Hepatitis B virus infection: Understanding its epidemiology, course, and diagnosis
ABSTRACTAlthough hepatitis B virus (HBV) infection is not as common in the United States as in some countries, 5,000 Americans die from it every year. This number can be significantly decreased with proper screening and by vaccinating people at risk. Internists should be aware of the natural history of HBV infection, a vital prerequisite to correctly assessing disease severity and subsequently determining the need for antiviral therapy.
KEY POINTS
- HBV infection is much more likely to persist and become chronic if it is acquired at birth or in early childhood rather than during adulthood.
- Chronic HBV infection is defined as persistence of HBV surface antigen in the serum for more than 6 months.
- Although many cases of chronic HBV infection resolve spontaneously, some progress to cirrhosis, hepatocellular carcinoma, and death.
Four phases of chronic HBV infection
The immune tolerance phase, the initial phase of chronic HBV infection, is seen almost exclusively in those who acquired HBV infection vertically or during early childhood. Although patients have high HBV DNA levels, they do not have significant liver disease. This discrepancy is thought to be related to the immune tolerance to HBV; however, the exact mechanism of that tolerance is unclear.31
Only 15% of those with immune tolerance have spontaneous HBV e antigen seroconversion (ie, loss of e antigen and appearance of anti-e antibody) within 20 years after infection. 32
The immune clearance phase (HBV e antigen-positive chronic hepatitis) appears about 20 to 30 years after the onset of the immune tolerance phase in patients who acquire HBV early in life. It is also often seen in patients with infections acquired late in childhood or in adulthood.
This phase marks the start of an immunemediated process aimed at clearing the viral infection, but it also leads to concomitant hepatocellular injury. Spontaneous clearance of the e antigen increases in this phase to an annual rate of 10% to 20%.32,33 The strongest predictors of spontaneous e antigen seroconversion are old age, an elevated ALT level, and an acute exacerbation.26
Although ALT levels are elevated and there is evidence on liver biopsy of chronic active hepatitis, this phase is usually asymptomatic. Rarely, however, it presents with an acute flare of hepatitis, sometimes accompanied by IgM antibodies against the HBV core antigen (in low titer), leading to an incorrect diagnosis of acute HBV infection.
Depending on the duration of the chronic hepatitis and the frequency and severity of flares, about 12% to 20% of patients in the immune-clearance phase develop serious liver disease within 5 years.31
The inactive carrier phase following HBV e antigen seroconversion is characterized by undetectable or low HBV DNA levels (< 1,000 copies/mL), normal ALT levels, and minimal or no necroinflammation on liver biopsy. 30 Such patients should be followed with serial testing, as 4% to 20% of them spontaneously revert to being positive for e antigen at least once.16 On the other hand, only 0.5% to 2% of surface antigen carriers in western countries clear themselves of surface antigen yearly, but up to half of those who clear the surface antigen have low-level HBV viremia. 34
The reactivation phase (HBV e antigennegative chronic hepatitis) is seen in some HBV-infected patients, especially those from Asia and southern Europe, in whom the virus has a spontaneous pre-core or core mutation that makes infected cells unable to secrete the e antigen. Although these patients have no e antigen in their blood, they do have intermittent or persistent elevation of ALT, elevated HBV DNA, and histopathologic findings of chronic hepatitis. Compared with those in the immune clearance phase, patients in the reactivation phase tend to be older and to have lower HBV DNA levels but advanced hepatic damage.
Immunity to HBV infection is characterized by loss of HBV surface antigen, DNA, e antigen, and anti-core antigen IgM with development of anti-surface antigen antibody and anti-core antigen IgG (total anti-core antigen antibody). The presence of anti-surface antigen antibody and anti-core antigen IgG together differentiates natural immunity through resolved infection from that which is acquired through vaccination, which is denoted by isolated anti-surface antigen antibody.
Cirrhosis, liver failure, cancer
Cirrhosis, hepatic decompensation, and hepatocellular carcinoma are the major long-term complications of HBV infection. In untreated patients, the annual rate of progression to cirrhosis has been estimated to be 2% to 6% in patients with HBV e antigen-positive chronic hepatitis and 8% to 9% in those with e antigen- negative chronic hepatitis.30
The likely explanation for these surprising cirrhosis rates is that e antigen-negative chronic hepatitis usually represents a late stage of the disease, and patients in this phase are usually older and have more advanced liver disease.
Subsequently, the annual rate of progression from compensated cirrhosis to hepatic decompensation has been estimated to be about 5%.35
Across all the stages described above, a high serum HBV DNA level has been shown to be a strong predictor of progression to cirrhosis in patients with chronic HBV infection. In a population-based prospective cohort study of 3,582 untreated HBV-infected patients in Taiwan, Iloeje et al36 found that, compared with patients with serum HBV DNA levels lower than 104 copies/mL, those with levels of 104 or higher had an adjusted relative risk of cirrhosis of 2.5. The relative risk rose to 5.9 with HBV DNA levels of 105 or higher, and 9.8 with levels of 106 copies/mL or higher. More studies in different patient populations are needed for confirmation.
The most important risk factor for hepatocellular carcinoma in HBV-infected patients is cirrhosis, but this cancer can also develop in noncirrhotic livers.37 The annual rate of hepatocelluar carcinoma has been estimated to be higher (2.5%–3%) in patients with cirrhosis than in noncirrhotic carriers (0.5%–1%).30,35–38 Risk factors for cirrhosis and hepatocellular carcinoma are summarized in Table 4.16,30
