Hepatopathology of hepatitis B


  • Potential conflict of interest: Nothing to report.


Watch a video presentation of this article

Answer questions and earn CME

Liver disease in patients with hepatitis B virus (HBV) infection represents an interaction between viral replication and the host immune response that attempts to eradicate the virus. The degree and the nature of the injury in any individual patient are determined by the balance between these two factors: how effectively the virus replicates and how vigorously and effectively the immune system reacts to the presence of the virus. Because HBV is not directly cytopathic, it is the immune response that causes tissue damage in the liver, which over time may lead to scarring and eventually to cirrhosis and its complications. These processes are reflected in changes in liver histology that can be readily assessed in a liver biopsy.1–3


HBV, hepatitis B virus.

Immune Tolerant Phase

Individuals infected during infancy or early childhood, when the immune system is still immature, often develop chronic infection with active viral replication but little response from the immune system. This immune tolerant state, which typically lasts into early adulthood, is characterized histologically by only minimal inflammation or fibrosis and normal liver architecture and function. A liver biopsy may reveal hepatocytes with ground-glass cytoplasm (Fig. 1), indicating overproduction and storage of hepatitis B surface antigen.

Figure 1.

Immune tolerant phase. This liver biopsy is from an asymptomatic hepatitis B e antigen–positive carrier with normal liver enzymes and no inflammation or fibrosis but high levels of viremia. Note the ground-glass hepatocytes with uniformly eosinophilic cytoplasm, indicating hepatitis B surface antigen overproduction and storage.

Immune Clearance

Most persons with chronic infections acquired in childhood eventually develop active chronic liver disease as the immune system attempts to control viral replication. Persons infected after early childhood usually mount an immune response that is adequate to halt HBV replication and eradicate the virus over the course of a few months, but some fail to control viral replication and develop chronic hepatitis similar to neonatally acquired disease. Histologic features associated with the active immune response to HBV include:

  • 1Hepatocellular injury, characterized by varying degrees of hepatocellular ballooning, apoptotic bodies, and liver cell dropout (Fig. 2). In the most severe cases, there may be confluent hepatocyte dropout and stromal collapse, producing bridging or submassive necrosis.
  • 2Predominantly lymphocytic inflammation in the parenchyma at sites of liver cell dropout, in the portal areas, and—most importantly—at the interface between the parenchyma and portal connective tissue, a feature known as interface hepatitis (Fig. 3).
  • 3Repair of the damage with activation of Kupffer cells and hepatocellular regeneration (Fig. 2).
Figure 2.

Immune clearance. This liver biopsy from a patient with a severe flare shows hepatocellular ballooning and apoptosis, hypertrophied Kupffer cells, sinusoidal lymphocytes, and a few binucleate regenerating hepatocytes.

Figure 3.

Interface hepatitis. This liver biopsy from a patient with markedly active chronic hepatitis B has considerable chronic portal inflammation (top), predominantly lymphocytes, which migrate out of the portal tract to surround and destroy adjacent hepatocytes (bottom).

In patients with acute self-limited HBV infection, a liver biopsy shows predominantly hepatocellular injury and lobular inflammation, regeneration, and repair with relatively less portal-periportal injury. Chronic HBV infection, by contrast, has a predominance of portal inflammation and interface hepatitis with relatively less lobular injury. During an exacerbation or flare, features of acute hepatitis and increased lobular injury are superimposed on the underlying chronic hepatitis. In such cases, it may be impossible to distinguish a flare of chronic HBV from other acute injuries, such as superinfection by another type of hepatitis virus (A, C, D, or E) or drug-induced liver injury in a patient with chronic HBV.


Interface hepatitis, which is an integral part of the immune clearance phase of chronic HBV, is invariably accompanied by scarring. This produces fibrous expansion of portal areas that can extend to link adjacent vascular structures and result in bridging fibrosis. As the disease progresses, the scarring can completely surround groups of liver cells, and along with hepatocellular regeneration, this produces the nodules of cirrhosis.

Grading and Staging

The stage of any disease is a measure of how far it has progressed in its natural history, with the end stage resulting in death of the patient or failure of the organ.2 In chronic hepatitis B, the end stage is cirrhosis with clinical decompensation, whereas earlier stages have lesser degrees of fibrosis or cirrhosis. The grade of a disease should reflect how quickly the disease will progress to the end stage. In chronic hepatitis, it is thought that hepatocellular injury and inflammation, especially interface hepatitis, cause progression of fibrosis; grading is therefore an appropriate assessment of these features. Alanine aminotransferase levels, hepatitis B e antigen status, and serum HBV DNA correlate to some degree with histologic severity and likelihood of complications of advanced liver disease, but definitive grading and staging requires an adequate liver biopsy. The American Association for the Study of Liver Diseases practice guidelines recommend a biopsy that is at least 2 to 3 cm long and contains a minimum of 11 portal tracts for accurate assessment. Although complex scoring systems have been devised for use in clinical trials, simple three- or four-category systems are recommended for use in routine clinical practice (Table 1).

Table 1. Comparability of Three Simple Systems for Histologic Grading and Staging of Chronic Hepatitis, IASL,4 Metavir,5 and Batts-Ludwig6
Grade (activity, inflammation)Minimal chronic hepatitisA1Grade 1
 Mild chronic hepatitisA1Grade 2
 Moderate chronic hepatitisA2Grade 3
 Severe chronic hepatitisA3Grade 4
 Severe chronic hepatitis with bridging necrosisA3Grade 4
Stage (fibrosis)Mild: portal fibrosisF1Stage 1
 Moderate: periportal fibrosis or portal-portal septaF1Stage 2
 Severe: bridging fibrosis (few)F2Stage 3
 Severe: bridging fibrosis (many)F3Stage 3
 CirrhosisF4Stage 4

Response to Therapy

Seroconversion (naturally acquired or following therapy) or marked suppression of viral replication by any of the available antiviral agents are both associated with decreased hepatocellular injury and inflammation followed by decrease in fibrosis. In long-term follow-up studies, many patients show improvement in fibrosis when biopsied after 1 year of therapy, and most who do not develop drug-resistant viral mutants show improvement in fibrosis stage at 5 years.7 In some cases, the regression of cirrhosis appears absolutely miraculous (Fig. 4).

Figure 4.

Reversal of cirrhosis. Low-power photomicrographs of sirius red–stained liver biopsies from a patient with chronic hepatitis B. The baseline biopsy at the top of the picture has advanced cirrhosis. The lower half of the picture shows a biopsy taken after 1 year on nucleoside analog with only mild portal fibrosis.