Problem Based Learning Module

1. Problem Based Learning Module February 25, 2013

2. Chief Complaint: “My abdomen is bloated” RF is a 55-year-old African American woman referred to the hepatology clinic by her primary care physician because of an increase in abdominal girth over the past month in association with abnormal liver tests. RF reports progressive increase in abdominal girth, and leg swelling for the past month, associated with symptoms of abdominal discomfort, early satiety and nausea, without vomiting. She has had no change in bowel habits. She has no fever, chills or weight loss. She has no prior known history of liver disease and no family history of liver disease. She drinks 2-3 glasses of wine daily with dinner but she has not had any since she developed her symptoms. She has no history of drug use and does not recall having had blood transfusions, tattoos or body piercing. She noted increased itching in the evening for the past year; she is taking Benadryl OTC which is controlling her symptoms.

3. Past Medical History • Hypertension dx 5 years ago • Hysterectomy for vaginal bleeding in 1999 • Splenectomy after a motor vehicle accident at age 6 • Screening colonoscopy at age 53 with no polyps detected ROS • Increased fatigue and difficulty sleeping at night: has been on medical leave from her work for the past 3 weeks. • Chronic back pain relieved with ibuprofen

4. Medications • Atenolol 50 mg daily • Ibuprofen 400 mg po tid as needed for back pain • Calcium and vitamin D twice a day • Multivitamin once daily • Benadryl 25 mg QHS for itching Family History • Mother with hypertension • Father with hypertension, diabetes and CAD • Sister with hypertension and cervical cancer • No liver disease Social History • Never smoked • Never used drugs • Drinks wine with dinner regularly (as in HPI) • Works as a teller at a bank. Married, lives with her husband and has 2 adult children.

5. Physical Exam • Vital signs: P: 68, BP: 122/76, R: 10, T: 98.9, 98% sat on room air • Wt 220 lbs, Ht 5’7” • General: Evidence of temporal wasting • HEENT: Slightly icteric • Neck: supple without adenopathy or jugular venous distention • Cardiovascular: normal rate, regular rhythm, no murmurs • Chest and lungs: symmetrical expansion, clear to auscultation and percussion • Abdomen: LUQ scar of prior splenectomy. Distended abdomen, tense, mild diffuse tenderness to palpation. Dull to percussion at the flanks with evidence of shifting dullness. No fluid wave detected. • Extremities: without clubbing or cyanosis; 1+ lower extremity edema appreciated bilaterally. • Neurologic examination: normal exam. Fully alert and oriented. No asterixis.

6. Labs

7. Imaging Ultrasound of the abdomen was obtained. The liver had a heterogeneous echotexture, but did not appear nodular. No focal liver lesions. The hepatic and portal veins appeared patent by Doppler. Large amount of ascites noted. Gallbladder is normal. Spleen is absent. Kidneys are of normal size and echogenicity, no hydronephrosis.

8. Ascites • Ascites occurs when there is a disruption in the pressure forces between intravascular and extravascular fluid spaces, which allows extravascular fluid to accumulate in the anterior peritoneal cavity • Ascites in cirrhosis results from sinusoidal HTN and sodium retention. • Peripheral arterial vasodilation hypothesis • Renal sodium (and water retention) is due to reduced effective blood volume 2/2 peripheral arterial vasodilatation. • The overfill hypothesis • Renal retention of sodium is primary with secondary vascular changes and accumulation of ascites and edema. Sherlock's Diseases of the Liver and Biliary System. Twelfth Edition. Edited by James S. Dooley, Anna S.F. Lok, Andrew K. Burroughs, E. Jenny HeathCote. 2011.

9. Pathophysiology of Ascites Central veins compressed and obstructed by fibrosis and regenerative nodules, reducing venous outflow Lymph from subdiaphragmatic and peritoneal lymphatics removal via thoracic duct to limit of capacity Sinusoidal pressure elevated Sinusoidal baroreceptors stimulated Central vein Portalsystemic collateral vessels Portal vein engorged pressure increased Some lymph reabsorbed by peritoneal and subdiaphragmatic lymphatics Increased splanchnic lymph flow adds to ascites If lymph formation > lymph reabsorption, excess accumulation in peritoneal cavity as ascites

10. Classification by mechanism of ascites formation I. Elevated hydrostatic pressure (portal hypertension) A. Cirrhosis B. Hepatic congestion: Congestive heart failure Constrictive pericarditis Inferior vena cava syndrome Hepatic vein obstruction (Budd-Chiari syndrome) C. Portal vein occlusion II. Decreased osmotic pressure A. Hypoalbuminemia: Nephrotic syndrome Protein-losing enteropathy Malnutrition B. Cirrhosis or hepatic insufficiency III. Fluid production exceeding resorptive capacity (associated with peritoneal disease) A. Infections: B. Bacterial peritonitis (acute; spontaneous forms) Tuberculosis, Fungal, Parasitic C. Malignancy: Metastatic carcinoma Primary mesothelioma D. Granulomatous peritonitis Infections Cancer Iatrogenic: starch, barium Vasculitis http://depts.washington.edu/physdx/liver/path.html

11. Discuss the finding of a distended abdomen on exam in our patient and the diagnostic accuracy of physical exam maneuvers in identifying ascites as a cause of abdominal distention.

12. Ascites: Physical Exam Reliability • Findings: distension, bulging flanks, flank dullness, shifting dullness, and fluid wave • Reliability? Depends on examiner… • In one study, 3 internists, 90 inpatient veterans • Presence/absence of abdominal distension (86%), Bulging flanks (79%), shifting dullness (78%), fluid wave detection (76%) • In one study, 6 GI MDs, 50 alcoholics examined for ascites • ICC was 0.75 (overall) and 0.95 (senior physicians) Espinoza P, Ducot B, Pelletier G, et al. Dig Dis Sci. 1987;32:244-247. Cummings S, Papadakis M, et al West J Med. 1985; 142:633-636.

13. Accuracy of Physical Exam Maneuvers • No single sign is specific and sensitive, but flank dullness (≥0.8) and bulging flanks (≥0.72) are sensitive! • Absence of a fluid wave is very specific (≥0.82)! Cummings S, et al. West J Med. 1985; 142:633-636; Simel DL, et al. J Gen Intern Med. 1988;3:423-428; CattauEL Jret al. JAMA. 1982; 247:1164-1166.

14. Accuracy of Physical Exam Maneuvers (Pooled Data) • Useful for ruling in ascites: Presence of fluid wave and • shifting dullness! • Useful for ruling out ascites: Absence of bulging flanks, • flank dullness, and shifting dullness! • Accuracy depends on examiner, technique used, clinical • setting (habitus), and amount of fluid present! Williams JWet al. JAMA. 1992; 267 (19): 2645-2648.

15. What other physical exam findings would you look for that would you look for that would help with the differential diagnosis? Features of Cirrhosis in Physical Exam: Spider angiomata, palmar erythema, caput medusae, jaundice, icterus, fetorhepaticus, dupuytren’s contracture, hepatomegaly, firm/nodular liver Elevated JVP: heart failure or constrictive pericarditis as a cause. However, Cirrhosis with tense ascites or pulm HTN can cause this. Lymphadenopathy: Sister Mary Joseph nodule with ascites may be caused by gastric or colon CA, HCC, or lymphoma. Hypothyroidism: thyroid may be enlarged, skin dry with brittle hair, tongue enlarged, peri-orbital edema, delayed peripheral deep tendon reflexes Hemochromatosis: skin grayish or bronze and appears dirty,degenerative arthritis of extremities (usually hands and fingers, especially affected are PIPs of the middle and ring fingers) Wilson’s disease:before age 50 – Eye –Kayser-Fleisher ring: brownish green ring near limbus edge of iris – represents copper deposition in Descemet’s membrane Nails: bluish discoloration of the lunula (azure lunule; not specific) Sleisinger & Fordtran’sGastointestinal and Liver Disease Pathophysiology/Diagnosis/Management

16. What is your assessment of the patient’s alcohol intake? • Our patient takes in 36 g/alcohol based on 3 drinks/day • Standard drink in the US: 12 oz of 5% ABV beer, 5 oz of 12% ABV wine, or 1.5 oz of 80 proof spirit • Assuming a standard drink has 12 g of alcohol • Risk of developing cirrhosis is >60-80 g/day of alcohol for >10 years in men and 20 g/day in women. This leads to a 6-41% chance of developing cirrhosis www.aasld.org/practice guidelines: Alcoholic Liver disease January 2010

17. What other elements of history would you like to obtain to ascertain whether the patient has signs of alcohol dependence? • The amount and duration of alcohol intake is important • How long have you been drinking for? • How much do you consider one glass of wine? • How many days per week do you drink? • Do you drink anything else with your wine? • DSM criteria for Alcohol Dependence • Tolerance: Have you noticed the need for increased amounts of alcohol to get the desired effect? or Do you feel the effects of alcohol less despite drinking more? • Withdrawal: Do you experience symptoms of withdrawal and does alcohol relieve these symptoms? • Have you used alcohol for longer or in more amounts then you originally intended? • Have you tried to cut down but failed? • Do you find yourself spending a lot of time trying to either get/use alcohol or recover from its effects? • Have you shunned other obligations because of alcohol? • Did you know that cirrhosis can be caused by drinking? If yes, did you keep drinking knowing this? Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC: APA, 2000.

18. Discuss the abnormalities in liver associated enzymes, markers of liver synthetic function, and CBC on presentation in our patient and how this helps you in formulating a differential diagnosis for the cause of her symptoms. Aminotransferases • AST> ALT but not 2X • T. bili elevated (presumably direct) • Alkaline phosphatase elevated CBC • Thrombocytopenia • Normocytic anemia Synthetic function • INR elevated • Albumin low

19. Discuss the finding of a low Ferritin level on initial evaluation.

20. Ferritin • Levels are difficult to interpret in chronic liver disease • Chronic HCV may lead to a in serum ferritin, but marked hepatic iron overload is rare • Hyperferritinemia is also seen in inflammation, alcohol abuse, liver necrosis, steatosis, DM2, metabolic syndrome, etc. • A low ferritin in a patient with chronic liver disease and anemia is concerning for iron deficiency anemia

21. What was the significance of a positive hepatitis C antibody? What are the sensitivity and specificity of this finding in detecting a chronic hepatitis C infection? The serologic tests used to diagnose HCV include three different types of assays that can detect antibodies to hepatitis C virus: enzyme immunoassay (EIA), chemiluminescent assay (CIA), and recombinant immunoblot assay (RIBA) EIA – 3rd generation … detects antibodies against epitopes derived from the HCV core, nonstructural 3,4, and 5 regions. Recombinant immunoblot assay (RIBA) identifies the specific antigens to which antibodies are reacting in the EIA, and the results are interpreted as positive (2 or more antigens), indeterminate (1 antigen), or negative (0 antigens) 3rd generation HCV EIA has an estimated 98% sensitivity for detecting antibody to HCV. Sensitivity is almost 100% in healthy adults with chronic HCV infection False negative result in pt with acute HCV infection, patients on long term hemodialysis, and immunosuppressed persons Good specificity but the predictive value of a positive result varies substantially based on the pre-test probability of HCV infection. False positive results can occur in some patients who have autoimmune liver disease or hypergammaglobulinemia Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:13

22. All positive EIA results should be verified with an independent supplemental test of high specificity (HCV RNA testing or RIBA). The serologic tests can establish that a person has been infected with HCV at some point in time, but they do not distinguish active from past (resolved) infection. http://depts.washington.edu/hepstudy/hepC/clindx/virus/discussion.html

23. http://depts.washington.edu/hepstudy/hepC/clindx/acutediscussion.htmlhttp://depts.washington.edu/hepstudy/hepC/clindx/acutediscussion.html

24. http://depts.washington.edu/hepstudy/hepC/clindx/acute/discussion.htmlhttp://depts.washington.edu/hepstudy/hepC/clindx/acute/discussion.html

25. What are the risk factors for chronic HCV? Risk Factors: • Health care worker who has been exposed to infected blood • Prior injection of illicit drugs, especially with shared needles, or intranasal cocaine • History of HIV • Received a piercing or tattoo in an unclean environment using unsterile equipment • Received a blood transfusion or organ transplant before 1992 • Received clotting factor concentrates before 1987 • Have been on HD treatments for a long period of time • Mother infected with HCV at the time of child’s birth www.aasld.org/practice guidelines: Diagnosis, Management, and Treatment of Hepatitis C 2009

26. Who should be screened in the general population? www.aasld.org/practice guidelines: Diagnosis, Management, and Treatment of Hepatitis C 2009

27. CDC screening guidelines MMWR, August 17, 2012; Vol 61;4

28. What is the likely mode of transmission of HCV to our patient? Denies • Injection drug use (currently the most common means of HCV transmission in the United States) • Receipt of donated blood, blood products, and organs (blood screening became available in 1992) • Needlestick injuries in health care settings • Birth to an HCV-infected mother • HCV can also be spread infrequently through sex with an HCV-infected person • Sharing personal items contaminated with infectious blood, such as razors or toothbrushes • Other health care procedures that involve invasive procedures, such as injections Splenectomy at age 6 No history of needlestick No family history of liver disease Low likelihood Low likelihood Low likelihood http://www.cdc.gov/hepatitis/hcv/hcvfaq.htm#b1

29. What are the factors associated with a severe liver injury due to hepatitis C?

30. Factors Associated with Severe Liver Injury due to HCV • Age • Race • Gender • Co-infection (HIV/HBV) • Alcohol use • High BMI • Hepatic steatosis • Insulin resistance • Genetics • Mode of acquisition? • Marijuana • Environment/geography • Viral factors? • Amount of inflammation/fibrosis on liver biopsy Chopra S. Clinical Manifestations and natural history of chronic hepatitis C infection. In: Up to Date, Basow, DS (Ed), Up to Date, Waltham, MA 2012.

31. Discuss the clinical significance of a positive ANA and elevated IgG fraction in our patient. The problem is that ANA is not a specific test. Because it tests for several different antibodies, cross-reactions can occur. And up to 45 percent of people with autoimmune thyroid conditions or rheumatoid arthritis and up to 15 percent of people with HIV or hepatitis C can have a positive ANA test result. In addition, up to 3 percent of the normal population can have a false positive ANA test result. Hypergammaglobulinemia is frequently observed in patients with chronic liver disease (CLD) of different causes. Narciso-Schiavon JL et al. Antinuclear antibody positivity in patients with chronic hepatitis C: clinically relevant or an epiphenomenon. Eur J Gastroenter Hepatol. 2009 Apri; 21(4) 440-6. Muryama S. et al. Serum immunoglobulins in patients with chronic hepatitis C: a surrogate marker of disease severity and treatment outcome. Hepatogastroenterology 2007; 54:493-8.

32. Are there additional tests that you would like to obtain at the time of the initial evaluation of our patient? • HCV RNA • HCV genotype • HIV • Ascites tap for cbc with differential, total protein, albumin, and culture • MELD calculation: currently 18 • EGD • Liver biopsy? We already know she has cirrhosis so unnecessary

33. Are there additional management interventions that you would recommend after initial evaluation? • Alcohol cessation • Paracentesis • Analyze ascites for: • Cell count + differential • Albumin • Culture • Protein • Diuretics, Na restricted diet • Vitamin K trial • Avoid NSAIDS • Referral to tertiary care for transplant evaluation • Immunize for HAV, HBV, influenza, and pneumovax

34. Follow UpVisit A - Initial Intervention The patient underwent an 8.1 L paracentesis with albumin replacement. Ascitic fluid analysis revealed an ascitic fluid protein of 1.0, albumin < 1.0, WBC 35. Ibuprofen was stopped, she received diet counseling for a 2 gram Na restricted diet. Spironolactone 100 mg daily and furosemide 40 mg daily were started.

35. Visit B- Two months follow up She presents for follow up 2 months later. She has been abstinent of alcohol. Ascites is controlled on diuretics. The following laboratory tests are obtained on follow up.

36. Pathogenesis of HCV – Determinants of Persistence • Inability to clear virus due to host-virus interplay -> immune response mediating hepatocyte destruction and fibrosis • Evasion of immune responses via several viral mechanisms • Inadequate induction of innate immune response • Insufficient induction or maintenance of an adaptive immune response • Production of viral quasispecies • Induction of immunologic tolerance Feldman M, ed (et al.) Sleisinger and Fordtran’s Gastrointestinal and Liver Disease. Pathophysiology/Diagnosis/Management. 9th edition. Philadelphia: Saunders: 2010.

37.  What is the current standard of care in treatment of hepatitis C infection and the expected outcome of treatment in the general population of infected patients?

38. Treatment for HCV (Genotype 1) • Standard of care:PegIFN α, weight based ribavirin, and PI (telaprevir or boceprevir) • Telaprevir is effective in treatment-naïve patients, relapsers, partial responders, and null responders • Boceprevir is effective in treatment-naïve patients, relapsers, and partial responders • Efficacy is influenced by prior treatment status and by changes in viral load during therapy, which in turn influences the recommended duration of treatment. • www.aasld.org/practice guidelines: Treatment of Genotype 1 HCV 2011 Practice Guidelines

39. www.hepatitiscnewdrugs.blogspot.com

40. www.hepatitiscnewdrugs.blogspot.com

41. Response Rates with Genotype 1 (on Triple Therapy) • Treatment-naïve patients: 67-75% • Prior relapsers: 69-88%  • Prior partial responders:40-59% • Prior null responders: 23-38% • African American: 40-50% • Cirrhotics (compensated): 14-62% • www.aasld.org/practice guidelines: Treatment of Genotype 1 HCV 2011 Practice Guidelines; Sherman KE et al. Hepatology2010; • 52:401A. Poordad F et al. N Engl J Med. 2011;364(13):1195. Kwo PY et al. Lancet. 2010;376(9742):705. Hezode C et al. N Engl • J Med. 2009;360(18):1839. Akuta N et al. Hepatology. 2010;52(2):421. Jacobson IM et al. N Engl J Med. 2011;364(25):2405. • McHutchinsonJG et al. N Engl J Med. 2009;360(18):1827. Bacon BR et al. N Engl J Med. 2011;364(13):1207. McHutchinson JG • et al. N Engl J Med. 2011;364(13):1207. Zeuzem S et al. N Engl J Med. 2011;364(25):2417. Flamm SL et al. • ClinGastroenterolHepatol. 2013;11(1):81.

42. Genotype 2 & 3 • 24 weeks of peginterferonα and non-weight based ribavirin (800 mg/day) • www.aasld.org/practice guidelines: Diagnosis, Management, and Treatment of Hepatitis C 2009

43. Genotype 4 • Plan for 48 weeks of peginterferonα and weight based ribavirin BUT treatment should be stopped if: • At week 12 patient does not have at least a 2 log10 reduction in HCV RNA (EVR) • Patient had at least a 2 log10 reduction in HCV RNA but still has detectable HCV RNA (i.e. lacks complete RVR)at week 12 and subsequently is still detectable at week 24 • www.aasld.org/practice guidelines: Diagnosis, Management, and Treatment of Hepatitis C 2009

44. Genotype 5 and 6 • Genotype 5: Insufficient data to make recommendations on dose and duration (?48 weeks peginterferon α and ribavirin) • Genotype 6: 24-48 weeks of peginterferon α and ribavirin • www.aasld.org/practice guidelines: Diagnosis, Management, and Treatment of Hepatitis C 2009

45. Response Rates with Interferon/Ribavirin • Genotype 1: 40-50% • Genotype 2: 80% • Genotype 3: 80% • Genotype 4: 50-70% • Genotype 5: 60% • Genotype 6: 60-80% • www.aasld.org/practice guidelines: Diagnosis, Management, and Treatment of Hepatitis C 2009; Bisceglie AM. • Predictors of a Sustained Virologic Response Following Treatment with Peg-Interferon and Ribavirin for • Chronic Hepatitis C Infection. In: Up to Date, Basow, DS (Ed), Up to Date, Waltham, MA 2012.

46. What are the potential adverse effects of the standard of care treatment? • IFN - Insomnia, Anxiety, Depression, Fatigue, hypothyroidism, headaches, fever, muscles and body aches, poor appetite, bitter/metallic taste, nausea and vomiting, hair loss, SOB, neutropenia, thrombocytopenia, retinopathy, rash Ribavirin – Fatigue, muscle inflammation, dehydration, muscle aches, mouth sores, and dehydration, rash, nausea and vomiting, anemia, teratogen. Addition of telaprevir(TVR) or boceprevir (BOC) to IFN and ribavirin:Increase in the frequency and severity of anemia Skin disorders (rash) – mild to moderate in > 90% of the cases. Anorectaldiscomfort Drug-Drug Interactions Dysgeusia UptoDate Hezode C. Boceprevir and telaprevir for the treatment of chronic hepatitis C: safety management in clinical practice. Liver International. 2012 1478-3223

47. What are the risks and benefits of HCV treatment in the case of our patient at initial presentation and at the time of the first follow-up visit? • Our patient falls into the category of a decompensated cirrhotic • Benefits: • If patient is to undergo transplant at a future date, eradication of HCV infection pre-transplant will lower the likelihood of post-transplantation infection • Treatment of HCV 1 decompensated cirrhotics has a 13% likelihood of achieving SVR and 12/15 patients who were HCV-RNA negative before transplant remained negative 6 months out (Everson et. al. Hepatology 2005) • May stabilize course of disease • If we hold until patient has stopped drinking and converts to a compensated cirrhotic then SVR rates are higher • Risks: • Worsening or leading to hepatic decompensation and liver failure • Increased risk of infections • Flu like symptoms • Depression • Neutropenia, Anemia, and thrombocytopenia www.aasld.org/practice guidelines: Diagnosis, Management, and Treatment of Hepatitis C 2009

48. Visit C- One month later RF continued to be well until about 1 month after her follow up visit when she started developing leg swelling, followed by increased abdominal distention and confusion progressing over 5 days prior to presentation. She is brought to the ED by her husband who reported that she has not been drinking alcohol and has been taking all of her medication as instructed. She has not had fever or chills. No cough or shortness of breath or headache. No urinary symptoms. She has been complaining of a mild abdominal discomfort and nausea and has a reduced oral intake over the past 48 hours. Vitals BP110/65, Pulse 88, RR 14, Temp 99.2 She is icteric, has a distended abdomen with flank dullness, +2 LE edema, she opens her eyes when her name is called. She responds to questions with an incomprehensible mumbling. Milk maid sign is positive.

49. Labs

50. What is your interpretation of the patient’s history and physical exam findings at presentation to the ED? Altered mental status suggestive of hepatic encephalopathy