Key Points

• 
  

  Disease summary:

  
  
  
  
  • 
    

    Hepatitis B infection is caused by the hepatitis B virus (HBV), which is transmitted through percutaneous and sexual routes. With an estimated 400 million people with chronic hepatitis B worldwide, HBV infection is currently one of the most prevalent infections. In the United States, there are an estimated 1.25 million people with chronic hepatitis B. A hepatitis B infection acquired in adulthood results in development of protective antibodies approximately 95% of the time. In the remaining approximately 5%, a chronic hepatitis B infection is established, which can lead to end-stage liver disease in 2% to 10% per year and in some infection progresses to liver failure and hepatocellular carcinoma. In HBV acquired in infancy or childhood, the majority of people become chronically infected. Several drugs are available for treatment of chronic hepatitis B, but in the majority of patients, treatment is long term (lifelong in some) since HBV is difficult to eradicate.

  
  
• 
  

  Major clinical forms of infection include

  
  
  
  
  • 
    

    Chronic hepatitis B—Chronic hepatitis B is defined as persistence of the hepatitis B surface antigen (HBsAg) for more than 6 months. It can be divided into active and inactive disease based on detection of HBV DNA and degree of necroinflammatory disease in the liver. It can be subdivided into HBeAg positive (usually active disease) and HBeAg negative (can be active or inactive) chronic hepatitis B.

    
    
  • 
    

    Resolved hepatitis B—Previous HBV infection without further virologic, biochemical, or histologic evidence of active virus infection or disease. Serologically this is distinguished by absence of HBsAg but presence of antibodies to the hepatitis B core antigen (anti-HBc) and surface antigen (anti-HBs)

  
  
• 
  

  Differential diagnosis:

  
  
  
  
  • 
    

    Autoimmune hepatitis, viral hepatitis A, C, and E, HDV coinfection or superinfection, alcoholic hepatitis, nonalcoholic steatohepatitis (fatty liver), sclerosing cholangitis, Wilson disease, alpha-1-antitrypsin-deficiency-related liver disease, drug-induced liver disease

  
  
• 
  

  Monogenic forms:

  
  
  
  
  • 
    

    Not available

  
  
• 
  

  Family history:

  
  
  
  
  • 
    

    Not available

  
  
• 
  

  Twin studies:

  
  
  
  
  • 
    

    One study showed that monozygotic twins, who were infected with HBV, were more likely to become chronically infected compared to dizygotic twins or siblings.

  
  
• 
  

  Environmental factors:

  
  
  
  
  • 
    

    Hepatitis B is an infectious virus so exposure to virus via percutaneous or sexual contact is necessary to acquire the infection.

  
  
• 
  

  Genome-wide associations:

  
  
  
  
  • 
    

    Strong association established between genetic variation around HLA-DPA1 and HLA-DPB1 genomic region and chronic outcome of acute infection in Asian populations.

  
  
• 
  

  Single-nucleotide polymorphism (SNP) in KIF1B on chromosome 1p36.22 is associated with hepatocellular carcinoma (HCC) development in Asian chronic HBV carriers.

  
  
• 
  

  Pharmacogenomics:

  
  
  
  
  • 
    

    Not available

Diagnostic Criteria for Hepatitis B

Diagnostic Evaluation

• 
  

  Initial testing: HBsAg. Two positive tests separated by 6 months are required for the diagnosis of chronic hepatitis B.

  
  
• 
  

  If chronic hepatitis B is diagnosed, then additional testing includes HBV DNA, hepatitis B e antigen, hepatitis B e antibody, liver function tests, liver imaging, and in some cases, a liver biopsy.

Clinical Characteristics

Symptoms of Acute HBV Infection

Acute infection symptoms and their severity can vary. The symptoms may include fever, fatigue, abdominal pain, jaundice, dark urine, light- or clay-colored stools, scleral icterus, nausea, vomiting, and anorexia. However, the infection can be asymptomatic.

Disease Patterns in Chronic Hepatitis B

Chronic hepatitis B is usually asymptomatic. Chronic liver disease develops slowly over decades and when symptoms occur can include abdominal pain, ascites, jaundice, easy bruising, decreased appetite, or encephalopathy. Laboratory manifestations include thrombocytopenia, coagulopathy, low albumin, and elevated transaminases. Hepatocellular carcinoma is usually asymptomatic until lesions become large. Diagnosis of hepatocellular carcinoma is with either liver ultrasound, computed tomography (CT) scan, or magnetic resonance imaging (MRI). The diagnosis is confirmed with a biopsy of the hepatic lesions.

Extrahepatic Manifestations of Chronic HBV

Many extrahepatic syndromes are immune mediated and are a consequence of deposition of circulating immune complexes, local immune complex formation induced by viral antigens, viral-induced autoantibodies, or a direct viral reaction to extrahepatic tissue sites. Examples include

• 
  

  Polyarteritis nodosa—affects small- and medium-sized vessels, more common in Caucasian patients than in Asian patients.

  
  
• 
  

  Glomerulonephritis—mainly seen in children but can occur in adults.

  
  
• 
  

  A serum-sickness like “arthritis-dermatitis” prodrome—occurs with HBV acquisition and has variable joint and skin manifestations. Occasionally, the arthritis following the acute prodromal infection may persist; however, joint destruction is rare.

  
  
• 
  

  Skin manifestations—usually palpable purpura.

Screening

• 
  

  Routine screening of family members for HBV is recommended if unvaccinated.

Counseling

• 
  

  Counseling of family members includes vaccination against HBV. Counseling does not involve human genetic information.

Since adult-acquired acute hepatitis B usually results in the development of protective antibodies without treatment, most cases of acute hepatitis B do not need treatment. The exception to this is cases of acute infection with fulminant liver failure where treatment may be beneficial. In chronic hepatitis B, the HBV DNA level correlates with the risk for developing end-stage liver disease and hepatocellular carcinoma. Thus, patients with higher HBV DNA levels and evidence of inflammation are treated. Guidelines from the American Association of Liver Disease and the Infectious Diseases Society of America exist regarding who should be treated.

Therapeutics Currently Approved by the FDA

Nucleoside or Nucleotide Analogues

These are oral agents, which inhibit the HBV polymerase. The major problem is emergence of drug-resistant variants, which occur most frequently with lamivudine. The most potent agents are tenofovir and entecavir and they have the highest genetic barrier to resistance, so development of drug resistance is uncommon in treatment-naïve patients. For that reason, these two agents are recommended first-line agents to treat chronic hepatitis B in treatment-naïve patients.

• 
  

  Lamivudine (Epivir)

  
  
• 
  

  Adefovir (Hepsera)

  
  
• 
  

  Tenofovir (Viread)

  
  
• 
  

  Telbivudine (Tyzeka)

  
  
• 
  

  Entecavir (Baraclude)

Other Treatments

• 
  

  Interferon alpha-2a—no longer used since pegylated interferon is available

  
  
• 
  

  Pegylated interferon alpha-2a (Pegasys)

  
  
• 
  

  Pegylated interferon alpha-2b (Intron A)

Patient’s age, HBeAg status, ALT levels, liver disease stage, coinfection with HIV and/or hepatitis D virus (HDV) and/or hepatitis C virus (HCV), HBV DNA level, HBV genotype, previous treatment history, or presence of drug-resistant mutations are factors considered in treatment of hepatitis B.

Liver transplantation: Transplantation is reserved for people with advanced liver disease as measured by the model for end-stage liver disease (MELD) score, which estimates survival rates. Reinfection of the transplanted organ occurs universally without treatment, so prevention of reinfection with hepatitis B immune globulin and oral anti-HBV agents is recommended.

Pharmacogenetics has not yet been incorporated routinely in HBV treatment.

A recent genome-wide association study (GWAS) revealed a strong association of HLA-DP polymorphisms and HBV recovery in Asian populations (Japanese and Thai) (Table 85-1). The mechanism for this association has not been discovered.

Another GWAS carried on Chinese population revealed association between polymorphism in KIF1B on chromosome 1p36.22 and development of HCC. They suggested that carcinogenesis may be associated with decreased expression of KIF1B that might play a tumor-suppressor function.

Genetic Testing

The clinical role of genetic testing in diagnostics and treatment response is not yet established.

Future Directions

A study in European and Blacks found that a HLA-DP variant is also associated with HBV outcome although a different SNP was responsible for the association. The functional significance of these associations needs to be determined. Studies to determine genetic associations with treatment outcomes need to be performed.