Topics in Liver Disease

Educational Objectives

The goals of this program are to improve the management of cirrhosis and its complications and to improve manage­ment of hepatitis B. After hearing and assimilating this program, the clinician will be better able to:

1.   Identify the causes of cirrhosis.

2.   Describe and implement primary prophylaxis for esophageal variceal bleeding.

3.   Screen for and treat major complications of cirrhosis, including ascites, spontaneous bacterial peritonitis, he­patic encephalopathy, and hepatocellular carcinoma.

4.   Identify hepatitis B patients at risk for progressive liver disease.

5.   Describe current concepts of viral resistance and treatment in hepatits B.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships with the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, Dr. Han reports having received research grants from and serving on the Speakers’ Bureaus and Advisory Boards for the following: Roche, Gilead, and Bristol-Myers Squibb. Dr Moseley and the planning committee reported nothing to disclose. In his lecture, Dr. Moseley presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgments

Dr. Moseley spoke in Mackinac Island, MI, at 27th Annual Internal Medicine Update, presented July 31 to August 2, 2009, by the University of Michigan Medical School. Dr. Han spoke in Pasadena, CA, at Third Annual UCLA Liver Disease Sym­posium, presented November 14, 2009, by the Dumont-UCLA Transplant Center, Dumont-UCLA Liver Cancer Center, and the Pfleger Liver Institute. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Caring for the Patient with Cirrhosis

Richard H. Moseley, MD, Professor, Division of Gastroenterology, Department of Internal Medicine, Associate Chair, Veterans Affairs Ann Arbor Healthcare Systems Programs, University of Michigan Medical School, Ann Arbor

Epidemiology: in year 2000, 12th leading cause of death in United States; expected to enter top 10 in next decade be­cause of increase in persons with chronic hepatitis C and increase in obesity epidemic and associated nonalcoholic fatty liver disease (NAFLD); estimated health care costs from hepatitis C–related disease in next decade $11 billion

Case example: 50-yr-old man presents to outpatient clinic; history of long-standing alcoholism; abstinent for 2 yr; no history of ascites or hepatic encephalopathy (HE); laboratory tests show mild serum bilirubin elevation, normal al­bumin, mild elevation of international normalized ratio (INR), and thrombocytopenia; evidence of splenomegaly and portal hypertension

Causes of cirrhosis

Chronic viral infections: hepatitis B  —  particularly with significant risk factors; delta virus (hepatitis D)  —  cofactor in development of cirrhosis in patients with hepatitis B; hepatitis C (HCV)

Inherited metabolic diseases: Wilson’s disease  —  rare chronic liver disease; devastating if not diagnosed; hemochromatosis  —  most common inherited metabolic disorder; coexistent alcohol use factor in development of cirrhosis; alpha-1 antitrypsin deficiency (AATD)  — causes lung and liver diseases

Other causes: autoimmune disorders  —  eg, autoimmune hepatitis; chronic toxic injury  —  eg, alcohol use; occupa­tional exposures; chronic cholestatic disorders  —  eg, primary biliary cirrhosis, primary sclerosing cholangitis, biliary atresia; venous outflow obstruction  —  Budd-Chiari syndrome; cryptogenic causes  —  eg, NAFLD

Serologic evaluation: antinuclear antibody and anti-smooth muscle antibody  —  to rule out autoimmune hepatitis; 25% of patients with autoimmune hepatitis negative for anti-smooth muscle antibody; iron and total iron-binding capacity (TIBC)  —  iron test sufficient, but in presence of cirrhosis, also measure serum ferritin; if serum ferritin >1000 ng/mL, suspect hemochromatosis; alcohol raises serum ferritin; antibodies to hepatitis C virus (HCV)  —  if positive, confirm with measurement of HCV RNA by polymerase chain reaction (PCR) test; hepatitis B virus (HBV) surface antigen (HBsAg)  —  if HBsAg positive, cirrhosis or chronic HBV infection unlikely; since patients lose HBsAg over time, HBV DNA essential to exclude HBV; serum protein electrophoresis  —  to look for AATD; normal alpha-1 globulin peak excludes AATD; serum ceruloplasmin (SCP)  —to look for Wilson’s disease; most pa­tients present before age 30 yr, but disease presentation in septuagenarians now reported; inexpensive; low SCP found in 95% of Wilson's disease patients; order 24-hr urine test for copper to exclude completely; anti-mitochon­drial antibody  —  for primary biliary cirrhosis

Severity of cirrhosis: screening  —  presence of gastroesophageal (GE) varices; ultrasonography (US) to look for fo­cal lesions in liver and ascites; AFP as marker for hepatocellular carcinoma (HCC)

Case example continued: patient has large esophageal varices; US suggests cirrhosis and confirms splenomegaly; alpha-fetoprotein (AFP) normal

Esophageal varices: large varices present in 40% of nondecompensated cirrhosis and 60% in decompensated liver disease; new varices develop at rate of 5%/yr in patients without previous varices; progression from small to large varices  — occurs at rate of 10% to 15% per year; related to degree of liver dysfunction; cause for concern in patients with small varices and ascites; variceal bleeding  —  occurs within 2 yr in £25% of patients newly diagnosed with varices; in patients with varices <5 mm, risk 7% in 2 yr; in patients with varices >5 mm, risk 30% in 2 yr; 25% risk for death with first variceal bleed

Primary prophylaxis for variceal bleeding: general measures  —alcohol abstinence; avoidance of activities that in­crease intra-abdominal pressure; nonselective b-adrenergic blockers decrease risk of bleeding from 25% to 15%; 5% absolute reduction in mortality; use noncardioselective b-blockers (eg, propranolol, nadolol); dose ranges  —  40 to 400 mg/day of propranolol, 40 to 200 mg/day of nadolol; long-acting form of propranolol, administered at night, preferred due to greater risk for bleeding at night; side effects  —  25% of patients on b-blockers in clinical trials quit due to side effects; lower lipid solubility of nadolol (once daily) may decrease risk for central nervous system side effects; goal of treatment  —  25% reduction in heart rate (HR) or HR <55 beats/min; take baseline HR before start­ing therapy; no difference shown between band ligation and nonselective b-blockers; speaker argues that b-block­ers more cost-effective for primary prophylaxis and uses band ligation only in patients with large varices or significant contraindications to b-blockers

Case example continued: patient lost to follow-up; returns in 6 mo; physical examination reveals ascites and bilat­eral pedal edema

Complications of chronic liver disease: ascites; variceal bleeding; HE; hepatorenal syndrome; HCC; hepatopulmo­nary syndrome; portopulmonary hypertension

Ascites: in United States, 80% of patients with ascites have cirrhosis; 50% of patients with compensated cirrhosis de­velop ascites within 10 yr; 2-yr mortality 50% once ascites develops; abdominal paracentesis  —  easiest outpatient evaluation for patients with new-onset ascites; bleeding sufficiently uncommon to preclude need for prophylactic blood product support; tests on fluid  —  cell count with differential; albumin concentration; cytology if malignancy suspected; inoculate into blood culture bottles if infection suspected; total protein, lactate dehydrogenase (LDH), and glucose to differentiate spontaneous from secondary bacterial peritonitis; serum-ascites albumin gradient  —categorizes ascites better than pleural fluid exudate and transudate; gradient ³1.1 g/dL indicates portal hypertension with 97% accuracy

Treatment of ascites: 90% of patients respond to simple measures; 10% have refractory ascites; dietary sodium restriction  —  2 g/day or 88 mEq/day; 10% respond to sodium restriction alone; target urinary sodium excretion >78 mmol/day; oral diuretics  —  spironolactone 100 mg/day; furosemide 40 mg/day; if weight loss or natriuresis inade­quate, increase both diuretics simultaneously, maintaining 100 mg/day to 40 mg/day ratio to maximum of 400 mg/day and 160 mg/day; 90% of patients respond to maximum dose; no fluid restriction necessary if serum sodium >120 mEq/L; in cases of pedal edema, diuretics do not risk renal dysfunction; once edema resolved, target weight loss to 0.5 kg/day maximum

Spontaneous bacterial peritonitis (SBP): defined as polymorphonuclear neutrophil (PMN) count ³250/mm³ or pos­itive ascitic fluid culture; peripheral leukocytosis does not result in false-positive elevation of ascitic fluid PMN counts; neutropenic patients with SBP still have high PMN count in ascites; treatment  —  hospitalization; broad spectrum intravenous (IV) antibiotic therapy against Escherichia coli, Klebsiella pneumoniae, and Streptococcus pneumoniae; European literature suggests use of oral fluoroquinolones without hospitalization; prevention  —  »70% SBP recurrence within 1 yr; fluoroquinolones reduce risk for recurrence; short-term antibiotics in hospital­ized patients with cirrhosis and gastrointestinal (GI) bleeding

Hepatic encephalopathy: characterized by altered mental status, ranging from mild changes to deep coma; associ­ated with elevated serum ammonia in cirrhotic patients, although ammonia levels do not correlate with degree of HE; precipitating factors  —  infection; GI bleeding; azotemia, hypokalemia, and metabolic alkalosis induced by di­uretics; protein load; changes in bowel function (eg, constipation, ileus); sedatives; hypnotics; progressive liver dis­ease; treatment  —  identify and remove precipitating factors; titrate lactulose to 2 to 3 soft bowel movements per day; antibiotics (eg, nonabsorbable neomycin, rifaximin, metronidazole); protein restriction not recommended

Model for end-stage liver disease (MELD) score: based on objective criteria; evidence-based means of organ allo­cation; characterizes severity of liver disease; if MELD score <15, transplantation not necessary; MELD score >15, better survival with transplantation; MELD £9 equivalent to 4% probability of 3-mo mortality and score of 20 to 29 equivalent to 76% probability of 3-month mortality; consider transplantation for patients with  —  cirrhosis and Child-Turcotte-Pugh score >7 and MELD score >10 or first major complication (eg, ascites, variceal bleeding, HE); type I hepatorenal syndrome (50% 4-wk mortality)

Hepatocellular carcinoma: all cirrhotic patients at risk, particularly patients with chronic hepatitis B, chronic hepa­titis C, or hemochromatosis; adjust MELD score if patient has stage 2 HCC (ie, 1 lesion >2 cm but <5 cm, or £3 le­sions not >3 cm); screening  —  AFP best marker for HCC, but not expressed in 40% of HCC; biannual AFP and annual or biannual US recommended; do not test for AFP unless US unavailable

Statins: not associated with increased hepatotoxicity; some therapeutic benefit in patients with NAFLD; shown to improve survival in patients with HCC; if indicated, do not withhold from patients with chronic liver disease

NAFLD: treatment  —  manage underlying comorbidities; control diabetes; reduce weight; control hypertension

Chronic Hepatitis B: A Clinical Update

Steven Han, MD, Associate Professor of Medicine and Surgery, David Geffen School of Medicine at the Uni­versity of California, Los Angeles

Worldwide incidence: twice as many people with chronic hepatitis B as hepatitis C worldwide; causes cirrhosis and liver cancer; leading cause of death; Asians comprise 75% of HBV carriers

HBV distribution: high prevalence in Asia and some parts of Africa; prevalence in United States  —  low, except for Alaska; highest in Asians in southern California; 10% of all Asians in Los Angeles chronic HBV carriers

Transmission: Western hemisphere  —  acquired through parenteral route, eg, injection drugs, sexual contact, blood transfusions; Asia  —  acquired by infants and neonates; transmitted vertically from mother to infant; when infected, less mature immune systems in younger patients unable to mount sufficient immune response against HBV; major­ity of Asian infants exposed to HBV at birth become chronic HBV carriers; in Western world, immune systems of young adults mount sufficient defense against HBV; low percentage of chronic carriers among patients infected as adults; strategy for elimination of transmission  —  routine vaccination of all infants, high-risk patients, and children of family members with hepatitis B

HBV virology: small size; replication efficient but error-prone; virus unable to repair itself, and therefore has many mutations; mutants  —  hepatitis B virus e-antigen (HBeAg)–negative most common and highly aggressive; others result from treatment that allows development of viral resistance; some mutants more aggressive than others

Viral infection: 30 to 50 yr of infection necessary for progression to liver cancer, cirrhosis, and death; most Asian pa­tients 40 to 50 yr of age appear healthy, but at risk for cirrhosis and cancer; phases of hepatitis B  — immunotolerant; chronic active hepatitis; inactive carrier state; 30% to 50% of HCC found in patients with hepati­tis B without cirrhosis; in all other liver disease, cirrhosis precedes development of cancer

Identifying at-risk patients: Risk Evaluation of Viral load Elevation and Associated Liver disease (REVEAL) study (2006)  —15-yr natural history study in Taiwan; followed 3600 patients without treatment; identified groups that de­veloped cirrhosis and cancer; attempted to predict development of cirrhosis or cancer by analyzing certain factors, eg, sex, age, alcohol use, ALT level, smoking, baseline VL; found baseline VL significant predictor of cirrhosis and cancer; cancer  —  low incidence if baseline VL £10,000 copies/mL; increased incidence if baseline VL >10,0000 copies/mL; cirrhosis  —  increased incidence if baseline VL >10,000 copies/mL

Goals of treatment: to decrease VL and thereby decrease risk for cirrhosis and liver cancer; one study started pa­tients with advanced liver disease on lamivudine to decrease VL; found dramatic 3 yr decrease in incidence of cir­rhosis, decompensation, and cancer, compared to placebo

National Institutes of Health treatment guidelines: therapy indicated in patients with clear progressive advanced disease; may be indicated in patients with active disease, manifested by high VLs and elevated alanine aminotrans­ferase (ALT); not recommended for patients in inactive phase (ie, low VL, normal ALT); categorize patients to de­cide whether to treat; criteria  —  ALT, VL, and liver biopsy; think of ALT and VL as “lights”; 2 green lights, treat; 2 red lights, do not treat; one green light and one red light, perform liver biopsy as tie breaker

Treatment criteria consensus: HBeAg-positive wild type virus  —  VL >20,000 IU/mL, green light; VL <20,0000 IU/mL, red light; abnormal ALT, green light normal ALT, red light (19 units/L for Asian woman and 30 units/L for Asian man); HBeAg-negative  —  VL criteria 2,000 IU/mL

Treatment options: 7 Food and Drug Administration-approved treatments; 5 oral drugs; 2 injectable interferons; oral medications inhibit enzyme that causes viral replication; interferon stimulates host immune system to fight HBV; both types of drugs decrease VL; HBeAg-positive wild type  —  data derived from separate studies; newer antiviral drugs decrease VL better than older antivirals; HBeAg seroconversion  —  occurs after VL decreases; patients lose HBeAg and develop HBe antibody; target clinical end point; once achieved, patients theoretically well and can dis­continue medication; seroconversion dependent on immune system, not specific drug; maintained by >80% HBeAg-positive patients after discontinuing drugs; HBeAg-negative patients  —  newer antivirals lowered VLs in 90% of patients in 1 yr, and normalized ALT in 75% of patients

Resistance: less resistance with newer drugs (except telbivudine) than older drugs (eg, lamivudine); guidelines  —  low-resistance drugs recommended as first tier treatment; lamivudine  —  worst resistance among antivirals (70% resistance in 4 yr); unfavorable resistance with adefovir and telbivudine, but less than lamivudine; <1% resistance with entecavir in untreated patients; in data from 2- to 3-yr studies, 0% resistance with tenofovir; entecavir and te­nofovir now recommended as first-line therapy; resistance negates viral suppression and compromises use of other drugs; sequential monotherapy  —  results in multiple drug resistance; no longer recommended; if resistance devel­ops, add new drug, but do not discontinue previous drug

Suggested Reading

Angeloni S et al: Efficacy of current guidelines for the treatment of spontaneous bacterial peritonitis in the clinical practice. World J Gastroenterol 14:17, 2008; Arase Y et al: Long-term outcome after hepatitis B surface antigen seroclearance in patients with chronic hepatitis B. Am J Med 1:119, 2006; Boursier J et al: Comparison and improvement of MELD and Child-Pugh score accuracies for the prediction of 6-month mortality in cirrhotic patients. J Clin Gastroenterol 6:43, 2009; Garcia-Tsao G et al: Prevention and man­agement of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 3:46, 2007; Khokhar A, Afdhal NH: Thera­peutic strategies for chronic hepatitis B virus infection in 2008. Am J Med 12 Suppl: 121, 2008; Lai CL et al: Telbivudine versus lamivudine in patients with chronic hepatitis B. N Eng J Med 25:357, 2007; Marcellin P et al: Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Eng J Med 23:359, 2008; Marrero JA et al: Alpha-fetoprotein, des-gamma carboxypro­thrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology 1:137, 2009; Moylan CA et al: Disparities in liver transplantation before and after introduction of the MELD score. JAMA 20:300, 2008; Onofrei MD et al: Safety of statin therapy in patients with preexisting liver disease. Pharmacotherapy 4:28, 2008; Senousy BE, Draganov PV: Evaluation and management of patients with refractory ascites. World J Gastroenterol 1:15, 2009; Sharma BC et al: Secondary prophylaxis of he­patic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo. Gastroenterology 3:137, 2009; Sharma P et al: Predictors of nonresponse to lactulose for minimal hepatic encephalopathy in patients with cirrhosis. Liver Int 9:29, 2009; Tenney DJ et al: Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology 5:49, 2009; Vuppalanchi R, Chalasani N: Nonalcoholic fatty liver disease and nonalcoholic steatohep­atitis: Selected practical issues in their evaluation and management. Hepatology 1:49, 2009; Yuen MF et al: HBsAg Seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology 4:135, 2008.