1. Hepatic Disease Clinical Medicine I Patrick Carter MPAS, PA-C February 14, 2011

2. Objectives Discuss the major metabolic functions of the liver. Identify the categories of viral agents that cause hepatitis. For each of the following, describe the etiology, risk factors, transmission, clinical features, diagnostic findings, treatment, and prophylaxis: HAV HBV HCV HDV HEV HGV Discuss the possible complications of viral hepatitis.

3. Objectives Differentiate between toxic and drug induced injury of the hepatic system. Define autoimmune chronic active hepatitis. Identify the typical clinical presentation of alcoholic liver disease. Identify the pathophysiologic mechanisms of alcohol injury to the liver.

4. Objectives Identify the typical treatment options for alcoholic liver disease including pharmacological, dietary, and life style treatments Discuss the association between alcoholic liver disease and portal hypertension. State the major complications of alcoholic liver disease including presentation, laboratory findings, and treatment of: spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatic encephalopathy Indicate the prognosis for alcoholic liver disease.

5. Assessment Parameters Acute or chronic Focal or diffuse Mild or severe Reversible or irreversible Fulminant – development of hepatic encephalopathy within 8 weeks Sub-fulminant -- development of hepatic encephalopathy at 8 weeks – 6 months

8. Hepatic Physiology Energy metabolism Protein synthetic functions Solubilization, transport, and storage Protective and clearance functions

10. Etiology of Hepatic Disease Cholelithiasis Excessive alcohol intake Inherited disorders Viruses/bacterial Infection Medications Cirrhosis Cancer

11. Jaundice (Icterus)

12. Causes of Jaundice Diminished hepatocyte function Inability to conjugate Problems transfer/excretion Biliary obstruction

13. Jaundice Pathology Smart Charts, Groysman; McGraw-Hill. 2001

14. Jaundice Pathology Smart Charts, Groysman; McGraw-Hill. 2001

15. Acute Viral Hepatitis

16. Hepatitis - Viral Pathology Smart Charts, Groysman; McGraw-Hill. 2001

17. Viral Hepatitis Essentials of diagnosis Prodrome of anorexia, nausea/vomiting, malaise, aversion to smoking Fever, enlarged and tender liver, jaundice Normal to low WBCs, markedly elevated aminotransferases early in the course Liver biopsy rarely indicated, but might show hepatocellular necrosis

18. Hepatitis A Virus (HAV) Fecal/oral transmission Poor sanitation or crowded living situations Contaminated water & food ~ 30 days incubation Low level of mortality Fulminant cases are rare Never chronic

20. Hepatitis B Virus (HBV) Blood and blood products Sexual transmission Maternal-fetal transmission Prevalent in homosexuals and IV drug users Incidence has decreased by 75% since the 1980’s Onset is more insidious than HAV

21. Hepatitis B Virus (HBV) 6 week – 6 month incubation Aminotransferase levels higher than in HAV Risk of fulminant hepatitis is less than 1% but has a 60% mortality rate Infection persists in 1-2%, higher in immunocompromised

22. Hepatitis B Virus (HBV) Patients with chronic HBV have substantial risk of cirrhosis and hepatocellular carcinoma (up to 40%) HBsAg – first evidence of infection Anti-HBs – signals recovery from HBV infection and immunity Vaccination exists

24. Hepatitis C Virus (HCV) Transmission IV drug use Intranasal cocaine Body piercings Blood transfusion Low risk of transmission Sexual Maternal/fetal

25. Hepatitis C Virus (HCV) 30 – 50% of HIV patients are coinfected with HCV Faster progression of chronic HCV to cirrhosis Incubation period is 6-7 weeks Clinical illness is generally mild or asymptomatic 80% will become chronic

26. Hepatitis C Virus (HCV) Screening to detect HCV antibodies Confirmation by an assay for HCV RNA About 20% of patients infected with HCV will clear the infection No vaccination available Treatment exists with varying results

28. Hepatitis D (Delta agent) Defective RNA virus that causes hepatitis ONLY in association with HBV Usually percutaneous exposure As superinfection with HBV, may cause fulminant hepatitis or severe chronic hepatitis In US, occurs mainly in IV drug users 3 x risk of hepatocellular carcinoma

29. Hepatitis E (HEV) Rare in the US Endemic areas are India, Burma, Afghanistan, Algeria and Mexico Waterborne Illness is self-limited Mortality rate of 10-20% in pregnant women

30. Hepatitis G (HGV) Percutaneously transmitted and associated with chronic viremia lasting at least 10 years Has been detected in 1.5% of blood donors 50% of IV drug users 30% of hemodialysis patients 20% of hemophiliacs 15% of patients with chronic hepatitis B or C

31. Hepatitis G (HGV) Does not cause important liver disease Does not affect the response of patients with chronic hepatitis B or C to antiviral therapy HGV coinfection may improve survival in patients with HIV infection

32. Viral Hepatitis Symptoms Prodromal phase General malaise, myalgia, arthralgia, fatigue and anorexia Distaste for smoking Nausea/vomiting Serum sickness in HBV Fever, usually low-grade RUQ or epigastric pain, usually mild

33. Viral Hepatitis Symptoms Icteric phase – jaundice after 5-10 days Convalescent phase – gradual disappearance of symptoms Signs Hepatomegaly Liver tenderness Splenomegaly in about 15% of cases

34. Viral Hepatitis Prevention Thorough handwashing Universal precautions Screening of blood supply Vaccinations HAV – close contacts of infected patients, persons traveling to endemic areas HBV – universal vaccination of infants and children, healthcare workers

35. Chronic Viral Hepatitis

36. Chronic Hepatitis Defined as chronic inflammatory reaction of the liver of more than 3-6 months duration HBV +/- HDV, HCV, autoimmune hepatitis, Wilson’s disease, etc. Traditionally classified as chronic active or chronic persistent

37. Chronic Hepatitis B Affects 1.25 million people in the US Males > females Coinfection with HIV is associated with increased frequency of cirrhosis Treatment Interferon alpha-2b for 4 months for active stage Lamivudine 100 mg po qd – better tolerated

38. Chronic Hepatitis C Diagnosed by detection of HCV RNA in the blood About 20% will progress to cirrhosis in 20 years EtOH use more than 50 g/day increases risk of cirrhosis

39. Chronic Hepatitis C Treatment Most effective for genotypes 2 and 3 Combination therapy with pegylated interferon and ribavirin 600 mg po BID Response rates up to 55% Treatment is for 48 weeks May reduce the risk of hepatocellular carcinoma

40. Autoimmune Hepatitis Usually a disease of young women Onset is usually insidious May have multiple spider nevi, striae, acne, hirsutism and hepatomegaly Serum gamma globulin levels are usually elevated Liver biopsy is indicated

41. Autoimmune Hepatitis Treatment Prednisone with or without azathioprine Prednisone 30 mg daily tapered down to maintenance dose of 10 mg daily Azathioprine 50 mg daily Response rate to therapy is 80% Cirrhosis does not reverse with therapy Liver transplant may be required for treatment failures, may recur in 1/3 of patients

42. Hepatic Injury Direct hepatic toxins Dose related severity Latent period following exposure Susceptibility in all individuals Examples Acetaminophen, EtOH, carbon tetrachloride, chloroform, heavy metals, mercaptopurine (6-MP), tetracycline, vitamin A

43. Hepatic Injury Drug induced idiosyncratic reactions Sporadic Not dose associated Features suggest allergic reaction (fever and eosinophilia) Examples Amiodarone, ASA, carbamazepine, chloramphenicol, diclofenac, halothane, isoniazid, ketoconazole, phenytoin, etc.

44. Alcoholic Hepatitis medlib.med.utah.edu/

45. Alcoholic Hepatitis Acute or chronic inflammation and parenchymal necrosis of the liver induced by EtOH Often reversible Most common cause of cirrhosis in the US 4-5 times more common cause of death as HCV which is the second most common

46. Alcoholic Hepatitis Frequency estimated at 10-15% of daily drinkers (more than 50 g) for over 10 years 50 g = 4 drinks (4 oz. 100 proof whiskey, 15 oz. wine or 48 oz. beer) Women > men Concurrent HBV or HCV increases risk

47. Alcoholic Hepatitis Signs and symptoms Enlarged liver Anorexia and nausea Hepatomegaly and jaundice Abdominal pain Splenomegaly Ascites Fever Encephalopathy

48. Recent Heavy Drinking Anorexia Nausea Hepatomegaly Jaundice Abdominal pain Splenomegaly Ascites Fever Encephalopathy

49. Treatment Strict EtOH abstinence - ESSENTIAL Caloric supplement and nutritional support Vitamin supplement – folic acid and thiamine Glucose administration increases Vitamin B1 needs and can precipitate Wernicke-Korsakoff syndrome – must co-administer thiamine

50. Treatment Prednisone 32 mg/day for 1 month May reduce short-term mortality for patients with alcoholic hepatitis and encephalopathy or greatly elevated bilirubin Experimental therapy with pentoxifylline 400 mg TID for 4 weeks may decrease risk of hepatorenal syndrome

51. Treatment Liver transplant Usually requires abstinence for 6 months prior to transplant Absolute contraindications Malignancy, advanced cardiopulmonary disease and sepsis Relative contraindications Age > 70, HIV infection, portal vein thrombosis, active substance abuse, severe malnutrition

52. Cirrhosis 12th Leading Cause of Death in U.S. Hepatocellular injury that leads to: Fibrosis Nodular Regeneration Risk Factors Chronic Viral Hepatitis Alcoholic Hepatitis Drug Toxicity Autoimmune Hepatitis

53. Clinical Features are Secondary to: Portal HTN Hepatic Cell Dysfunction Portosystemic Shunting Cirrhosis

54. Portal Hypertension Pathology Smart Charts, Groysman; McGraw-Hill. 2001

55. Signs of Portal HTN

57. Major Complications Ascites Diagnostic paracentesis indicated for new ascites Cell count and culture Albumin level Restriction of dietary sodium and fluid intake Diuretics – spironolactone +/- Lasix Large-volume paracentesis (4-6 L) TIPS (transjugular intrahepatic portosystemic shunt

58. Major Complications Spontaneous bacterial peritonitis Abdominal pain, increasing ascites, fever and progressive encephalopathy Paracentesis shows high WBC count Cultures are usually positive – most common E. coli or pneumococci

59. Major Complications Spontaneous bacterial peritonitis Treatment with IV cefotaxime 2 g q 8-12 hours for 5 days Overall mortality rate is up to 70% in 1 year Hepatorenal syndrome Azotemia in the absence of shock or significant proteinuria in a patient with end-stage liver disease

60. Major Complications Hepatorenal syndrome Does not improve with IV isotonic saline Oliguria and hyponatremia Diagnosis of exclusion Cause is unknown Treatment is generally ineffective Mortality is high without liver transplant TIPS procedure may buy time until transplant

61. Major Complications Hepatic encephalopathy Disordered CNS function due to failure of the liver to detoxify noxious agents originating in the gut Ammonia is most readily identified Dietary protein withheld during acute episodes Lactulose to acidify colon contents NH4+↔ NH3 + H+

62. Major Complications Hepatic encephalopathy NH4+ is not absorbable Lactulose should be dosed at 30 mL 3 or 4 times daily Avoid opioids and sedatives that are metabolized or excreted by the liver Zinc deficiency should be corrected if present

63. Prognosis Survival less than 12 months

64. Non-Alcoholic Fatty Liver Disease (NAFLD) Up to 30% US population Etiology Obesity Diabetes Hypertriglycerides Corticosteroids Physical Activity protects against NAFLD Don’t worry about NASH

65. Non-Alcoholic Fatty Liver Disease (NAFLD) Signs & Symptoms Asymptomatic Mild Right Upper Quadrant Pain Hepatomegaly (up to 75%) Chronic Liver Disease uncommon

66. Non-Alcoholic Fatty Liver Disease (NAFLD) Laboratory Findings Mild elevated Aminotransaminases & Alkaline Phosphatase levels Ratio ALT to AST > 1 (opposite ETOH) Ratio does decrease if fibrosis/cirrhosis develop Imaging CT/MRI/US demonstrate fatty liver Does not distinguish hepatitis

67. Non-Alcoholic Fatty Liver Disease (NAFLD) Liver Biopsy Percutaneous Diagnostic & “Standard Approach” Assess degree of inflammation & fibrosis BARD Score used to predict advanced fibrosis

68. Non-Alcoholic Fatty Liver Disease (NAFLD) Treatment Remove offending factors Weight Loss Exercise Fat Restriction Gastric Bypass with BMI > 35 Statins are NOT contraindicated

69. Questions?