Discussion

Initial Assessment of Positive Hepatitis B Surface Antigen

Initial laboratory screening to diagnose hepatitis B virus (HBV) infection in an asymptomatic individual generally consists of testing for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc)[1,2]. For those patients who have a positive HBsAg, follow-up laboratory testing is indicated to define the stage of their hepatitis B infection. The follow-up laboratory evaluation of a patient with a positive HBsAg should include:

  • Hepatitis B core IgM antibody (IgM anti-HBc)
  • Hepatitis B e antigen (HBeAg) and hepatitis B e antibody (anti-HBe)
  • HBV DNA level
  • Hepatic panel, including measurement of alanine aminotransferase (ALT or SGPT) and aspartate aminotransferase (AST or SGOT), levels, albumin, and prothrombin time

The interpretation of the results of these tests (Figure 1) can determine whether the patient has acute HBV infection, chronic immune tolerant infection, chronic immune active infection with wild-type virus, chronic immune active infection with precore or core promoter mutant virus, or chronic inactive infection (carrier). The phases and classification of chronic HBV infection are discussed in detail in the case Natural History of Chronic Hepatitis B Infection and as noted in the discussion of the natural history, patients with chronic hepatitis B virus infection can have a dynamic transition between the different phases of chronic infection.

Acute Infection with HBV

In the setting of acute HBV infection, HBsAg typically becomes detectable 4 to 8 weeks after infection. Shortly thereafter, IgM anti-HBc appears in the blood. Thus, the diagnosis of acute hepatitis B is generally made by the simultaneous detection of HBsAg and IgM anti-HBc[3]. The serologic and virologic response to acute HBV infection is discussed in detail in the case Serologic and Virologic Markers of Hepatitis B Virus Infection. Rarely, acute hepatitis B may be diagnosed during the period when HBsAg titers have declined below detectable levels and anti-HBs have not yet appeared. In this scenario, known as the "window period", the diagnosis of acute HBV infection is made based on the presence of positive IgM anti-HBc titers (Figure 2). These patients will thus have isolated anti-HBc as the only marker of acute hepatitis B infection; other scenarios exist that can cause isolated anti-HBc as discussed in detail in the case Interpretation of Isolated Hepatitis B Core Antibody (anti-HBc). The HBV DNA titers are extremely high early in acute infection, often reaching 200 million IU/mL (1 billion copies/ml)[4]. At this stage, HBeAg is also usually detected, hepatic aminotransferase levels become elevated after HBsAg turns positive, and serum bilirubin may also increase. In severe cases, hepatic production of albumin may significantly decline and other evidence of hepatic dysfunction, such as prolonged prothrombin time, may be present[5].

The differential diagnosis of acute hepatitis B infection includes exacerbation of chronic hepatitis B, superinfection of hepatitis B carriers with hepatitis A, C, or D, and acute hepatotoxicity caused by drugs or other toxins[1,2]. During exacerbations of chronic hepatitis B, anti-HBc IgM may become transiently positive, making differentiation from acute hepatitis B difficult. In such cases, previous test results or a history of recent exposure may assist in the diagnosis of acute hepatitis B. In the other conditions mentioned above, anti-HBc IgM is usually not present[5]. For the patient discussed in this case, the initial laboratory workup should include measurement of anti-HBc IgM. If this test is positive, the diagnosis of acute hepatitis B is likely, although an acute exacerbation of chronic hepatitis B cannot be ruled out without further information.

Chronic Immune Tolerant HBV

Immune tolerant hepatitis B infection refers to the clinical scenario of persistently normal hepatic aminotransferase levels in the presence of high titers of circulating HBeAg and HBV DNA. These patients with immune-tolerant hepatitis B usually have become infected early in life through vertical or early horizontal infection. Such infection most often occurs in areas with high rates of endemic infection, low rates of maternal screening, and lack of widely available neonatal prophylaxis with HBV vaccine and hepatitis B immune globulin[6]. Clinically, it is important to determine if patients have evidence of immune tolerance, because such patients generally respond poorly to antiviral therapy, and their management differs from patients with more active hepatic inflammation[7].

Chronic Immune Active HBV Infection (Wild-Type)

Patients with chronic hepatitis B infection caused by wild-type virus (defined as a naturally-occurring strain without known mutations) have high titers of circulating HBeAg, almost always coupled with high titers of HBV DNA (defined as greater than 200,000 IU/ml). Indeed, prior to the widespread availability of HBV DNA assays, HBeAg was considered to be the principle marker of HBV replication and high infectivity[3]. The laboratory profile of patients with chronic immune active (wild-type) hepatitis B typically shows the following:

  • HBsAg positive longer than 6 months
  • HBeAg positive, anti-HBe negative
  • Serum HBV DNA greater than 200,000 IU/ml
  • Elevated or normal hepatic aminotransferase levels

The natural history for patients with immune active chronic hepatitis B is substantially worse than that of patients in the inactive carrier state. Patients with chronic hepatitis B who become inactive carriers either through spontaneous or treatment-induced HBeAg seroconversion demonstrate improvement in clinical and biochemical evidence of liver disease[6,8,9]. Furthermore, patients with HBeAg positive chronic hepatitis B have a greater than six-fold increased relative risk of developing hepatocellular carcinoma compared with HBeAg-negative inactive hepatitis B carriers (relative risk, 60.2 versus 9.6)[10]. Patients with chronic immune-active HBV infection usually have intermittently elevated, or persistently elevated liver enzymes.

Chronic Immune Active HBV (Precore and Core Promoter Mutants)

Some individuals with chronic hepatitis B are infected with a mutant HBV variant that results in HBeAg negative chronic hepatitis. In such patients, viral mutations in the precore or core promoter regions prevent HBeAg production in an otherwise normally replicating HBV. Thus, these patients typically have high serum HBV DNA levels, but negative HBeAg titers. The prevalence of precore or core promoter mutations is highest among persons from Southern Europe and Asia, with prevalence estimates of 60 to 70%[11]. Chronic HBeAg-negative hepatitis B is diagnosed in a patient with the following laboratory profile:

  • HBsAg positive longer than 6 months
  • HBeAg negative, anti-HBe positive
  • Serum HBV DNA greater than 20,000 IU/ml
  • Persistently elevated or intermittently normal hepatic aminotransferase levels

Accurate diagnosis of chronic HBeAg-negative hepatitis B is imperative because the clinical management is markedly different from that of chronic inactive hepatitis B carriers (who are also HBeAg negative but have low serum HBV DNA titers).

Chronic Inactive Carrier of HBV

Chronic inactive hepatitis B infection is defined as persistent HBV infection of the liver without significant ongoing hepatic inflammation and necrosis[12]. Blood tests on such patients are typically show four characteristic features:

  • HBsAg positive for longer than 6 months
  • HBeAg negative, anti-HBe positive
  • Serum HBV DNA less than 2,000 IU/ml
  • Persistently normal hepatic aminotransferase levels

The "chronic inactive carrier" state may persist for decades. Patients who remain in this phase of infection have lower rates of disease progression and hepatocellular carcinoma[13]. Generally, antiviral treatment is not indicated for such patients, unless histologic or clinical signs of cirrhosis are present[12].

Case Summary

The patient's blood tests yielded the following results:

  • HBsAg positive, anti-HBs negative
  • Anti-HBc IgM negative, Anti-HBc IgG positive
  • HBeAg positive, anti-HBe negative
  • Serum HBV DNA 200 million IU/ml
  • ALT = 120 U/L, AST = 86 U/L, Albumin = 4.1 g/dL

Because the patient is HBeAg positive with a high viral load, he has chronic immune active hepatitis B infection with wild-type virus. Because the ALT and AST are elevated, he is not in the immunotolerant phase of infection, but instead has evidence of hepatic inflammation.

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    Figure 1 - Interpretation of Laboratory Tests in the Patient with Positive HBsAgFigure 1
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    Figure 2 - “Window Period” following Acute Hepatitis B InfectionFigure 2