subungual exostosis is the great toe (80%), but lesions can appear on any of the other toes as well.8 Their clinical appearance is often misdiagnosed as a disease of the nail bed, and thus they must also be evaluated by their radiologic and histopathologic features.8 The etiology of subungual exostoses is unknown, but the lesions are thought to be precipitated by trauma, specifically fibrocartilaginous metaplasia with endochondral ossification from microtrauma or chronic infection.8,9 A history of trauma to the affected toe is reported in approximately 30% of patients.10 The chromosomal translocation t(X;6) (q22;q13-14) has been linked to subungual exostosis, which supports it being a true neoplasm rather than a response to trauma.10 Other possible etiologies include infection, tumor, hereditary abnormality, or activation of a cartilaginous cyst.10 Subungual exostoses are more common in adolescent girls and women; they typically develop during adolescence and 55% of patients are younger than age 18 years.8,10 The most common complaint is pain (77%), followed by swelling in the nail (31%), and nail change (15%).10 Subungual exostoses begin as small, firm, painful, pink or flesh-colored nodules beneath the free edge of the nail.7 The skin surrounding the exostosis may appear normal, ulcerated, or hyperkeratotic.7 As exostoses expand, they cause increasing pain and push up the nail plate until it separates from the skin below.8 Elevation of the nail plate is also seen with subungual warts, and subungual exostoses are often clinically mistaken for warts.7 The most common complication reported is onychodystrophy (malformation or discoloration of the nail), which occurs in approximately 16% of patients.10 The exposed nail bed surface may ulcerate and become infected, leading to nail deformity and increased pain in the affected digit.9 Patients can suffer ingrown toenails as a result of erosion and infection of the nail bed.7 When a patient presents with a subungual exostosis, the lesion must be differentiated from a subungual verruca, pyogenic granuloma, carcinoma of the nail bed, glomus tumor,

keratoacanthoma, melanoma, and subungual epidermoid inclusion.8 Radiographs can aid in confirming the diagnosis of subungual exostosis and reveal a bony projection on the dorsomedial aspect of the distal phalanx.8 Histopathology of the lesion shows a mature trabecular pattern, which helps differentiate it from a chondrosarcoma.8 It remains a matter of debate whether subungual osteochondromas are the same entity as subungual exostoses, but the two do have distinct histologic appearances.10 The cartilaginous caps of exostoses are composed of fibrocartilage, whereas those of osteochondromas are made of hyaline cartilage that is confluent with the underlying trabecular and cortical bone.10 An additional difference between the two is that exostoses form directly from fibrous tissues, whereas osteochondromas are derived from endochondral ossification.10

The etiology of subungual exostoses is unknown, but the lesions are thought to be precipitated by trauma. Treatment of subungual exostoses involves surgical excision, as the condition is generally progressive and unresponsive to nonoperative management.10 The recurrence rate is reduced to approximately 4% when complete resection is achieved.8,10 Prior to surgery, a radiograph should be obtained to determine the extent of the lesion.5 The skin overlying the lesion should be excised, and the exostosis dissected and clipped off at its base with a bone rongeur or nail clipper.5 The nail plate may need to be partially avulsed in order to gain access to the exostosis.5 Features of periungual warts and subungual exostoses Periungual wart

Subungual exostosis

Location

Adjacent to any fingernail

Predominantly affects the great toe

Origin

Human papillomavirus

Benign tumor of bone

Clinical presentation

Oval, 10-20 mm, flesh-colored

Firm, painful, pink or flesh-colored

Associated with a history of trauma

Yes

Treatment

Liquid nitrogen, salicylic acid, podophyllin, cantharidin, carbon dioxide laser

Surgical excision

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CME CE

Dermatologic Look-Alikes

Primary suture is usually possible, and the regrowing nail will eventually widen the nail bed and retain a normal appearance.5 In our case, the patient’s lesion was suspicious for a subungual exostosis, and a radiograph of the affected toe was obtained in order to confirm the diagnosis. The location, clinical appearance, history of trauma, and time course of the lesion helped differentiate it from a periungual wart, pyogenic granuloma, melanoma, or other pathology. The patient was referred to an orthopedic surgeon who dissected the exostosis and excised it at its base. The patient received regular follow-up in clinic following the procedure, and no signs of recurrence were noted. ■

2. Word AP, Nezafati KA, Cruz PD Jr. Treatment of warts with contact allergens. Dermatitis. 2015;26(1):32-37. 3. Kwok CS, Gibbs S, Bennett C, et al. Topical treatments for cutaneous warts. Cochrane Database Syst Rev. 2012;9:CD001781. 4. Suh DW, Lew BL, Sim WY. Investigations of the efficacy of diphenylcyclopropenone immunotherapy for the treatment of warts. Int J Dermatol. 2014;53(12):e567-e571. 5. Haneke E. Nail surgery. Clin Dermatol. 2013;31(5):516-525. 6. Ashique KT, Kaliyadan F. Transillumination: a simple tool to assess subungual extension in periungual warts. Indian Dermatol Online J. 2013;4(2):131-132. 7. Richert B, André J. Nail disorders in children: diagnosis and management. Am J Clin Dermatol. 2011;12(2):101-112.

Kelly Stiegel, BS, is a medical student and Maura Holcomb, MD, is a dermatology resident at Baylor College of Medicine in Houston.

8. Daragad MS, Srinivas SD, Varghese J. Exostosis masquerading as a subungual wart. Indian Dermatol Online J. 2014;5(1):92-93. 9. Bach DQ, McQueen AA, Lio PA. A refractory wart? Subungual exostosis.

References

Ann Emerg Med. 2011;58(5):e3-e4.

1. Schuller-Levis G, Levis W, Dvoretzky I. Treatment of recalcitrant

10. DaCambra MP, Gupta SK, Ferri-de-Barros F. Subungual exostosis of

warts with occlusive warming patches. J Drugs Dermatol. 2014;13(10): 1194-1196.

the toes: a systematic review. Clin Orthop Relat Res. 2014;472(4):1251-1259.

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CME CE

POSTTEST Expiration date: February 15, 2017

DERMATOLOGY COURSES CREDITS: 0.5

For more credit information, please turn to p. 52.

Dermatology Clinic

page 53

Case #1: Pellagra 1. A 40-year-old man presenting with dermatitis and watery diarrhea is suspected of having primary pellagra. Which of the following scenarios would explain the etiology of his disease? a. The patient is homeless and has been taking isoniazid for treatment of tuberculosis. b. The patient is of low socioeconomic status and has a diet primarily consisting of Mexican maize. c. The patient has a history of abdominal pain and anal fistulas consistent with Crohn disease. d. The patient has a history of anorexia nervosa and psychiatric disturbances. 2. Which of the following statements is correct about the treatment for pellagra? a. Topical corticosteroids and anticholinergics quickly resolve the symptoms of dermatitis and diarrhea. b. Oral niacin replenishes the coenzymes in oxidation-reduction reactions and does not cause headache and flushing. c. Oral nicotinamide replenishes the coenzymes in oxidation-reduction reactions involved in the synthesis of fats, carbohydrates, and proteins. d. Oral vitamin supplementation reverses all symptoms of pellagra within 2 days.

Dermatologic Look-Alikes

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Case #1: Periungual warts 1. A patient presents with a firm, rubbery, hyperpigmented mass that measures 7 mm × 4 mm × 6 mm and is located at the junction of the fingernail and nail bed on the fourth finger of his left hand. The patient states that there used to be a wart in that exact location, for which he was treated at another clinic several months ago. This mass slowly began to grow after he received treatment for the wart. What type of therapy was used to treat this patient? a. Liquid nitrogen cryotherapy c. Podophyllin b. Electrosurgery d. Contact immunotherapy 2. A 24-year-old woman seen regularly for cutaneous viral warts reports that she has had no new lesions after recently completing a 3-course vaccination with the quadrivalent human papillomavirus (HPV) vaccine. Why has her verruca vulgaris resolved? a. The quadrivalent HPV vaccine protects against the strains of HPV that cause common warts. b. Common warts are caused by strains present in the quadrivalent HPV vaccine as well as other strains of HPV. c. There is antigenic epitope cross-reactivity between the vaccine’s HPV types and those responsible for common warts. d. The quadrivalent HPV vaccine increases the host’s immune response to all strains of HPV.

Case # 2: Laugier–Hunziker syndrome 3. Which of the following is not in the differential diagnosis for the lesions seen in Laugier–Hunziker syndrome? a. Bandler syndrome b. Peutz–Jeghers syndrome c. Albright hereditary osteodystrophy d. McCune–Albright syndrome

Case #2: Subungual exostosis 3. A 16-year-old boy presents with a worsening lesion on his right great toe. He was seen at another clinic, diagnosed with a periungual wart, and treated with several rounds of liquid nitrogen cryotherapy. The mass has continued to grow despite the cryotherapy and is elevating the nail plate and causing great pain. On examination, a flesh-colored nodule is located beneath the free edge of the nail, with local ulceration and hyperkeratosis of the skin. What is the next best step? a. Continue liquid nitrogen cryotherapy treatments b. Salicylic acid therapy c. Carbon dioxide laser therapy d. Surgical excision

4. Bandler syndrome includes labial and genital hyperpigmentation and which finding? a. Intestinal polyposis b. Intestinal vascular malformations c. Precocious puberty d. Nail hyperpigmentation

4. Which of the following factors would NOT support a diagnosis of subungual exostosis? a. History of trauma to the affected toe b. Elevation of the nail from the nail bed c. Pruritus of the affected toe d. Histopathology consistent with a mature trabecular pattern

TO TAKE THE POSTTEST please go to: myCME.com/Feb16CAderm

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LEGAL ADVISOR CASE

Violation of patient privacy

BY ANN W. LATNER, JD

Ms. V, aged 39 years, was a nurse working in a medical clinic in upstate New York. She had been working for the clinic for the past 7 years and was pleased with both her career and the professional direction it was taking. Over the last several years, she had received glowing reviews from both supervisors and patients, and the clinic had responded by giving her increasingly greater responsibility. The best part of the job was its regular hours, which enabled Ms. V to spend quality time with her 3 young children. Ms. V heard stories from nurses at other facilities who had to work weekends, nights, and double shifts, and she appreciated her working situation. She imagined a long and successful career at the clinic. Unfortunately, this was not to be the case. One typical day at the clinic, Ms. V was treating a new patient, Mr. D, 30, for a sexually transmitted disease (STD). Although Ms. V had never met the patient before, there was something very familiar about him that she puzzled over as she conducted the examination. As she stepped out of the examination room

A nurse divulges a patient’s sexually transmitted disease to his girlfriend, who happens to be the nurse’s sister-in-law. Ms.V was dismissed from her job at the clinic after divulging private patient information to the patient’s girlfriend.

for a moment to retrieve a prescription pad, she suddenly realized why the patient seemed familiar. His name, age, and description were the same as the new boyfriend of Ms. V’s sisterin-law, Mary. Mary had been dating someone who sounded just like Mr. D for a few months, and although Ms. V had not met him, she had heard a lot about him from Mary, who was clearly taken with him. Ms. V’s heart sank. She did not know what to do. Assuming this was the same man, how could she not tell her sister-in-law about this distressing news, which could potentially affect her health? Although Ms. V was well aware of privacy issues and knew she should not be discussing her patient’s health in this manner, she decided to contact Mary to find out if the patient in her Continues on page 68

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.

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LEGAL ADVISOR clinic was Mary’s boyfriend. In the hallway, Ms. V texted her sister-in-law to ask the name and description of her boyfriend on her cell phone. Mary responded promptly, answering with a name and description that matched the patient in the exam room. Now Ms. V was even more torn. She was close to her sister-in-law, who was only in her 20s and who viewed Ms. V as a role model. Ms. V felt that Mary had the right to know this information since she was either already having sexual relations with Mr. D, or was considering it. With only a few moments to think it through, Ms. V made the decision. She picked up her cell phone again and began texting her sister-in-law, letting her know that her boyfriend was at the clinic and had an STD. Then, she went back to the exam room and finished up with her patient, who thanked her and left. The next day, Ms. V’s sister-in-law broke off her relationship with Mr. D, after confronting him with her knowledge about his STD. Mr. D realized that this information must have been conveyed by Ms. V, and he called the clinic to angrily complain that Ms. V had no right to tell anyone about his personal health information. The administrator who spoke with Mr. D promised him that the clinic would look into it and get back to him. When Ms. V was summoned to the administrator’s office, she had a sinking feeling. When the administrator asked her about what had happened, Ms. V answered truthfully.

A lower court and an appeals court ruled that there was no liability for the employer when the employee acts outside the scope of her employment. “I realized that my patient was the boyfriend of my sisterin-law,” she said, “and that he was suffering from an STD that he hadn’t told her about. I didn’t know what to do. I understand that he is entitled to his privacy, but I had to protect my sister-in-law too....” The administrator put her head in her hands and sighed loudly. She asked Ms. V to return to her office at the end of the day to discuss it further. At the end of the day when Ms. V returned to the administrator’s office, she found that the clinic’s managing physician and its security guard were in the office along with the grim-faced administrator. Regretfully but firmly, the physician and administrator informed Ms. V that she was being dismissed from her

position due to her improper sharing of patient information. They told her that she should not use them for a reference, and Ms. V should not contact them for a referral in the future. They further informed her that if a future employer called to ask about her, they would feel compelled to share the information about the breach of privacy, even though Ms. V’s previous work had been exemplary. The security guard then escorted Ms. V out of the clinic. The clinic followed up with Mr. D and informed him that appropriate disciplinary action had been taken and that Ms. V had been fired. Ms. V spent months trying to find a job equal to the one she had lost, but without a recommendation or reference to explain the previous 7 years, it was difficult. After close to a year of searching for a new position, she finally accepted a position at a much lower level, with a lower salary and fewer chances for growth. Legal background

Mr. D did not opt to sue Ms. V directly, although he could have. He did, however, attempt to sue Ms. V’s former employer, the clinic, but the case was dismissed. The lower court, followed by an appeals court, held that under New York law there is no liability for the employer when the employee acts outside the scope of her employment. Protecting yourself

Although Ms. V was not, herself, sued in this case, her life and career were forever changed by her decision to reveal Mr. D’s personal health information. Certainly, her desire to protect her sister-in-law was understandable, but actually texting the information was absolutely unacceptable and clearly was a violation of her patient’s privacy, as Ms. V was aware. So what could she have done instead? The best option would have been to talk to her patient about the importance of conveying his STD information to current and potential sexual partners. She should have encouraged him to be the one to share that information himself (without letting him know that she was related to his girlfriend). Instead, her decision to convey the patient’s private information damaged her career path and her future. If you are ever in a similar position, remember that a patient’s privacy is paramount. Your patient has trusted you with his or her most personal information, and it is your responsibility to respect that trust and your patient’s privacy. n Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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Clinical Challenge Markedly elevated serum transaminase levels LAURA A. FOSTER, CRNP, FNP

An incidental finding in an asymptomatic woman is followed by rapid deterioration of her condition.

Histological section of striated muscle taken from the quadriceps.

Annabelle, an 18-year-old white woman, was referred by her primary care provider to our gastroenterology practice for markedly elevated serum transaminase levels. Her mother and grandmother accompanied her. The patient had no complaints at presentation. Her only sibling, a 20-year-old sister, had recently been given a diagnosis of hereditary hemochromatosis; she was not undergoing phlebotomy at that time. Annabelle had come in for screening and was found to have markedly elevated serum transaminase levels: aspartate aminotransferase (AST) 539 U/L and alanine aminotransferase (ALT) 361 U/L. The remaining levels were within normal limits: alkaline phosphatase 31 U/L, total bilirubin 0.5 mg/ dL, direct bilirubin 0.1 mg/dL, albumin 3.9 g/dL, and total protein 6.8 g/dL. Her hepatitis panel was nonreactive. Her hepatitis B surface antibody was reactive, and this suggested immunity. An ultrasound of her abdomen was unremarkable. At 2 years prior, her AST and ALT levels had been normal: 23 and 16 U/L, respectively.

CASE

HISTORY Two months earlier, under the direction of a local allergist, Annabelle had begun treatment with allergy serum for Raynaud phenomenon. A friend of the family, who is an oncologist, remarked that the histamine in the allergy serum could cause elevated transaminase levels. However, the allergist maintained that he had never encountered this type of reaction in his 20-plus years of practice. In addition, Annabelle had had a tattoo placed on her right lower abdomen 3 months earlier and had undergone umbilical piercing 1 year earlier. She denied past and present use of illegal drugs and promiscuous behaviors. She was not using acetaminophen or alcohol in excess. She was planning to enter a nearby university as a freshman in the coming fall. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2016 73

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Clinical Challenge LABORATORY TESTS AND IMAGING The immediate plan was to rule out conditions that can cause hepatocyte injury, such as autoimmune hepatitis, Wilson disease, hemochromatosis, cytomegalovirus infection, Epstein-Barr virus infection, and celiac sprue. Therefore, the following laboratory tests and measurements were ordered: serum immunoglobulin A (IgA), IgG, and IgM; protein electrophoresis; anti-mitochondrial antibody; antinuclear antibody; gamma-glutamyl transpeptidase (GGT); ceruloplasmin; serum iron, ferritin, and fasting transferrin; vitamin B12; cytomegalovirus antibody titer; monospot with reflex Epstein-Barr virus antibody panel; IgA tissue transglutaminase; hemoglobin A1C; and thyroidstimulating hormone (TSH). All values were within normal limits. Annabelle’s vitamin B12 level was low normal at 197 pg/mL. Her AST and ALT levels had risen to 670 and 487 U/L, respectively. Magnetic resonance imaging of the liver was ordered, and it showed mild hepatomegaly, a homogeneous liver parenchyma, no enhancing lesions or biliary duct dilation, and no evidence of cholelithiasis or choledocholithiasis. The utility of a liver biopsy was discussed, and the patient was advised to follow up with the supervising gastroenterologist, Dr. S.F.M. After 9 days, Annabelle returned for a visit with Dr. S.F.M., who, because of the AST>ALT pattern and the recent history of Raynaud phenomenon, suspected a mixed connective tissue disease or perhaps scleroderma. Additional laboratory measurements were ordered: anti-double-stranded DNA antibody, complement C3 and C4, liver/kidney microsomal antibody, and other autoimmune antibodies. All values were within normal limits. Dr. S.F.M. then referred Annabelle to a rheumatologist at a nearby tertiary center. In the meantime, Annabelle experienced the rapid onset of progressively worsening proximal muscle weakness, with marked weakness of her limbs. She had obvious difficulty standing up from a sitting position. She went to see the rheumatologist, who, because of the AST>ALT pattern and her new complaint of muscle weakness, suspected a muscular etiology. Serum creatine kinase (CK) and aldolase levels were ordered. An evaluation by a neurologist was considered to rule out the possibility of Guillain-Barré syndrome, as she had received the meningococcal vaccine 4 to 6 weeks earlier. A vascular pathology was also considered. Interestingly, her laboratory test results included a markedly elevated CK level at 23,822 U/L, and the aldolase level was also high at 226 mg/dL (range 88-174). A provisional diagnosis of myositis with proximal myopathy was made.

Annabelle was admitted to the hospital for further testing and intravenous hydration, as a CK level above 16,000 U/L is associated with acute renal failure. Computed tomography of the abdomen and pelvis with contrast showed bilateral anterior thigh compartment–predominant myositis and mild third spacing. A left deltoid muscle biopsy was performed under monitored anesthesia care (MAC) with local anesthesia. The pathology report indicated that (1) the exact subtype of autoimmune inflammatory myopathy was not clear, with some features favoring dermatomyositis and some consistent with a synthetase syndrome (a rare medical condition associated with interstitial lung disease, dermatomyositis, polymyositis, and autoimmune diseases), and that (2) substantial perimysial pathology and substantial necrosis were present. Electromyography showed electrodiagnostic evidence of myopathy with irritable muscle membrane and evidence of active denervation and myopathic motor unit action potentials (MUAPs), with recruitment seen predominantly in the proximal limb muscles. In acute myopathic disorders with active inflammation and/or necrosis, denervation activity can be prominent, MUAPs will be small and polyphasic, and recruitment patterns will be full with decreased amplitudes.

DIAGNOSIS AND TREATMENT The final diagnosis was autoimmune inflammatory myositis of the necrotizing myopathy subtype. Annabelle was treated with a loading dose of methylprednisolone sodium succinate (1 g intravenously daily for 3 days), followed by pulsed prednisone (by mouth beginning at 60 mg). Vitamin B12 (1 mg, subcutaneously weekly) and folic acid (1 mg by mouth daily) were also prescribed. At follow-up after discharge from the hospital, Annabelle reported only a modest decrease in muscle weakness, although she had been on high-dose prednisone for 15 days. She still could not raise her arms against gravity, nor could she stand up from a sitting position. A family member had to pull her up from her chair. She had been to several sessions of physical therapy for passive range of motion. Furthermore, the prednisone was causing sleep disturbance. On examination, Annabelle had normal passive range of motion in both her upper and lower extremities. Muscle weakness was 3– in the proximal upper and lower extremities and 4– in the distal extremities. Her gait was slow, and she dragged her legs. Her CK level decreased to 3,000 U/L. The antisynthetase antibody work-up was negative for Continues on page 77

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Clinical Challenge antisynthetase syndrome. She was advised to decrease the prednisone by 10 mg per week until the dose was 40 mg daily, then by 5 mg per week until it was 20 mg daily, then by 2.5 mg every 2 weeks until it was 10 mg daily, and then by 1 mg every 2 weeks until it was 5 mg daily. Methotrexate was initiated at a dosage of 15 mg by mouth weekly with slow titration upward to a maximum dose of 25 mg weekly. She was also given 50 mg of trazodone as needed for sleep. After 6 weeks, her indolent course persisted. A trial of intravenous rituximab was started. Rituximab is a monoclonal antineoplastic, antirheumatic, and immunosuppressant agent. Pretreatment with acetaminophen and an antihistamine is recommended for all indications.

OUTCOME Annabelle is followed regularly at the rheumatology clinic. Her medication includes an intravenous infusion of rituximab every 4 weeks and low-dose prednisone daily. Her oral methotrexate was switched to a subcutaneous injection weekly. Overall, her condition has improved. She no longer needs a wheelchair to get around the university campus. She walks independently but still requires occasional assistance to stand up from a sitting position. Her spirits are good, and she has a great support system with family and friends.

DISCUSSION Hepatocyte injury. Mild elevations in the levels of AST and ALT are commonly discovered in asymptomatic patients. Evidence to guide the diagnostic work-up is limited. If the history and physical examination findings do not suggest a cause, a stepwise evaluation should be initiated based on the prevalence of diseases that cause elevated serum transaminase levels. Common causes include nonalcoholic fatty liver disease, alcoholic liver disease, medication-associated hepatocyte injury, viral hepatitis, and hemochromatosis. Less common causes include alpha1antitrypsin deficiency, autoimmune hepatitis, and Wilson disease. Extrahepatic conditions such as thyroid disorders, celiac sprue, hemolysis, and muscle disorders can also cause elevated serum transaminase levels. Initial testing should include a lipid panel and measurement of the serum iron and ferritin levels, total iron-binding capacity, and hepatitis B surface antigen and hepatitis C virus antibody titers.1 Raynaud phenomenon. Annabelle’s Raynaud phenomenon is believed to be secondary to her autoimmune inflammatory myositis. Because a variety of possible insults

TABLE 1. Disorders and factors associated with Raynaud phenomenon DRUGS/TOXINS

• Chemotherapeutic agents • Cocaine • Ergotamines • Interferons • Nicotine • Polyvinyl chloride • Sympathomimetic agents

ENDOCRINE

Hypothyroidism

ENVIRONMENTAL

• Emotional stress • Frostbite • Vibration injury

HEMATOLOGIC/ ONCOLOGIC

• Cold agglutinin • Cryofibrinogenemia • Cryoglobulinemia • Paraneoplastic syndrome • Paraproteinemia • POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) syndrome

NEUROLOGIC

• Carpal tunnel syndrome • Migraine headache

RHEUMATOLOGIC

• Mixed connective tissue disease • Polymyositis/dermatomyositis • Scleroderma • Sjögren syndrome • Systemic lupus erythematosus • Undifferentiated connective tissue disease

VASCULAR

• Atherosclerosis • Emboli • Prinzmetal angina • Thoracic outlet syndrome • Thromboangiitis obliterans • Vasculitis

Source: Adapted from Block JA, Sequiera W. Raynaud’s phenomenon. Lancet. 2001;357(9273);2042-2048.

can disrupt the normal complex regulation of regional blood flow to the digits and skin, the number of disorders associated with Raynaud phenomenon is extensive (Table 1). The most commonly associated disorders are scleroderma, systemic lupus erythematosus, mixed connective tissue disorder, overlap syndromes, polymyositis, rheumatoid arthritis, Sjögren syndrome, undifferentiated connective tissue disorder, and vasculitis.2 Inflammatory myopathies. The inflammatory myopathies are a group of disorders that share the feature of immune-mediated muscle injury. Clinical and histopathologic distinctions among these various conditions suggest that a different pathogenic process underlies each inflammatory myopathy (Figure 1). The most common of these disorders

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Clinical Challenge TABLE 2. Neuromuscular causes of elevated muscle enzymes Drugs/toxins Alcohol Antimalarials Cocaine Colchicine Lipid-lowering agents: statins, fibrates, niacin Penicillamine Zidovudine

Infectious myopathies • Bacterial pyomyositis • Fungal myositis • Mycobacterial myositis • Parasitic myositis • Spirochetal myositis • Viral myositis

Motor neuron disease • Amyotrophic lateral sclerosis • Spinal muscular atrophies

Dystrophinopathies Becker muscular dystrophy Duchenne muscular dystrophy Duchenne and Becker carriers Facioscapulohumeral muscular dystrophy Limb-girdle muscular dystrophy Myotonic dystrophy

Inflammatory myopathies • Behçet disease • Dermatomyositis and polymyositis • Inclusion body myositis • Juvenile dermatomyositis and polymyositis • Localized myositis • Myositis with associated connective tissue disease: Sjögren syndrome, scleroderma, lupus, and rheumatoid arthritis • Polymyositis associated with graft-versus-host disease • Sarcoidosis • Systemic necrotizing vasculitis

Periodic paralysis • Familial periodic paralysis • Thyrotoxic periodic paralysis

Endocrine myopathies • Acromegaly • Hypothyroidism

Malignant hyperthermia

Post-exercise

Iatrogenic • Electromyography • Intramuscular injection • Intraoperative muscle injury

Metabolic myopathies • Carbohydrate, lipid, and purine metabolite deficiencies

Rhabdomyolysis • Electrolyte disturbances: hypokalemia, hypophosphatemia • Environmental heat illness • Extreme exertion • Seizures, delirium tremens • Trauma, crush injuries, coma

Source: Adapted from Miller ML. Muscle enzyme evaluation in neuromuscular diseases. UpToDate website. http://www.uptodate.com/contents/muscle-enzymes-in-the-evaluation-ofneuromuscular-diseases. Updated April 8, 2013. Accessed January 11, 2016.

are dermatomyositis overlap syndromes with other rheumatic disease, inclusion body myositis, and polymyositis. Neither environmental factors nor infectious causes have known roles in these disorders. Other subtypes of inflammatory myopathies include necrotizing myopathy, eosinophilic myositis, and granulomatous myositis. Many patients with inflammatory myopathy cannot be assigned to any category and may be classified as having nonspecific myositis. The precise mechanisms leading to tissue injury in the inflammatory myopathies are poorly defined in most cases.3 A study by Mathur et al. found a strong correlation between CK and serum transaminase levels. Serum transaminases were elevated in 80% of patients at the time of presentation and normalized in 85% of patients at the time of CK normalization. Appropriate recognition of these changes in laboratory parameters in the inflammatory myopathies help reduce unnecessary hepatic evaluation, delayed diagnosis,

unnecessary administration of second-line immunosuppressant agents, and misdiagnosis of primary liver disease.4 Patients presenting with nonspecific arthralgias, myalgias, or constitutional symptoms that may overshadow the presence of muscle weakness are commonly evaluated with a multichannel chemical analyzer in which elevated lactate dehydrogenase and transaminase levels may first suggest the presence of liver disease. In this setting, a careful assessment of muscle strength and measurement of the CK and aldolase levels should lead to the correct diagnosis of muscle disease and the avoidance of unnecessary liver biopsy.5 Neuromuscular causes of elevated muscle enzymes are listed in Table 2. Treatment of inflammatory myopathy. The first-line treatment of an inflammatory myopathy is a corticosteroid at a dose of 1 mg/kg. The sooner the therapy is started, the better the outcome. The timing of the addition of other

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immunosuppressive agents is controversial, but methotrexate and azathioprine are the most commonly used agents. If the condition flares during the corticosteroid taper, then additional medication is absolutely warranted. However, many rheumatologists add a second medication earlier in the hope of limiting the significant side effects of corticosteroids. Patients who respond poorly to corticosteroids or have rapidly progressive disease can be treated with intravenous immunoglobulin (IVIG) at a dosage of 2 g/kg divided over 2 to 5 days. A trial of rituximab in patients with resistant disease is ongoing.6 Multiple options exist for treating patients who do not respond adequately to corticosteroids plus azathioprine or methotrexate. Evidence of clinically significant benefit is greatest with intravenous rituximab and IVIG. If effective, rituximab may lead to a prolonged period of disease control, whereas many patients who respond to IVIG require monthly infusions. Unfortunately, long-term follow-up of these patients is limited. The largest trial of rituximab in inflammatory myositis, the Rituximab in Myositis (RIM) trial, involved 195 patients, including 75 with adult dermatomyositis and polymyositis and 48 with juvenile dermatomyositis, who had disease refractory to corticosteroids and at least one immunomodulatory agent. The results suggested that rituximab may be effective in these populations.7 n

“O.K., kid. Busy man here. Quality time. Here we go.”

Laura A. Foster, CRNP, FNP, practices family medicine with Palmetto Primary Care Physicians in Charleston, S.C. References 1. Oh RC, Hustead TR. Causes and evaluation of mildly elevated liver transaminase levels. Am Fam Physician. 2011;84(9):1003-1008.

2. Wigley FM. Clinical practice. Raynaud’s phenomenon. N Engl J Med. 2000;347(13):1001-1008. 3. Greenberg SA. Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications. Neurology. 2007;69(21): 2008-2019. 4. Mathur T, Manadan A, Thiagarajan S, et al. Serum transaminases are frequently elevated at time of diagnosis of idiopathic inflammatory myopathy and normalize with creatine kinase. J Clin Rheumatol. 2014;20(3):130-132. 5. Helfgott SM, Karlson E, Beckman E. Misinterpretation of serum transaminase elevation in “occult” myositis. Am J Med. 1993;95(4):447-449. 6. Cronin ME. Idiopathic inflammatory myopathies. Just Joints. 2014;11(1). Available at: www.wi-rheum.org/files/file/Idiopathic%20Inflammatory%20 Myopathies%202_09.pdf 7. Mahler EA, Blom M, Voermans NC, et al. Rituximab treatment in patients with refractory inflammatory myopathies. Rheumatology. 2011;50(12):2206-2213.

“I’m only a good dane.”

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Evidence-Based Medicine This department uses the best available scientific findings to offer practice guidance on a wide range of conditions seen in primary care.The author, Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Mass., and assistant clinical professor in Family Medicine, University of Massachusetts Medical School in Worcester. DynaMed (www.ebscohost.com/dynamed/) is a database that provides evidence-based information on more than 3,000 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.The most important evidence identified is summarized here.

IN PATIENTS WITHOUT CVD OR DIABETES, POOLED COHORT EQUATIONS MAY UNDERESTIMATE RISK FOR CV EVENT IF OTHER RISK FACTORS ARE PRESENT Circulation. 2015;132(10):916-922 Level 2 (mid-level) evidence

Accurate prediction of cardiovascular disease risk is crucial for the success of preventive measures. The American College of Cardiology/ American Heart Association (ACC/AHA) 2013 guidelines recommend using race- and sexspecific Pooled Cohort Equations (PCE) to determine risk for atherosclerotic cardiovascular disease in patients aged 40 to 79 years. Treatment with high- or moderate-intensity statins is recommended for patients with a 10-year risk for atherosclerotic cardiovascular disease ≥7.5% on PCE. ACC/AHA guidelines also suggest considering other risk factors in those with PCE risk <7.5%, but this recommendation is limited by a lack of empiric evidence. In a recent cohort study, 5,185 adults without baseline cardiovascular disease, statin use, or ankle brachial index ≥1.4 were evaluated to determine how PCE statin eligibility corresponded to observed cardiovascular events. The study evaluated 5 additional risk factors for cardiovascular disease: elevated coronary artery calcium score, myocardial infarction or stroke in first-degree relative, high-sensitivity C-reactive protein level ≥2 mg/dL, ankle brachial index <0.9; and low-density lipoprotein cholesterol level ≥160 mg/dL but <190 mg/dL. Atherosclerotic cardiovascular events, defined as myocardial infarction, coronary heart disease death, or fatal/nonfatal stroke, occurred in 6.2%

Study results suggest that Pooled Cohort Equations are not perfect and may underestimate the risk for atherosclerotic cardiovascular events in some patients.

of adults during the median 10.2-year follow-up. The event rate was 13.8% in the 1,000 adults with ≥7.5% risk and 4.7% in 4,185 adults with <7.5% PCE risk. These additional risk factors were reassessed in the 3,882 adults in the study without diabetes and with an initial PCE risk <7.5% to more accurately determine the degree of risk for purposes of statin initiation. Overall, 11.1% were reclassified using at least 1 additional factor to ≥7.5% 10-year risk for atherosclerotic cardiovascular events, and according to the 2013 ACC/AHA guidelines, should receive statin therapy. Adults reclassified using coronary artery calcium level, family history, or highsensitivity C-reactive protein had an observed 10-year cardiovascular event rate >10%, and were therefore at greater risk than the 7.5% threshold. Three of the 5 additional risk factors examined identified patients originally classified as low risk who actually had a higher risk for cardiovascular events. The results of this study suggest that these equations may underestimate the risk for atherosclerotic cardiovascular events in some patients without diabetes who are classified as low risk. These results underscore that the PCE is not perfect. The PCE is a valuable risk assessment tool, but it should not be used blindly. The decision to initiate statin therapy requires individualized decision making, including consideration of additional factors that influence risk assessment. The quality of the evidence supporting each item is rated from Level 1 (highest) to Level 3 (lowest). Absolute risk reductions are presented as the number needed to treat (NNT) for one patient to benefit. Absolute risk increases are presented as the number needed to harm (NNH).

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IN PATIENTS WITH FIRST UNPROVOKED VENOUS THROMBOEMBOLISM, ADDING CT TO LIMITED CANCER SCREENING MAY NOT LEAD TO STATISTICALLY HIGHER RATE OF CANCER DETECTION N Engl J Med. 2015;373(8):697-704 Level 2 (mid-level) evidence

Unprovoked venous thromboembolism (VTE), a VTE occurring in the absence of triggering events or risk factors, has been associated with the presence of occult malignancies. The prevalence of undiagnosed cancer 1 year after VTE may be as high as 10%; a systematic review found that, at the time of VTE event, the rate of missed diagnosis was approximately 4%. In those with unprovoked VTE, routine evaluation should include basic cancer workup comprised of history and physical examination, complete blood count, erythrocyte sedimentation rate, renal and liver function tests, urinalysis, and chest x-ray. The addition of imaging tests (such as computed tomography [CT] or ultrasound) and molecular biomarkers have been proposed to reduce the rate of missed cancer diagnoses at the time of VTE. However, in previous studies that compared the use of limited screening with the use of extensive screening procedures, no significant differences were found in overall cancer detection or in cancer-related mortality. To look at the specific role CT might play in cancer detection, a recent randomized trial compared limited cancer screening plus pelvic and abdominal CT versus limited cancer screening alone in 852 adults (mean age 53 years, 67% male) with first unprovoked symptomatic VTE. Limited cancer screening included a complete history and physical examination, basic blood tests (complete blood count, serum electrolyte level, creatinine level, and liver function testing), chest x-ray, and sex-specific cancer screening if not performed in the prior year (breast, cervical, and prostate). Pelvic and abdominal CT screening included a virtual colonoscopy and gastroscopy, biphasic enhanced liver CT, parenchymal pancreatography, and uniphasic enhanced distended bladder CT. Of the total patients, 95% completed the 1-year follow-up. Rates of cancer detection at screening were 3.3% with limited screening plus CT versus 2.3% with limited screening alone (not significant). At 1-year follow-up, 4.5% of patients who had limited cancer screening plus CT and 3.2% of patients who had limited screening alone were diagnosed with cancer, resulting in rates of missed diagnosis at screening of 1.18% and 0.93%, respectively (not significant). These results correspond to 5 of 19 cancers (26%) missed with the more extensive protocol

A virtual colonoscopy permits the 3D-reconstruction of the inner colon from computerized color scanner images.

and 4 of 14 cancers (29%) missed with limited screening alone. There were also no significant differences in mean time to cancer diagnosis, recurrent VTE, overall mortality (1.4% vs 1.2%, P=1), or cancer-related mortality (1.4% vs 0.9%, P=.75). The results of this randomized trial suggest that, after initial cancer screening in those with VTE, the rate of cancers detected during the subsequent year is not enhanced by the use of extensive abdominal and pelvic CT scanning. The key issue is whether extensive screening at initial workup results in a slight increase in the rate of detected cancers. Although not statistically significant, the 1% higher detection rate using extensive screening at initial workup is consistent with results of previous systematic reviews, randomized trials, and other studies that have shown 1% to 2% additional yield for cancer detection when extensive screening was used. There are, however, significant limitations to the interpretation of these results, including low event rates and wide confidence intervals, which make it impossible to rule out a small benefit associated with CT imaging for cancer detection. Regardless, whether a small increase in cancer detection rate translates to meaningful clinical outcome remains unproven, and the use of multiphasic CT of the abdomen and pelvis includes a risk for subsequent radiationinduced malignancy. This risk has been estimated at 1 in 460 to 500 persons for a 40-year-old person (Arch Intern Med. 2009;169[22]:2078-2086). For now, the use of limited screening, including routine screening for cancer based on age- and sex-based recommendations for the general population, seems appropriate for most patients.

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Evidence-Based Medicine GLASGOW COMA SCALE MAY UNDERESTIMATE SEVERITY OF ISOLATED TRAUMATIC BRAIN INJURY IN PATIENTS AGED ≥65 YEARS Emerg Med J. 2015;32(8):613-615 Level 2 (mid-level) evidence

The Glasgow Coma Scale (GCS) is a simple and well-validated tool used to assess the degree of brain injury in patients with head trauma. The GCS is used not only as part of the patient assessment to help guide initial treatment and potential transfer to major trauma centers, but it also plays an important role in determining continued patient care and prognosis. Previous reports have suggested that elderly adults with moderate-to-severe traumatic brain injury may have higher presenting GCS scores than younger adults ( J Trauma. 2004;56[5]:1042-1048), but that study included only 44 patients aged ≥65 years. A recent retrospective cohort study assessed the GCS scores of 561 patients with significant isolated traumatic brain injury, defined as a head Abbreviated Injury Scale (AIS) score of 3 to 5 and no additional injuries. About 57% of patients were aged ≥65 years. There were no significant differences in distribution of head AIS scores between those ≥65 years and those <65 years. Presenting GCS scores and survival rates were significantly different between elderly and younger patients, however (Table). Patients <65 years

P value

Severe GCS score (3-8)

9.8%

22.1%

<0.001

Survival

77.6%

93.6%

<0.001

Median GCS score in nonsurvivors

4.5

<0.01

Median GCS score in patients with head AIS score 5 (critical injury)

<0.05

The results of this study suggest that GCS may be less accurate for predicting the extent of isolated traumatic brain injury in those aged ≥65 years compared with younger adults. This is consistent with current guidelines that recommend age >65 years as an indication to perform noncontrast head computed tomography in patients with no loss of consciousness or posttraumatic amnesia (Ann Emerg Med. 2008;52[6]:714-748; NICE Guidelines. 2014; Jan 22:CG176). Given the role of GCS in assessing and treating patients with traumatic brain injuries, it is important to consider these results when treating elderly patients with traumatic head injury. n

“E.”

“O.K., we get it—big and dangerous.”

Patients ≥65 years

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Gaylord Palms, Orlando, FL April 7-9, 2016

This activity is provided by Haymarket Medical Education This program was planned in accordance with AANP CE Standards and Policies and AANP Commercial Support Standard This educational activity is supported by Dopomed, Inc.

Putting the Critical Pieces Together for NPs and PAs in Primary Care Leading Topics To Be Addressed at the Summit: Principal Practice Issues • Improving Healthcare Delivery • Interprofessional Collaboration • Patient Health Literacy • Understanding the ICD-10 Coding Language • What’s New With DSM-5? Prevalent Patient Conditions • Aging • Diabetes • Hypertension • Obesity • Women’s Health

The Clinical Advisor Summit is a 3-day educational and networking event offering a comprehensive agenda to advance an NP’s and PA’s primary care practice. The Summit features more than 15 sessions (up to 14 CE/CME credits) that will address patient management, including chronic disease management such as diabetes, respiratory disease, and obesity, as well as current issues in immunization. CA SUBSCRIBERS SAVE $50 ON CURRENT REGISTRATION FEE! Mention required code CAPA4Feb when registering on or before 3/11/16 and the fee per clinician will be $175. Offer is valid for new registrants only and cannot be combined with other offers.

Visit www.ClinicalAdvisorSummit.com CA NavSum_fullpg_0216.indd 1

PHYSICIAN ACCREDITATION STATEMENT Haymarket Medical Education is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

NURSE PRACTITIONER CONTINUING EDUCATION

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1/29/16 10:05 AM

Stat Consult

A quick review of common conditions, using the best global evidence

Background

Norovirus infection ALAN DRABKIN, MD

Dr. Drabkin is a senior clinical writer for DynaMed (www.ebscohost. com/dynamed), a database of comprehensive updated summaries covering more than 3,200 clinical topics, and assistant clinical professor of population medicine at Harvard Medical School.

Ultrastructural morphology displayed by Norovirus virions.

• leading cause of both sporadic and epidemic gastroenteritis worldwide — non-enveloped RNA virus — genotype GII.4 associated with majority of global outbreaks since mid-1990s but new pandemic strains emerge every 2 to 4 years — reported to cause about 50% of epidemic gastroenteritis and >90% of nonbacterial epidemic gastroenteritis • estimated at 21 million cases, >70,000 hospitalizations, and 800 deaths annually across all age groups • most common viral cause of traveler’s diarrhea • important cause of traveler’s diarrhea in Latin America and Africa • Highly contagious due to — low infectious dose (as few as 18 viral particles) — environmental stability able to withstand temperatures from 0° to 60° C (32° to 140° F) — survives up to 10 parts per million chlorine — stable for long periods (up to 2 weeks) on environmental surfaces, which may act as a reservoir during outbreaks — in water, virus able to infect human volunteers after 2 months and intact viral capsid detected after 3 years — multiple potential routes of transmission • Fecal-oral transmission is main means of spread, but may also be transmitted from person to person, via fomites or aerosolized from vomitus. • Short incubation period from time of exposure to infection (typically 24 to 48 hours). • Peak incidence typically occurs in winter months in temperate climates • Risk factors — Proximity to infected persons (primary risk factor) with outbreaks often occurring in ■ cruise ships ■ healthcare settings ■ child care centers ■ nursing homes ■ hotels or other food service locations

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Stat Consult ——Ingestion of contaminated food or water associated with infection, particularly ■■ raw shellfish ■■ prepared foods ■■ recreational water facilities ——Immunocompromised patients may be predisposed to severe or prolonged disease Evaluation

• Classic clinical presentation ——acute-onset vomiting (may be projectile) ——non-bloody diarrhea ——short-lived fever (<50% ) • Most pathologic changes found in proximal jejunum • Examination ——Assess for signs of dehydration ——Abdominal examination usually benign Diagnosis

• suspect norovirus gastroenteritis in patients with acute onset nausea, vomiting, and diarrhea • laboratory testing not needed in most cases as illness is often self-limited • when laboratory confirmation needed, such as in cases of severe or prolonged illness, options for testing stool include ——real-time reverse transcription polymerase chain reaction (RT-PCR) ■■ test of choice (not available in all areas) ■■ high sensitivity and specificity ——stool antigen testing (immunoassays) ■■ low sensitivity, often genotype-dependent (negative outbreaks should be assessed with RT-PCR) ■■ high specificity ——multiplex assays for simultaneously detecting multiple enteric pathogens are in development • Kaplan criteria ——may aid in distinguishing norovirus from other causes of gastroenteritis in outbreak settings when laboratory confirmation is not possible ——presence of all 4 of the following features has highpositive predictive value during an outbreak ■■ mean or median incubation period 24 to 48 hours ■■ mean or median duration of illness 12 to 60 hours ■■ ≥50% cases having vomiting ■■ stool culture negative for bacterial and parasitic pathogens • Immunity short-lived

Differential diagnosis

• other viral causes of gastroenteritis such as ——rotavirus ——other caliciviruses, such as sapovirus ——astrovirus ——adenovirus ——herpesviruses (typically in immunocompromised hosts) • bacterial gastroenteritides due to organisms such as ——Campylobacter spp. ——Shigella spp. ——Salmonella spp. ——pathogenic strains of Escherichia coli ——Mycobacterium spp. (typically in immunocompromised hosts) • toxin-mediated gastroenteritides such as ——Staphylococcus aureus ——Bacillus cereus ——Clostridium perfringens • parasitic causes of diarrhea such as ——Cryptosporidium spp. ——Giardia lamblia ——Entamoeba histolytica ——anisakiasis • food poisoning from marine toxins (most also associated with neurologic abnormalities), such as ——ciguatera poisoning ——scombroid poisoning ——paralytic shellfish poisoning ——neurotoxic shellfish poisoning ——diarrhetic shellfish poisoning • in transplant recipients, norovirus gastroenteritis may resemble ——allograft rejection ——gastrointestinal graft versus host disease Complications

• rare in immunocompetent hosts • diarrhea may result in dehydration and hypokalemia • may include ——post-infectious dyspepsia ——constipation ——gastroesophageal reflux disease (GERD) ——chronic diarrhea (especially in immunocompromised patients or children) Associated conditions

• May be associated with necrotizing enterocolitis Continues on page 96

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Stat Consult Management

• Oral or IV hydration is mainstay of treatment ——hospitalization for fluid and electrolyte replacement may be needed in some patients, particularly elderly or children • Medication ——No specific antiviral therapy is presently available. ——Treatment options under investigation with limited supporting evidence include ■■ nitazoxanide (may shorten duration of symptoms) ■■ oral immunoglobulin (does not appear to provide long-term symptomatic relief in immunocompromised hosts with prolonged diarrhea) ——reduction or adjustment of immunosuppressive regimen can be considered when feasible Prognosis

• symptoms usually last 24 to 72 hours • outbreaks associated with small increase in risk in all-cause mortality and hospitalization in patients in nursing homes Preventive measures include

Vaccination

• hand hygiene ——hand washing with soap and running water for at least 20 seconds preferred ——use of alcohol-based hand sanitizers controversial due to ■■ reports of higher outbreak rates in care facilities using alcohol-based hand sanitizers ■■ relative inefficacy of hand sanitizers compared with soap from in vitro studies ■■ social distancing of infected patients ——patients should not work during and for 48 to 72 hours after recovery from norovirus gastroenteritis

——food handlers may need to be excluded from work for longer periods, due to prolonged shedding after symptoms cease ——children ■■ should be excluded from school for 3 days from last episode of diarrhea ■■ longer exclusion may be appropriate for children who are younger than 5 years old or who are unable to maintain personal hygiene • isolate infected hospitalized patients ——place on contact precautions in single occupancy room ——cohorting patients may be required during outbreaks and may include placing patients in multi-occupancy rooms or designating contiguous patient care areas within the facility ——contact precautions should be maintained for minimum of 48 hours after symptoms resolve ——consider longer isolation for infants, young children, and immunocompromised patients who may experience prolonged diarrhea and viral shedding • environmental cleaning ——CDC recommends chlorine bleach at 1,000 to 5,000 parts per million (5 to 25 tablespoons household bleach per gallon of water) for hard, nonporous environmental surfaces ——healthcare settings should use cleaning and disinfecting products registered with Environmental Protection Agency (EPA) containing label claims for use in healthcare settings

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ALTERNATIVE MEDS UPDATE

What you should know about the herbs and supplements patients use By Sherril Sego, FNP-C, DNP Ms. Sego is an independent consultant in Kansas City, Mo.

Marijuana

A flowering plant, marijuana has for centuries been produced for its plant fiber, hemp. Because of its strength and endurance, hemp is widely used to make ropes and other fibrous products. Evidence of the existence of marijuana, or Cannabis sativa, can be found in prehistoric archaeological sites in Euro-Asia and Africa.1 The oldest known written description of cannabis use is by the Greek historian Herodotus, who wrote more than 400 years BC about Eurasian Scythians using cannabis in steam baths.1,2

Background Marijuana is the most commonly used illegal drug in the United States.3 Recently, there has been a push for legalization of marijuana because many people now believe that the overall effects of the drug are harmless. Marijuana for recreational use is legal in 4 states, with an additional 19 states approving it for medicinal use.3 Regardless of whether marijuana is legal in individual states, it is still illegal under federal law.

Science The first and most studied medical use of C sativa is in the control of nausea and vomiting caused by chemotherapy.4 For these patients, the antiemetic action is desirable, and the increased appetite resulting from marijuana use is also beneficial, as most patients need to increase food intake.4 Marijuana is also useful for those with wasting diseases such as acquired immune deficiency syndrome (AIDS).4

The component of C sativa that produces the euphoric feeling is tetrahydrocannabinol (THC).5 The mechanism of action that produces euphoria and relaxation is distributed among several receptors in the central nervous system, collectively recognized as the endocannabinoid system.6 When inhaled, THC is absorbed rapidly into the system, peaking within minutes. Marijuana is known to cross the blood-brain barrier and the placenta, but it is accumulated in fat cells. Some very small studies have indicated that THC is useful in lowering intraocular pressure in those with glaucoma. Although there have been findings that THC lowers intraocular pressure, the effect is short-term and nonspecific, indicating that low blood pressure and other central nervous system depressive responses also occur.7 In one study, 9 patients with refractory glaucoma were given THC by either smoking or oral tablet.7 At the end of 9 months, all patients had discontinued the study because of Continues on page 100

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ALTERNATIVE MEDS UPDATE the side effects of THC. A rapid tolerance to THC’s pressure-reducing action was also noted. Other areas of potential medical use of THC include the relief of spasticity in neurodegenerative diseases, for pain reduction, and for seizure control, but there have been few trials of adequate design and significance to recommend THC for these conditions. However, there are many anecdotal descriptions of successful treatment with THC in individuals. In 2014, the directors of the Epilepsy Foundation called for much more lenient policies to allow patients to access marijuana in cases in which traditional therapy was either not tolerated or ineffective.8

Safety, interactions It is unclear whether marijuana is addictive or leads to hard drug use. The impact of THC on an individual varies according to a multitude of circumstances, including age, frequency of use, concomitant substance use, and medication intake. Because of the known changes in visual and motor coordination following recent THC inhalation, researchers are in the process of developing a marijuana breathalyzer.9 Much like alcohol, exhaled levels of THC dissipate rapidly (0.5–2 hours), which may be a significantly limiting factor in the accuracy of the device.

to recommend medical marijuana to patients. FDA-approved dronabinol may be recommended in certain cases. n References 1. Butrica JL. The medical use of cannabis among the Greeks and Romans. Journal of Cannabis Therapeutics. 2002;2(2):51-68. 2. Rawlinson G, trans-ed. The History of Herodotus. The Internet Classics Archive website. http://classics.mit.edu/ Herodotus/history.html 3. Lee J. Which states have legalized marijuana? USA

Marijuana may be beneficial for pain and seizure control.

The impact of THC on an individual varies according to a multitude of circumstances, including age and the frequency of use.

How supplied, dose, cost

Today. http://www.usatoday.com/story/news/nationnow/2014/01/06/marijuana-legal-states-medical- recreational/4343199. January 6, 2014. 4. Beal J, Olson R, Shepard KV, Plasse T. Effect of dronabinol on appetite and weight in AIDS: longterm follow-up. Paper presented at: IX International Conference on AIDS; June 6-11, 1993; Berlin, Germany. 5. Marijuana. National Institute on Drug Abuse website. http://www.drugabuse.gov/drugs-abuse/marijuana. Updated March 2014. 6. Kumar RN, Chambers WA, Pertwee RG. Pharmacological actions and therapeutic uses of cannabis and cannabinoids. Anaesthesia. 2001; 56(1):1059-1068. 7. Jampel HD. Should you be smoking marijuana to treat your glaucoma? Glaucoma Research Foundation. http://www.glaucoma.org/treatment/should-you-be- smoking-marijuana-to-treat-your-glaucoma-1.php. Updated June 25, 2013. 8. Gattone PM, Lammert W. Epilepsy Foundation calls for

Summary

increased medical marijuana access and research. http:// www.epilepsy.com/article/2014/2/epilepsy-foundationcalls-increased-medical-marijuana-access-and-research. February 20, 2014. 9. Himes SK, Scheidweiler KB, Beck O, et al. Cannabinoids in exhaled breath following controlled administration of smoked cannabis. Clin Chem. 2013;59(12):1780-1789. 10. Marinol [package insert]. http://rxabbvie.com/pdf/ marinol_PI.pdf. North Chicago, IL: AbbVie Inc.; 2013. 11. Marinol cost. Costhelper Health website. http://health. costhelper.com/synthetic-marijuana.html 12. Medical marijuana cost. Costhelper Health website. http://health.costhelper.com/medical-cannabis.html

Regardless of the legal status of marijuana and its derivatives, there is insufficient evidence

All electronic documents accessed January 22, 2016.

Dronabinol, a synthetic delta-9-tetrahydrocannabinol approved by the US Food and Drug Administration (FDA), is taken at 2.5 to 20 mg/ day in divided doses and titrated slowly based on individual tolerance and effect.10 This form of medical-grade THC costs an average of $2 per pill, with a typical prescription costing up to $800.11 The cost of non-FDA-approved medical marijuana is up to $400 per ounce, not including any smoking or inhalation paraphernalia.12

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COMMENTARY Laura Odom, DNP, FNP-BC, is a clinical assistant professor at the University of Tennessee, Knoxville, and is the president and co-founder of Medic Apps, LLC.

ICD-10 codes may improve asthma care The new ICD-10 codes are fully implemented, and some of these diagnostic codes are implausible at best. For instance, code “V97.33XD: Sucked into jet engine, subsequent encounter” is absurd given the likelihood of surviving initial entry into the jet engine. There is also “Y93.D: V91.07XD: Burn due to water-skis on fire, subsequent encounter.” I believe this may not be in accordance with the laws of physics. According to preliminary feedback from primary care providers, the new ICD-10 coding system is frustrating and taking time away from patient care (Natale, 2015. Healthcare IT News & Healthcare Finance. www.icd10watch.com/blog/icd-10-transition-has-increased-frustrations-physicians). The modifications

The new ICD-10 coding system may seem inappropriate for some disease models, but asthma care may benefit from the required changes.

in codes for asthma are far-reaching, and these changes are time-consuming for primary care providers who often treat patients with asthma. The new ICD-10 codes for asthma may seem daunting, but there could be a silver lining to the new system. Previous ICD-9 codes for asthma were based on a clinician’s ability to determine whether the patient had extrinsic (allergic) or intrinsic (exercise- or irritant-induced) asthma. For a majority of providers, this information is unknown unless the patient had previously undergone allergy skin prick testing or serum radioallergosorbent testing. The new ICD-10 codes require the clinician to classify asthma into different levels of severity. Asthma continues to be one of the top reasons for emergency department visits (CDC, 2011). A recent article in BMJ pointed to a number of different reasons for inadequate asthma control and mortality rates, including use of asthma action plans, appropriate prescription therapy, and more closely followed care (Torjeson. 2014;348, g3108). This article noted that 70% of the patient deaths reported were due to primary care failings in routine care, and an additional 59% of asthma deaths occurred when asthma guidelines were not followed. According to the National Heart, Lung, and Blood Institute (NHLBI) guidelines, stratifying asthma severity is standard of care for asthma management (www. nhlbi.nih.gov/health-pro/guidelines/current/ asthma-guidelines/summary-report-2007).

Asthma severity classification is straightforward, and the new ICD-10 coding system will force providers to determine asthma severity at every patient encounter. Unfortunately, patients are often unaware of the severity of their asthma. A majority (55%) of patients receiving prescription asthma medications are considered uncontrolled using the NHLBI guidelines (Peters, et al. J Allergy Clin Immunol. 2007;119[6]:1454-1461). Providers must ask straightforward questions about symptom frequency and use of rescue inhalers to stratify asthma control and severity. If a patient is requiring a rescue inhaler daily, his or her asthma severity is moderate or severe persistent. A patient with this level of asthma severity should be on a minimum pharmaceutical regimen of daily inhaled corticosteroids or moderate-dose combination inhaled corticosteroid/long-acting beta agonist therapy. If the patient’s asthma control classification does not match the prescription therapy, it would be imperative to reconsider treatment options. The new ICD-10 coding system may seem inappropriate for some disease models, but asthma care may benefit from the required changes. Once providers begin taking a closer look at asthma control, it stands to reason that prescription therapy will be more appropriate. Take the time to ask specifically about your patients’ rescue inhaler use, and quantify their level of asthma control. It may lead to improved patient outcomes, reduced emergency room visits, and happier patients. n

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