Chronic Hepatitis

Emmet B. Keeffe, M.D.
Stanford University School of Medicine

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

Definition/Key Clinical Features

• Most common etiologies
  • Chronic hepatitis C
  • Chronic hepatitis B
  • Autoimmune hepatitis
• Highly variable course
  • Asymptomatic to rapidly progressive with fulminant hepatic failure
• Most common symptoms
  • Fatigue
  • Malaise
  • Mild abdominal pain
• Symptoms of advanced disease
  • Anorexia
  • Jaundice
  • Spider angiomas
  • Palmar erythema
  • Ascites
  • Edema
  • Hepatomegaly
  • Encephalopathy
• Extrahepatic manifestations
  • Arthralgias
  • Arthritis
  • Cryoglobulinemia
  • Glomerulonephritis
  • Skin rashes
  • Amenorrhea
  • Acne
  • Hirsutism
  • Thyroiditis

Differential Diagnosis

• Primary biliary cirrhosis
• Primary sclerosing cholangitis
• Drug-induced chronic hepatitis
• Wilson disease
• α₁-Antitrypsin deficiency

Best Tests

Serologic Testing

Autoimmune Hepatitis

• Type 1
  • Hypergammaglobulinemia
  • Presence of 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

Chronic Hepatitis B

• Positive HBsAg
• Negative IgM
• Negative anti-HBc
• HBeAg-positive (wild type HBV) or HBeAg-negative (precore or core promoter mutant HBV)
• Detectable HBV DNA with active viral replication

Chronic Hepatitis D

• Positive HBsAg
• Positive anti-HDV

Chronic Hepatitis C

• Positive anti-HCV (second-generation ELISA or recombinant immunoblot assay)
• Detectable HCV RNA
• Determination of genotype
  • 75% genotype 1
  • 20% genotypes 2 to 3
  • < 5% genotypes 4 to 6

Routine Laboratory Tests

• Serum ALT and AST usually elevated, often only minimally in chronic hepatitis B and C
• Increased γ-globulin level in autoimmune hepatitis
• Low serum albumin level and prolonged PT suggest advanced disease
• Abdominal CT, MRI, or ultrasound to determine
  • Liver and spleen size and contour
  • Evidence of portal hypertension
  • Presence of ascites
  • Presence or absence of hepatocellular carcinoma

Liver Biopsy

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

Best Therapy

Drug Therapy for Autoimmune Hepatitis

Corticosteroids

• 65% remission in 1 yr
• 80% remission in 3 yr
• 50% relapse with discontinuance of therapy
• Long-term therapy needed in some
• Prednisone
  • Dose
    • Initial: 40 mg/day, tapered over 6 wk
    • Maintenance: 15–20 mg/day
  • Cost/mo: $7.99
• Prednisone + azathioprine
  • Combination preferred for avoiding toxicity of corticosteroids, e.g., in diabetics, elderly
• Dose:
  • Prednisone, initial: 30 mg/day, tapered over 6 wk
  • Prednisone, maintenance: 10 mg/day
  • Azathioprine (initial and maintenance): 50 mg/day
• Cost/mo: $7.99 + $27.99

Drug Therapy for Chronic Hepatitis B

Interferon alfa-2b

• Tolerance poor
• Should avoid in ESLD
• Peginterferon under study
• Loss of HBV DNA and HBeAg in one third
• Loss of HBsAg in 10%–20% at 5 yr
  • Dose: 30–35 million U/wk, S.C. or I.M. x 4 mo given as 5 million U/day or 10 million U t.i.w.
  • Cost/mo: $2,066.54

Lamivudine

• Well tolerated
• Safe in ESLD
• Dose adjustments needed for patients with significant renal failure
• Resistance common
  • 15% at 1 yr, increasing to 65% at 5 yr. HbeAg seroconversion in 16%–18% at 1 yr
• Long-term therapy often needed, especially in HbeAg-negative patients
  • Dose: 100 mg/day
  • Cost/mo: $146.00

Adefovir

• Well tolerated
• Safe in ESLD; dose adjustments needed for patients with significant renal failure
• Resistance rare
  • 2%–3% at 2 yr
• HBeAg seroconversion in 12% at 1 yr
• Long-term therapy often needed, esp. in HBeAg-negative patients
  • Dose: 10 mg/day
  • Cost/mo: $450.00

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 5%–20%
• Long-term survival good in absence of reinfection

Drug Therapy for Chronic Hepatitis D

Interferon alfa

• Dose: 9 million U t.i.w. x 48 wk
• Cost/mo: $1549.91

Drug Therapy for Chronic Hepatitis C

Interferon and Ribavirin Combination Therapy

• Interferon
  • Overall SVR in 55%–60%
  • 1 yr Rx for genotype 1
    • SVR in 45%–50%
  • 6 mo Rx for genotypes 2 to 3
    • SVR in 75%–80%
  • Side effects
    • Flu-like
    • Psychiatric
    • Hematologic
  • Dose:
    • Peg alfa-2a: 180 μg/wk
    • Peg alfa-2b: 1.5 μg/kg/wk
  • Cost/mo: $1,294.99
• Ribavarin
  • Teratogenic; avoid in pregnancy
  • Reduce dose or discontinue if severe anemia develops
  • Dose: 800-1,200 mg/day in two divided doses
    • 800 mg/day adequate for genotypes 2 or 3
    • 1,000–1,200 mg/day for genotype 1
  • Cost/mo: $1,632.98

Liver Transplantation for Chronic Hepatitis C

• HCV reinfects allograft in nearly 100% of cases, but subsequent illness is usually mild and progresses to liver failure in the minority—15%–20% of cases

Best References

Czaja, et al: Hepatology 36:479, 2002

Lok, et al: Hepatology 34:1225, 2001

NIH Consensus Statement: Hepatology 36:S3, 2002

July 2004