Patients with chronic hepatitis B can progress through up to four phases of disease (Table 2). Understanding these phases is critical to determining the risk of liver damage and need for treatment.
Table 2 Recognising and managing the phases of chronic hepatitis B infection
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Phase 1 Immune tolerance
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Phase 2 Immune clearance
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Phase 3 Immune control
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Phase 4 Immune escape
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HBeAg
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Positive
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Positive
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Negative
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Negative
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Antibodies to HBeAg
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Negative
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Negative
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Positive
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Positive
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Viral DNA
(IU/mL)
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>20 000
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>20 000
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<2 000
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>2 000
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Alanine aminotransferase
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Persistently normal
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Elevated (1–2 x) and fluctuating
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Normal
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Elevated or fluctuating
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Liver histology
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Normal or mild hepatitis
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Moderate to severe hepatitis
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Normal to mild hepatitis
May have cirrhosis
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Moderate to severe hepatitis
May have cirrhosis
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General recommendations
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Monitor HBeAg and liver function annually
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Liver biopsy
Consider antiviral treatment
Monitor liver function and viral load every 3 months if on drug treatment
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Monitor liver function annually
Check for signs of cirrhosis and biopsy if > 40 years of age
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Liver biopsy
Consider antiviral treatment
Monitor liver function and viral load every 3 months if on drug treatment
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Phase 1 – immune tolerance
In this phase, which usually lasts for 20−40 years, the host immune system is 'tolerant' to the virus, resulting in high levels of viral replication and persistently normal alanine aminotransferase. Patients also have hepatitis B e antigen (HBeAg) (a protein which is secreted during viral replication), but no antibodies to this antigen.
Recommendation
During this phase there is minimal damage and so a liver biopsy and antiviral treatment are not required. However, the majority of patients will eventually progress to phase 2 and develop active disease. Patients should therefore be advised that periodic monitoring of liver function is important to detect a rise in alanine aminotransferase.
Phase 2 – immune clearance
This phase is characterised by a more vigorous immune response resulting in liver damage with intermittently elevated alanine aminotransferase and elevated viral DNA. Repeated episodes of inflammation lead to fibrosis, and the duration and severity of this phase determines the degree of long-term liver damage. Approximately 30–40% of patients emerge from this phase with established cirrhosis.3
During this phase, approximately 5–10% of patients each year will spontaneously lose HBeAg and develop antibodies to HBeAg. This is called seroconversion and is usually associated with reduced viral replication. The median age for seroconversion is 30−32 years.
Recommendation
It is common practice to initially observe patients with high alanine aminotransferase concentrations (greater than 2–5 times upper limit of normal) for three months to assess whether spontaneous HBeAg seroconversion will occur.
All patients with a persistently abnormal alanine aminotransferase should therefore be referred to a hepatologist for consideration of a liver biopsy and treatment.
Phase 3 – immune control
In this phase the immune response suppresses viral replication to low or undetectable levels. Inflammation reduces and serum alanine aminotransferase normalises. The establishment of immune control is associated with HBeAg seroconversion, and these patients are thought not to have ongoing damage. Once seroconversion occurs, patients may stay in this phase indefinitely.
Recommendation
Although most patients in this phase do not require antiviral treatment, a significant proportion will already have established cirrhosis and require regular careful assessment (Table 3). Carefully performed ultrasound can reveal coarse echo texture suggestive of cirrhosis. Low albumin and elevated prothrombin time are markers of synthetic dysfunction seen in advanced disease, and low platelets (150 x 109/L) may be due to portal hypertension. If any of these features are detected, a liver biopsy should be considered, and treatment is recommended for patients with confirmed cirrhosis and detectable viral DNA.
Patients in this phase can reactivate at any time and should still undergo regular monitoring with at least annual liver function tests. Prophylactic treatment is recommended if patients require immunosuppressive therapy, for example cancer chemotherapy.
Table 3 Signs and symptoms of liver cirrhosis
Clinical
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Fatigue Muscle wasting Dupuytren's contracture Palmar erythema Spider naevi Splenomegaly
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Radiological
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Coarse echotexture Features of portal hypertension - dilated portal vein - recanalisation of para-umbilical vein - varices
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Laboratory
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Synthetic dysfunction - low albumin - elevated prothrombin time
Portal hypertension - thrombocytopenia
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Phase 4 – immune escape
In this phase the virus mutates and loses its ability to make the HBeAg protein. Despite this, it can still replicate, resulting in recurrence of active liver disease and progressive fibrosis. This phase is characterised by persistently elevated or fluctuating levels of alanine aminotransferase, HBeAg negativity, but elevated viral DNA. Patients in this phase are usually older than 40 years.
Recommendation
Patients in this phase are at high risk of cirrhosis (8–10% per year) and require long-term treatment to suppress viral replication.