Hepatitis B and Hepatitis D

Key Points

1
Hepatitis B virus (HBV) infection is a major cause of acute liver failure, cirrhosis, and hepatocellular carcinoma (HCC).
2
HBV infection can be prevented by hepatitis B vaccination.
3
Acute HBV infection is most likely to resolve spontaneously in immunocompetent adults, especially if symptomatic. Progression to chronic infection is typical in children, the elderly, and immunocompromised persons, including hemodialysis patients.
4
HCC related to HBV infection can occur in a noncirrhotic liver.
5
Serum HBV DNA levels correlate with the risk of cirrhosis and HCC.
6
Indications for antiviral therapy are persistent viral replication with elevated serum aminotransferase levels.
7
Special populations such as pregnant patients with HBV infection and patients who are about to undergo immunosuppressive therapy should be considered for antiviral therapy even in the absence of standard indications.
8
Current first-line therapies for hepatitis B are entecavir, tenofovir, and pegylated interferon.
9
Long-term suppression of HBV with oral therapies has led to a reduction in the need for HBV-infected patients to undergo liver transplantation for decompensated cirrhosis. Regression of fibrosis and cirrhosis has been confirmed by serial liver biopsies with long-term therapy for HBV infection. A reduced frequency of HCC has also been observed with antiviral therapy for HBV.
10
Infection with hepatitis D virus (HDV) should be suspected in HBV-infected persons with clinically severe disease and low or absent HBV replication.

Hepatitis B Virus

Virology

1.
Human-infecting member, the Hepadnaviridae family of hepatotropic DNA-containing viruses
2.
Eight genotypes (A–H): Genotype C appears to be implicated in more severe chronic disease
3.
42-nm spherical particle with the following components:
- ▪
  A 27-nm-diameter, electron-dense, nucleocapsid core
- ▪
  A 7-nm-thick outer lipoprotein envelope
4.
HBV core containing circular, partially double-stranded DNA (3.2 kb long) and the following components:
- ▪
  DNA polymerase protein with reverse transcriptase activity
- ▪
  Hepatitis B core antigen (HBcAg) , a structural protein of the nucleocapsid, which does not circulate in serum
- ▪
  Hepatitis B e antigen (HBeAg) , a nonstructural, secretory protein that correlates imperfectly with active HBV replication
- ▪
  Hepatitis B X protein , a transcriptional activator, which is linked to hepatocarcinogenesis
5.
HBV outer lipoprotein envelope, which contains the following components:
- ▪
  Hepatitis B surface antigen (HBsAg) , with 3 envelope proteins: Major, large, and middle proteins
- ▪
  Minor lipid and carbohydrate components
- ▪
  HBsAg present in 22-nm spherical or tubular noninfectious particles, in excess of intact HBV particles
6.
Variants
- a.
  One major serotype; many subtypes based on HBsAg protein diversity
- b.
  HBV mutant viruses emerge spontaneously as a consequence of poor proofreading ability of reverse transcriptase or emergence of antiviral resistance during therapy:
  - ▪
    HBeAg-negative precore or core promoter mutants
  - ▪
    HBV vaccine-induced escape mutants (rare)
  - ▪
    Nucleos(t)ide-induced resistant mutants
7.
Replication occurs through reverse transcription of pregenomic RNA.
8.
The liver is the major, but not only, site of HBV replication.
9.
Replication in vitro is limited in primary adult and fetal human hepatocytes.

Epidemiology

1.
Incubation period: 15 to 180 days (average, 60 to 90 days)
2.
HBV viremia lasts for weeks to months after acute infection.
3.
Chronic infection with persistent viremia develops in 1% to 5% of adults, 90% of infected neonates, and 50% of infants.
4.
Chronic infection is linked to chronic hepatitis, cirrhosis, HCC, and premature mortality.
5.
Chronic infection can cause extrahepatic diseases: Vasculitis, lymphoma, membranous glomerulonephritis.
6.
Worldwide distribution: HBV carrier prevalence is <1% in the United States and 5% to 15% in Asia and sub-Saharan Africa; the incidence has declined in areas where HBV vaccine use has expanded.
7.
HBV is present in blood, semen, cervicovaginal secretions, saliva, and other body fluids.
8.
The risk of HBV transmission correlates with the serum HBV DNA level and presence of HBeAg.
9.
Modes of transmission
- a.
  Blood-borne
  - ▪
    Transfusion of blood and blood products
  - ▪
    Injection drug use
  - ▪
    Hemodialysis
  - ▪
    Exposure to blood in health care and other workers
- b.
  Sexual : Responsible for 50% of acute cases in the United States
- c.
  Tissue penetration (percutaneous) or permucosal transfer
  - ▪
    Needlestick accidents
  - ▪
    Muscosal exposure to body fluids
  - ▪
    Reuse of contaminated medical equipment
  - ▪
    Shared razor blades
  - ▪
    Tattoos
  - ▪
    Acupuncture, body piercing
  - ▪
    Shared toothbrushes
- d.
  Maternal-neonatal and maternal-infant
  - ▪
    Perinatal transmission is associated with maternal serum HBV DNA levels >1,000,000 copies/mL (200,000 IU/mL).
  - ▪
    Highest risk with maternal serum HBV DNA >10 ⁸ copies/mL (2 × 10 ⁷ IU/mL)
- e.
  No evidence for fecal-oral spread
- f.
  No identifiable risk factor in 25% of cases

Acute Hepatitis B

Pathogenesis

1.
Cell-mediated immune mechanisms are largely responsible for hepatocyte injury, including hepatocyte degeneration and apoptosis.
- ▪
  CD8+ and CD4+ T cell responses
- ▪
  Production of cytokines in the liver and systemically
2.
Direct viral cytopathic effect
- ▪
  Postulated in immunosuppressed patients with exceedingly high levels of viral replication (evidence is indirect)

Clinical Features

1.
Disease severity ranges from asymptomatic (subclinical) hepatitis, to clinical acute symptomatic hepatitis, to acute liver failure ( Fig. 4.1 ); severity is increased in those with preexisting liver disease or age ≥40 years.
2.
The initial clinical syndrome is similar to that for a general viral infection, with nonspecific constitutional and gastrointestinal symptoms.
- ▪
  Malaise, anorexia, nausea, and vomiting
- ▪
  Flulike symptoms, including pharyngitis, cough, coryza, photophobia, headache, and myalgias
3.
The onset of symptoms is usually insidious.
4.
Fever is uncommon.
5.
A syndrome that is immune complex mediated and resembles serum sickness occurs in <10% of patients with HBV infection; it includes polyarthritis, polyarthralgias, angioedema, urticaria, maculopapular eruptions, purpura, petechiae, and, more rarely, hematuria and proteinuria or cutaneous or systemic vasculitis.
6.
Prodromal symptoms abate or disappear with the onset of jaundice, although anorexia, malaise, and weakness may persist.
7.
Jaundice (the icteric phase) is heralded by the appearance of dark urine and lightening of stool color; pruritus (usually mild and transient) may occur as jaundice increases.
8.
The icteric phase lasts 1 to 3 weeks and is followed by a convalescent phase that may last for months and in which jaundice and symptoms abate and HBsAg, HBeAg, and HBV DNA disappear from serum.
9.
Physical examination reveals mild enlargement and slight tenderness of the liver.
10.
Mild splenomegaly and posterior cervical lymphadenopathy are noted in 15% to 20% of patients.

Laboratory Features

1.
Most prominent biochemical feature: Marked elevation of serum alanine (ALT) and aspartate (AST) aminotransferase levels
2.
Peak aminotransferase levels vary from 500 to 5000 U/L; ALT levels are generally higher than AST levels.
3.
The serum bilirubin level is uncommonly higher than 10 mg/dL, except in severe disease, acute liver failure, and cholestatic hepatitis.
4.
The serum alkaline phosphatase level is normal or mildly elevated.
5.
The prothrombin time is normal or increased by 1 to 3 seconds.
6.
The serum albumin level is normal or minimally depressed.
7.
Peripheral blood counts: Normal or mild leukopenia with or without relative lymphocytosis

Serologic diagnosis is based on detection of HBsAg and immunoglobulin (Ig)M antibody to HBcAg (anti-HBc) in serum ( Table 4.1 ).

TABLE 4.1

Interpretation of HBV Serologic Markers

HBsAg	IgG anti-HBc	IgM anti-HBc	Anti-HBs	Interpretation
–	–	–	–	Never infected and absence of immunity
+	+	–	–	Chronic infection
+	+	+	–	Acute infection or disease flare in chronic carrier
–	+	–	+	Recovered from past infection with immunity
–	–	–	+	Immunity from vaccination

Anti-HBc , Antibody to hepatitis B core antigen; anti-HBs , hepatitis B surface antibody; HBsAg , hepatitis B surface antigen; HBV, hepatitis B virus; IgG , immunoglobulin G; IgM , immunoglobulin M.

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