Hepatitis B, Chronic

Essentials of Diagnosis

• Chronic inflammatory reaction of the liver of more than 3–6 months' duration

• Repeated detection of hepatitis B surface antigen (HBsAg) in serum, often with elevated serum aminotransferase levels

General Considerations

• Early in the course, hepatitis Be antigen (HBeAg) and hepatitis B virus (HBV) DNA are present in serum

  • Indicative of active viral replication and necroinflammatory activity in the liver

  • These persons are at risk for progression to cirrhosis and for hepatocellular carcinoma

  • Low-level IgM anti-HBc is also present in about 70%

• Clinical and biochemical improvement may coincide with

  • Disappearance of HBeAg and HBV DNA from serum

  • Appearance of anti-HBe

  • Integration of the HBV genome into the host genome in infected hepatocytes

• If cirrhosis has not yet developed, such persons are at a lower risk for cirrhosis and hepatocellular carcinoma

• Chronic hepatitis is characterized on the basis of

  • The etiology

  • The grade of portal, periportal, and lobular inflammation (minimal, mild, moderate, or severe)

  • The stage of fibrosis (none, mild, moderate, severe, cirrhosis)

• Five phases of chronic HBV infection are recognized

  • Immune tolerant phase

  • Immune active (or immune clearance) phase

  • Inactive HBsAg carrier state

  • Reactivated chronic hepatitis B phase

  • HBsAg-negative phase

Demographics

• Chronic hepatitis B afflicts 248 million people worldwide and 2.2 million (predominantly males) in the United States

Symptoms and Signs

• Clinically indistinguishable from chronic hepatitis due to other causes

• Immune active phase (HBeAg-positive chronic hepatitis B)

  • HBeAg and HBV DNA are present in serum, indicative of active viral replication

  • Serum aminotransferase levels are normal, with little necroinflammation in the liver

  • This phase is common in infants and young children whose immature immune system fails to mount an immune response to HBV

• Inactive HBsAg carrier state (HBeAg-negative chronic HBV infection)

  • Patients have entered this phase when biochemical improvement follows immune clearance and cirrhosis has not yet developed

  • Patients in this phase are at a low risk for cirrhosis and hepatocellular carcinoma

  • Patients with persistently normal serum aminotransferase levels infrequently have histologically significant liver disease

• Reactivated chronic hepatitis B phase (HBeAg-negative chronic hepatitis B)

  • Risk factors for reactivation include

    • Male sex and HBV genotype C

    • Advanced age

    • Alcohol use

    • Cigarette smoking

    • Coinfection with HCV or HDV

  • In patients with either HBeAg-positive or HBeAg-negative chronic hepatitis B, the risk of cirrhosis and of hepatocellular carcinoma correlates with the serum HBV DNA level

  • HIV coinfection is also associated with an increased frequency of cirrhosis when the CD4 count is low

  • Occasional patients (only 1% of treated and untreated patients per year) reach the HBsAg-negative phase, in which

    • Anti-HBe may remain

    • Serum ALT levels are normal

    • HBV DNA is undetectable in serum but remains present in the liver

    • In some cases, anti-HBs appears in serum

Differential Diagnosis

• Hepatitis C and D (delta)

• Autoimmune hepatitis

• Alpha-1-antiprotease deficiency

• Drug-induced chronic hepatitis

• Wilson disease

Laboratory Tests

• Immune tolerant phase

  • HBeAg and HBV DNA are present in serum, indicative of active viral replication

  • When HBV infection is acquired in infancy or early childhood, serum aminotransferase levels often are normal and little necroinflammation is present in the liver

• Immune active phase

  • Aminotransferase levels are elevated

• Inactive HBsAg carrier state

  • Disappearance of HBeAg and reduced HBV DNA levels (< 10⁵ copies/mL, or < 20,000 international units/mL) in serum, appearance of anti-HBe, and integration of the HBV genome into the host genome in infected hepatocytes

• Reactivated chronic hepatitis B phase

  • May result from infection by a pre-core mutant of HBV or spontaneous mutation of the pre-core or core promoter region of the HBV genome during the course of chronic hepatitis caused by wild-type HBV

  • There is a rise in serum HBV DNA levels and possible progression to cirrhosis (at a rate of 8–10% per year), particularly when additional mutations in the core gene of HBV are present

• Elevated serum bilirubin level, low albumin level, and prolonged prothrombin time reflect advanced disease (severe inflammation or cirrhosis, or both)

• Table 16–5

Diagnostic Procedures

• Liver biopsy may be indicated for diagnosis, staging, and predicting response to therapy

Medications

• Patients with active viral replication (HBeAg and HBV DNA [≥ 10⁵ copies/mL, or ≥ 20,000 international units/mL] in serum; elevated serum aminotransferase levels) may be treated with a nucleoside or nucleotide analog or pegylated interferon

• Entecavir

  • Dosage: 0.5 mg orally daily for patients not resistant to lamivudine and 1 mg orally daily for patients who are already resistant to lamivudine

  • Entecavir resistance is rare unless a patient is already resistant to lamivudine

  • Suppression of HBV DNA in serum occurs in nearly all treated patients, and histologic improvement is observed in 70% of patients

  • Has been reported to cause lactic acidosis when used in patients with decompensated cirrhosis

• Tenofovir disoproxil fumarate (TDF)

  • Dosage: 300 mg orally daily

  • Equally effective against HBV and is used as a first-line agent or when resistance to a nucleoside analog has developed

  • Has a low rate of resistance when used as initial therapy

  • Long-term use may lead to an elevated serum creatinine level and reduced serum phosphate level (Fanconi-like syndrome) that is reversible with discontinuation of the drug

  • Classified as pregnancy category B; treatment is recommended starting in the third trimester when mother's serum HBV DNA level is > 200,000 international units/mL to reduce levels at time of delivery

• Tenofovir alafenamide (TAF)

  • Dosage: 25 mg orally daily

  • May be associated with a lower rate of renal and bone toxicity than tenofovir disoproxil fumarate

• Lamivudine

  • Dosage: 100 mg orally daily

  • No longer considered first-line therapy in the United States but may be used in countries in which its relative low cost is a deciding factor

  • By the end of 1 year, however, 15–30% of responders experience a relapse (and occasionally frank decompensation)

  • The rate of resistance reaches 70% by 5 years of therapy

  • Classified as pregnancy category C; safe to use in pregnant women with HIV; starting treatment in third trimester when serum HBV DNA level is > 200,000 international units/mL is recommended to reduce levels at time of delivery

• Adefovir dipivoxil

  • Dosage: 10 mg orally once daily for at least 1 year

  • Has activity against wild-type and lamivudine-resistant HBV but is the least potent of the oral antiviral agents for HBV

  • Adding the drug may be effective in patients who have become resistant to lamivudine

  • A small number of patients achieve sustained suppression of HBV replication

  • Resistance occurs in up to 29% of patients treated for 5 years

  • Patients with underlying kidney dysfunction are at risk for nephrotoxicity

• Telbivudine

  • Dosage: 600 mg orally daily

  • More potent than either lamivudine or adefovir but like them associated with resistance, especially in patients who are resistant to lamivudine

  • Elevated creatine kinase levels are common

  • Classified as pregnancy category B; treatment is recommended starting in the third trimester when mother's serum HBV DNA level is > 200,000 international units/mL to reduce levels at time of delivery

• Peginterferon alfa-2a

  • Dosage: 180 mcg subcutaneously once weekly for 48 weeks

  • Leads to sustained normalization of serum aminotransferase levels, disappearance of HBeAg and HBV DNA from serum, appearance of anti-HBe, and improved survival in up to 40% of treated patients

  • Response is most likely in patients with a low baseline HBV DNA level and high aminotransferase levels and is more likely in those infected with HBV genotype A than with other genotypes (especially genotype D) and who have certain favorable polymorphisms of the IL28B gene

  • Most complete responders eventually clear HBsAg and develop anti-HBs in serum, and are thus cured

  • Relapses are uncommon in complete responders who seroconvert from HBeAg to anti-HBe

  • Patients with HBeAg-negative chronic hepatitis B have a response rate of 60% after 48 weeks of therapy but the response may not be durable

  • Response to interferon is poor in patients with HIV coinfection

Therapeutic Procedures

• Activity is modified according to symptoms; bed rest is not necessary

• The diet should be well balanced, without limitations other than sodium or protein restriction if dictated by fluid overload or encephalopathy

Complications

• Cirrhosis

• Hepatocellular carcinoma

• Extrahepatic: polyarteritis nodosa, membranous glomerulonephritis

Prognosis

• Sequelae of chronic hepatitis B include

  • Cirrhosis

  • Liver failure

  • Hepatocellular carcinoma

• The 5-year mortality rate

  • 0–2% in those without cirrhosis

  • 14–20% in those with compensated cirrhosis

  • 70–86% following decompensation

• The risk of cirrhosis and hepatocellular carcinoma correlates with serum HBV DNA levels, and a focus of therapy is to suppress HBV DNA levels below 300 copies/mL (60 international units/mL)

• There is some evidence that HBV genotype C is associated with a higher risk of cirrhosis and hepatocellular carcinoma than other genotypes

• Antiviral treatment

  • Improves the prognosis in responders

  • Prevents (or leads to regression of) cirrhosis

  • Decreases the frequency of liver-related complications (although the risk of hepatocellular carcinoma does not become as low as that in inactive HBV carriers and hepatocellular carcinoma may even occur after clearance of HBsAg)

• A risk score (PAGE-B) based on a patient's age, gender, and platelet count has been reported to predict the 5-year risk of hepatocellular carcinoma in white patients receiving entecavir or tenofovir

Prevention

• Strict isolation of patients is not necessary

• Thorough hand washing by anyone who may contact contaminated utensils, bedding, or clothing is essential

• Screening of donated blood for HBsAg and anti-HBc has reduced the risk of transfusion-associated hepatitis markedly

• Pregnant women should be tested for HBsAg

• Persons with HBV should practice safer sex

• Vaccinate those with chronic hepatitis B against HAV (after prescreening for prior immunity)

When to Refer

• For liver biopsy

• For antiviral therapy

When to Admit

• Hepatic encephalopathy

• INR > 1.6