Chronic Hepatitis

Peter F. Malet, M.D., F.A.C.P.
University of Texas Southwestern Medical Center at Dallas

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• Liver disease lasting 6 mo or longer, mainly manifested by hepatocellular injury/necrosis
• Most common etiologies
  • Chronic hepatitis C
  • Chronic hepatitis B
  • Autoimmune hepatitis
• Highly variable presentation and course
  • Asymptomatic to rapidly progressive with fulminant hepatic failure
• Most common symptoms
  • Fatigue
  • Malaise
  • Mild abdominal pain
• Symptoms of advanced disease
  • Variceal bleeding
  • Jaundice
  • Spider angiomas
  • Palmar erythema
  • Ascites
  • Edema
  • Hepatomegaly
  • Encephalopathy
• Extrahepatic manifestations
  • Arthralgias
  • Arthritis
  • Glomerulonephritis
  • Skin rashes

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Differential Diagnosis

• Primary biliary cirrhosis
• Primary sclerosing cholangitis
• Alcoholic liver disease
• Fatty liver and nonalcoholic steatohepatitis (NASH)
• Drug-induced chronic hepatitis
• Wilson disease
• α₁-Antitrypsin deficiency

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Best Tests

Autoimmune Hepatitis

• Type 1
  • Hypergammaglobulinemia
  • Presence of antinuclear antibody (ANA), anti–smooth muscle antibody (ASMA), or both
• Type 2
• Absence of ANA and ASMA
• Presence of antibody to liver/kidney microsome (anti-LKM) type 1
• Type 3
  • Presence of antibody to soluble liver antigen, liver/pancreas antigen, or both
  • Some patients also positive for ASMA, antimitochondrial antibody, or both
• Some patients have no serologic markers (marker-negative autoimmune hepatitis) or have overlap syndromes

• Inactive HBsAg carrier
  • Positive HBsAg
  • Positive anti-HBc
  • Negative anti-HBs
  • Negative HBeAg
  • Positive anti-HBe
  • HBV DNA usually < 100,000 copies/ml
• High replicative state
  • Positive HBsAg
  • Positive anti-HBc
  • Negative anti-HBs
  • Positive or negative HBeAg
  • If HBeAg positive, Anti-HBe is negative
  • HBV DNA > 100,000 copies/ml

• Positive anti-HCV ELISA
• Detectable HCV RNA
• Determination of genotype
• 75% genotype 1
• 20% genotypes 2 or 3
• < 5% genotypes 4 to 6

• Serum ALT and AST usually elevated, often only minimally elevated or even normal in chronic hepatitis B (inactive carrier) and C
• Serum bilirubin usually normal in chronic viral hepatitis but often > 3 mg/dl in autoimmune hepatitis
• Increased γ-globulin level in autoimmune hepatitis
• Low serum albumin level and prolonged PT suggest advanced disease
• Abdominal CT, MRI, or ultrasound to determine the following:
• Liver and spleen size and contour
• Evidence of portal hypertension
• Presence of ascites
• Presence or absence of hepatocellular carcinoma

• Help confirm diagnosis
• Establish grade of inflammation
• Establish stage of fibrosis
• Exclude coexistent liver disease

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Best Therapy

Drug Therapy for Autoimmune Hepatitis

Corticosteroids

• 65% remission in 18 mo
• 80% remission in 3 yr
• 20%–90% relapse within 3–6 mo of tapering to lower doses (≤ 10 mg/day) or discontinuance of therapy
• Long-term therapy needed in many cases
• Prednisone alone
• Dose: initial, 40 mg/day p.o., tapered over 4 wk; maintenance, 20 mg/day p.o. until biochemical remission; then slower tapering to 10 mg/day maintenance
• Cost/mo: $8
• Prednisone + azathioprine: azathioprine helps maintain remission but may not be appropriate in cases of severe cytopenias, pregnancy, or active malignancy
• Dose
• Prednisone: initial, 30 mg/day, tapered over 6 wk to 20 mg/day until biochemical remission; then slower tapering to 10 mg/day maintenance
• Azathioprine: initial, 50 mg/day; maintenance, 50–150 mg/day (2 mg/kg/day)
• Cost/mo: $8 + $71
• Begin tapering drugs when clinical and biochemical remission is achieved; taper over a period of months; taper prednisone first, keeping azathioprine dose constant
• First relapse: increase medication doses
• ≥ 2 relapses: maintain disease quiescence (serum transaminases elevated ~ twofold) with lower doses
• Prednisone alone: ≤ 10 mg/day (as low a dose as possible), or
• Prednisone, gradually tapered + azathioprine, 2 mg/kg/day

Drug Therapy for Chronic Hepatitis B

Interferon alfa-2a or 2b

• Often difficult to tolerate
• Patients with cirrhosis need low, titrated doses with careful monitoring
• Seroconversion: loss of HBeAg and appearance of anti-HBe in ~ 35%; loss of HBsAg and appearance of anti-HBs in ~ 8%
• Dose: 5 million U/day s.c. or 10 million U 3 times/wk s.c. for 16–24 wk
• Use of peginterferon for chronic hepatitis B is still under study but is generally accepted in the U.S. at present
• Side effects
• Depression, other psychiatric symptoms
• Leukopenia and thrombocytopenia
• Thyroid dysfunction
• Insomnia
• Headaches
• Weight loss
• Neurologic dysfunctions
• Death from sepsis, suicide, or cardiovascular disease can occur
• Contraindications
• History of hypersensitivity to interferon
• Decompensated cirrhosis
• Immunosuppression associated with organ transplantation
• Active autoimmune disease
• Severe psychiatric disease
• Elderly or frail

Lamivudine

• Well tolerated
• Safe in end-stage liver disease (ESLD)
• Dose adjustments n?eded for patients with significant renal failure
• Resistance common
• 14%–32% at 1 yr, increasing to 69% at 5 yr
• HBeAg seroconversion in 17% at 1 yr, 50% at 5 yr
• Long-term therapy often needed, especially in HBeAg-negative patients
• Dose: 100 mg/day p.o.
• Cost/mo: $181

Adefovir

• Well tolerated
• Safe in ESLD; dose adjustments needed for patients with significant renal failure
• Resistance in 2%–3% at 2 yr when used as primary therapy, higher after 4–5 yr; resistance more frequent when used in patients who developed resistance to lamivudine
• HBeAg seroconversion in 12% at 1 yr
• Long-term therapy often needed, especially in HBeAg-negative patients
• Dose: 10 mg/day p.o.
• Cost/mo: $532

Entecavir

• Well tolerated
• Safe in ESLD
• Resistance data limited
• HBeAg seroconversion in 21% at 1 yr
• Long-term therapy often needed, especially in HBeAg-negative patients
• Dose: 0.5 mg/day p.o. in treatment-naive patients, 1 mg/day in lamivudine-resistant patients
• Cost/mo: $700 (0.5 mg/day)

Liver Transplantation for Chronic Hepatitis B

• HBV infects allograft in 80%–100% of cases if antiviral prophylaxis not given
• Use of HBIG and lamivudine/adefovir reduces reinfection to 10%–20%
• Long-term survival good in absence of reinfection
  

Reactivation in Inactive Carriers

• May occur spontaneously or after cessation of chemotherapy for malignancy and may be severe
• Monitor and treat prophylactically with lamivudine or adefovir

Drug Therapy for Chronic Hepatitis C

Pegylated Interferon and Ribavirin Combination Therapy

• HCV genotype 1
• Sustained virologic response (SVR) 42%–52%; if HCV RNA still detectable after 24 wk of treatment, stop treatment
• Dose: pegylated interferon alfa-2a, 180 µg s.c. weekly for 48 wk, plus ribavirin, 1,000–1,200 mg/day p.o. for 48 wk
• Cost/mo: $1,316 + $780
HCV genotype 1: alternate regimen
• SVR 42%–52%; if HCV RNA still detectable after 24 wk of treatment, stop treatment
• Dose: pegylated interferon alfa-2b, 1.5 µg/kg s.c. weekly for 48 wk, plus ribavirin, 800–1,200 mg/day p.o. for 48 wk
• HCV genotype 2 or 3
• SVR 76%–84%
• Pegylated interferon alfa-2a, 180 µg s.c. weekly for 24 wk, plus ribavirin, 800 mg/day for 24 wk
• Cost/mo: $1,316 + $520
• HCV genotype 2 or 3: alternate regimen
• SVR 76%–84%
• Pegylated interferon alfa-2b, 1.5 µg/kg s.c. weekly for 24 wk, plus ribavirin, 800–1,200 mg/day for 24 wk
• Factors that reduce likelihood of successful therapy
• High viral load (> 2 × 10⁶ copies/ml)
• African-American ethnicity
• Advanced fibrosis
• Side effects of interferon (see above)
• Contraindications of interferon
• Severe psychiatric illness
• Poorly controlled seizure disorder
• Poorly controlled diabetes mellitus
• Active malignancy
• Hemoglobin < 10–12 g/dl
• WBC < 1,500/µl
• Platelet count < 60,000–75,000/µl
• Pregnant or at risk of pregnancy
• Decompensated cirrhosis
• Side effects of ribavirin
• Reversible, dose-dependent hemolytic anemia
• Mild anema: temporarily reduce dose
• Greater degrees of anemia: epoetin or darbepoetin
• Severe anemia: discontinue ribavarin
• Teratogenic; avoid in pregnancy
• Rash
• Nasal or sinus problems

Liver Transplantation for Chronic Hepatitis C

• HCV reinfects allograft in nearly 100% of cases, but subsequent illness is usually mild
• A small percentage progress to cirrhosis and liver failure
• Post-transplant treatment is possible but difficult

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Best References

Chang TT, et al: N Engl J Med 354:1001, 2006 PMID 16525137

Craxi A, et al: J Hepatol 44(1 suppl):S77, 2006 PMID 16356581

Czaja AJ, et al: Hepatology 36:479, 2002 PMID 12143059

Keeffe EB, et al: Clin Gastroenterol Hepatol 4:936, 2006 PMID 16844425

Strader DB, et al: Hepatology 39:1147, 2004 PMID 15057920

The author has received grants for clinical research from Roche Pharmaceuticals and Schering-Plough Corporation.

March 2007

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