Etiology and pathogenesis
Although hepatitis B has a relatively low prevalence in the United States, an estimated 250 million people (approximately 3.6% of the world’s population) are HBsAg positive worldwide, representing one of the main causes of chronic liver disease. The prevalence of hepatitis B virus (HBV) infection is highly variable, being highest in sub-Saharan Africa and certain countries in the Middle-East, Asia, and Western Pacific region.12
HBV is an enveloped DNA virus, a member of the Hepadnaviridae family. Transmission occurs through blood and body fluid exchange, taking place predominantly during the perinatal period (vertical transmission) or during childhood in high-prevalence areas. In low-prevalence areas, such as the United States and Western Europe, infections are acquired mostly during young adulthood through sexual contact or injection drug abuse (horizontal transmission). The natural history of the disease is also deeply influenced by the timing of initial infection. The infection becomes chronic in approximately 90% of cases in perinatal transmission, whereas the opposite is seen in infections acquired in adulthood, where over 90% of infections have spontaneous resolution.
Patients with chronic infection, especially those acquired during the perinatal period or early childhood
years, as well as those with high levels of HBV replication (high HBeAg and HBV DNA levels), have the highest risk for developing hepatocellular carcinoma.13
Several HBV genotypes have been described (eight in total, A-H), showing distinct geographic and ethnic distributions around the world, as well as different risk levels for the development of cirrhosis and hepatocellular carcinoma.14
Finally, HBV viral replication occurs through reverse transcription but without an effective proof reading mechanism, leading to a high rate of viral mutations. Precore and basal core mutations18
have been linked to diminished or loss of HBeAg production, and YMDD mutants are associated with drug resistance.20
Following acute infection, the disease goes through several phases, with different serological, histologic, and immunophenotypic characteristics (Table 8.6
). In the initial phase—immune tolerance—there is a low level of immunologic response to the virus, variable but generally mild necroinflammatory activity, and high levels of viral replication, with corresponding serology that is HBeAg positive and anti-HBe negative. In the immune clearance phase, there is heightened immune response to the virus, and the histologic activity tends to be correspondingly high. This is followed by a low-replicative phase in which both viral replication and histologic activity are low. This sequence of events, however, is complex and variable from case to case. Disease activity can also flare above baseline for several reasons, including emergence of viral mutants, coinfection with delta virus, and treatment-related factors.
The hepatitis D virus (HDV, also called delta virus) is known as a “defective virus,” because it requires hepatocytes being also infected with HBV in order to replicate. HDV can be transmitted either as a coinfection with HBV or as a superinfection in patients with chronic hepatitis B. In cases of coinfection, HDV confers an increased risk of fulminant hepatitis,21
while superinfection has been associated with increased inflammatory activity (mimicking hepatitis B flares or other superimposed acute injuries). Higher rates of chronicity, increased liver-related mortality, and higher risk of hepatocellular carcinoma have also been reported with hepatitis D.22
Acute hepatitis B symptoms are nonspecific and mainly constitutional, including low-grade fever, fatigue, nausea, myalgia, and arthralgia. Approximately 70% of patients will present with subclinical or anicteric hepatitis. Jaundice, present in only 30% of acute HBV infections, typically begins within 10 days after the onset of symptoms. Marked transaminase elevations
are often seen, with levels over 1,000 to 2,000 IU/L, followed by hyperbilirubinemia. These symptoms usually resolve spontaneously within 1 to 3 months.
Table 8.6 Clinical features of different phases of chronic hepatitis B
Phases of chronic hepatitis B
Immune tolerant phase
High-serum HBV DNA levels
Mild or no hepatic necroinflammation
Mild or no fibrosis progression
Immune active or immune clearance phase
Inactive HBV carrier state
HBeAg negative HBeAb positive
HBeAg negative HBeAb positive
Fluctuating levels of serum HBV DNA
Mild-moderate liver necroinflammation
HBsAg-negative phase or occult HBV infection
Undetectable serum HBV DNA
Detectable HBV DNA in the liver
At risk for reactivation with immunosuppressive therapy
HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HBeAb, hepatitis B e antibody; HBsAb, hepatitis B s antibody; HBsAg, hepatitis B s antigen.
The vast majority of patients with chronic hepatitis B are asymptomatic, but acute exacerbations can manifest as fatigue, anorexia, nausea, and jaundice. The transaminase levels are often normal or only mildly elevated in chronic hepatitis B. Extrahepatic manifestations of chronic hepatitis B occur in 10% to 20% of patients and have been attributed to circulating immune complexes containing HBsAg. Extrahepatic manifestations include polyarteritis nodosa, membranous and membranoproliferative glomerulonephritis, and papular acrodermatitis.23
The diagnosis of hepatitis B is based on serologic markers and confirmed by the presence of HBsAg and/or HBV DNA in the serum (Table 8.7
The presence of HBsAg for longer than 6 months in the blood defines a hepatitis B infection as chronic. HDV exposure can be detected by the presence of IgG anti-HDV antibodies. The diagnosis of active HDV infection is confirmed by detection of serum HDV RNA by polymerase chain reaction (PCR).