Approach

The natural history of hepatitis B virus (HBV) infection is variable, complex, and dynamic. The best method for diagnosis is to have a clinical suspicion in at-risk individuals, and to evaluate the results of specific liver-related and HBV serological tests. Approximately 70% of patients with acute infection are asymptomatic, and diagnosis is often difficult.[80] Patients with chronic infection may also be asymptomatic, or may have signs and symptoms of chronic liver disease, including cirrhosis and its complications, hepatocellular carcinoma (HCC), and liver failure. Acute, chronic, and perinatal HBV infection are notifiable conditions.

History

The main risk factors for HBV infection include perinatal exposure, sexual transmission (multiple sexual partners, men who have sex with men), injection drug use, living in or travel to a highly endemic region, incarceration, or a family history of HBV infection, chronic liver disease, and/or HCC.[32]

Acute HBV infection

  • Acute infection is generally self-limited and resolves spontaneously in the majority of cases. Symptoms of acute infection can last anywhere from 6 weeks up to 6 months and symptoms may be mild. Rarely, acute infection can progress to hepatitis, cirrhosis, or HCC.[81] Approximately 70% of patients with acute infection are asymptomatic.​[80]​​​​

  • The key symptoms associated with acute infection, particularly in adults, are those of a serum sickness-like syndrome: fever, chills, malaise, fatigue, arthralgia, and a maculopapular or urticarial skin rash. Other possible symptoms include dark urine, clay-coloured stool, or loss of appetite.[81] Jaundice, nausea, vomiting, and right upper quadrant pain occur in approximately 30% of patients.[82]

  • Adults older than 30 years of age are more likely to be symptomatic during acute infection, while immunosuppressed adults are generally asymptomatic. Most children younger than 5 years of age are asymptomatic, while children older than 5 years of age are symptomatic in 30% to 50% of cases.[81]

Chronic HBV infection

  • Chronic infection is defined as the presence of hepatitis B surface antigen (HBsAg) beyond 6 months without spontaneous clearance and seroconversion.[2]

  • The vast majority of patients with chronic infection are asymptomatic, but can present with symptoms if they develop hepatitis, HCC, cirrhosis and its complications, or liver failure.[81]

  • Chronic infection has a complicated history and may be divided into distinct phases. See Criteria.

Physical examination

The key physical findings in patients with symptomatic acute infection are tender hepatomegaly and jaundice. However, patients with chronic infection without cirrhosis, liver failure, or HCC may have a normal physical examination. Some patients with chronic infection and cirrhosis may have palmar erythema and spider angiomata, with or without signs of portal hypertension, including ascites, jaundice, and asterixis (suggestive of hepatic encephalopathy).

Initial laboratory tests

Testing is recommended in all patients with symptoms, or those who are at increased risk for exposure to HBV, in order to confirm the diagnosis. Anyone who requests testing can receive it, regardless of their risk or disclosure of risk.[83] See Screening for serological testing of asymptomatic people who are not known to be at risk for exposure to HBV.

Order the following baseline tests for all patients as part of the initial evaluation:[2][29]

  • Hepatic panel (including alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, bilirubin, and albumin)

  • Full blood count (FBC)

  • Basic metabolic panel

  • Coagulation profile

  • HIV status (co-infection affects treatment options)

  • Hepatitis C and D status (co-infection affects treatment options)

  • Hepatitis A virus immunity (to determine the need for hepatitis A vaccination)

  • Hepatitis E status (to rule out co-infection, if indicated)

  • Tuberculosis status (to rule out co-infection, if indicated)

Order full HBV serological profiles in all patients to confirm the diagnosis, help differentiate between acute and chronic infection, and determine the phase of chronic infection.[2][29][83]​​

  • Hepatitis B surface antigen (HBsAg)

    • A protein on the surface of HBV that can be detected in serum during acute or chronic active infection. HBsAg will be detected an average of 4 weeks (range 1-9 weeks) after exposure to the virus. Persistence for 6 months or more indicates chronic infection. While qualitative HBsAg may be used for initial diagnosis and screening, quantitative HBsAg is used to characterise disease phase, guide treatment, and define prognosis.[2]​​[29][83] A positive result should always be rechecked since chronic infection can only be diagnosed if HBsAg persists for at least 6 months.

  • Antibody to hepatitis B surface antigen (anti-HBs)

    • Indicates recovery and immunity from infection or successful prior vaccination. Appears several weeks after HBsAg has disappeared, and provides lifelong immunity in most patients. Useful to determine immunisation status if HBsAg is negative, and to evaluate seroconversion after HBsAg loss.[2][29][83]

  • Antibody to hepatitis B core antigen (anti-HBc)

    • Appears at the onset of symptoms in acute infection, and persists for life. Presence of total anti-HBc (IgM and IgG) indicates previous or ongoing infection in an undefined timeframe. Presence of anti-HBc IgM indicates recent acute infection (<6 months).[2][29][83]

  • Hepatitis B e antigen (HBeAg)

    • Soluble viral protein found in serum in the early part of acute infection, but usually disappears at or soon after the peak in serum ALT level. Persistence ≥3 months after onset of illness indicates a high likelihood of chronic infection. Useful for classifying the phase of chronic infection. May also be recommended to establish the indication for treatment in resource-limited areas where HBV DNA is not available.[2][29]

  • Antibody to hepatitis B e antigen (anti-HBe)

    • Seroconversion from HBeAg-positive to anti-HBe usually suggests clearance of virus, although it may be temporary. Useful for classifying the phase of infection (especially if HBeAg is negative). Also used to assess disease progression and the patient’s response to therapy.[2][29]

  • Quantitative HBV DNA

    • A key marker for HBV viraemia. A number of commercial tests are available, most commonly real-time polymerase chain reaction (PCR). Required for establishing the indication for antiviral therapy and treatment monitoring.[2][29]

The Centers for Disease Control and Prevention (CDC) recommends a triple panel test for initial testing which includes HBsAg, total anti-HBc, and anti-HBs.[83]

A positive HBsAg result establishes the diagnosis and indicates active acute or chronic infection. In general, the results of HBV serological testing may be interpreted as per the following table.[83] However, it is important to note that results can be variable.

The phase of chronic infection is determined by HBeAg and anti-HBe status, serum HBV DNA level, and ALT level.[2][29]​ See Criteria.

Rapid point-of-care assays for HBV serological markers are available, but may not be widely available in practice as yet.

  • These tests have the potential to enable large-scale screening and allow diagnosis in areas with limited laboratory testing.[84]

  • HBsAg rapid diagnostic tests have excellent specificity and good sensitivity compared with laboratory immunoassays.[85]

Genotype and resistance testing

HBV genotype may play a role in HBV-related liver disease progression and response to treatment with peginterferon alfa, so determination of genotype may have prognostic value, but this needs to be further validated by additional research. Genotyping is not necessary in the initial evaluation, and is not currently recommended for routine testing or follow-up of patients with chronic infection. However, it may be useful for selecting patients to be treated with peginterferon alfa and estimate the risk for HCC.[2][29]

Hepatitis B antiviral drug resistance testing is not recommended in treatment-naive patients, but can be useful in patients who are treatment experienced, those with persistent viraemia despite antiviral therapy, or those who experience virological breakthrough during treatment.[2]

Imaging

Baseline liver disease assessment is strongly recommended in all patients who are HBsAg-positive. Order a baseline abdominal ultrasound in all patients to evaluate the liver for coexisting conditions (e.g., hepatic steatosis), fibrosis, cirrhosis, portal hypertension, and liver tumours.[2][29]

Triphasic contrast computed tomography or contrast magnetic resonance imaging of the abdomen can be used to diagnose HCC where this is thought to be likely, based on history, physical examination, and laboratory investigations that include elevated alpha-fetoprotein (AFP). See Hepatocellular carcinoma.

Liver disease staging

Staging of liver disease severity and fibrosis assessment is recommended in all patients who are HBsAg-positive to guide surveillance and assist with treatment decisions. Options include non-invasive methods and liver biopsy.[2][29]

Non-invasive methods are preferred over liver biopsy.[29]

  • Non-invasive methods include imaging- and serum-based tests.[2][29]

    • Imaging-based tests include vibration-controlled transient elastography (VCTE), shear-wave elastography (SWE), and acoustic radiation force impulse imaging (ARFI).

    • Serum-based tests include liver fibrosis markers (e.g., FIB-4®, FibroTest®), which take factors such as patient age, liver enzyme counts, and platelet count into consideration, and aspartate aminotransferase-to-platelet ratio index (APRI).

    • The availability, accuracy, and reliability of these tests varies.

  • Liver stiffness measurement by VCTE is the preferred non-invasive method, where available. VCTE is preferred over serum-based tests, and its use is supported by evidence.[29][75][86]

  • Serum-based tests are more widely available, but have limited accuracy.[29][87][88]​​​ APRI is the preferred non-invasive test to assess for significant fibrosis or cirrhosis in resource-limited settings.[75][89]

  • Imaging- and serum-based non-invasive tests may be combined, particularly for the detection of significant and advanced fibrosis.[90]​​

Liver biopsy may be required in select patients to assess fibrosis and inflammatory activity, determine the etiology in cases with unclear or negative serological results, or when alternative or additional aetiologies of liver disease are suspected.[2][29]

  • Liver biopsy is only recommended when there is diagnostic uncertainty, discordant non-invasive test results, or the presence of liver-related comorbidities. The decision to perform a biopsy is based on whether the results will directly influence treatment decisions.[29]​ However, it may also be considered in patients with persistent borderline normal, or slightly elevated, ALT level, particularly in patients >40 years of age who have been infected from a young age.[2]

  • The size of the liver biopsy is of paramount importance, since small-size biopsies may not be adequate to evaluate the stage of fibrosis and liver disease. Although there are risks with a percutaneous liver biopsy, the reported risk of complications is low, with one complication in every 4000 to 10,000 procedures.[91]​ The procedure carries an increased risk of bleeding in patients with advanced cirrhosis.[29]

Emerging tests

Novel biomarkers are being developed to assess the effects of new antiviral therapies which target different parts of the HBV cycle.[84]​ Non-invasive biomarkers reflecting the intrahepatic pool of transcriptionally active HBV covalently circular DNA (cccDNA) are being investigated (e.g., hepatitis B core-related antigen [HBcrAg], HBV RNA). However, these emerging biomarkers are not available for use in routine clinical practice.[29] Evidence regarding the use of HBcrAg for predicting relapse after antiviral therapy is conflicting. However, a meta-analysis found that HBcrAG is validated as a robust biomarker to optimise treatment cessation strategies.[92] Quantitative anti-HBc and circulating miRNAs are also promising novel biomarkers.[93][94]

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