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 HBV are asymptomatic, and diagnosis is often difficult.[69] Patients with chronic HBV 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.

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.

The key symptoms associated with acute HBV infection, particularly in adults, are those of a serum sickness-like syndrome: fever, chill, malaise, arthralgias, and a maculopapular or urticarial skin rash. Other possible symptoms include jaundice, nausea, vomiting, and right upper quadrant pain, which occur in approximately 30% of patients with acute HBV infection.[70]

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

Physical examination

The key physical findings in patients with symptomatic acute HBV infection are tender hepatomegaly and jaundice. However, patients with chronic HBV infection without cirrhosis, liver failure, or HCC may have a normal physical examination. Some patients with chronic HBV 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).

Laboratory investigations

Baseline tests

  • Order a full blood count, basic metabolic panel, coagulation profile, and hepatic panel (aspartate aminotransferase [AST], alanine aminotransferase [ALT], bilirubin, alkaline phosphatase, and albumin) initially in all patients.

  • Check the patient's HIV, hepatitis C, and hepatitis D status, as this affects management options.

Serological markers

  • Order full HBV serological profiles in all patients to help differentiate between acute and chronic infection.

  • Serological markers include:

    • Hepatitis B surface antigen (HBsAg)

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

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

    • Hepatitis B e antigen (HBeAg)

    • Antibody to HBeAg (anti-HBe)

    • HBV DNA.

  • HBsAg, anti-HBc, and anti-HBs are typically used to differentiate between acute and chronic infection, while HBeAg and anti-HBe are used to determine the phase of chronic infection. HBV DNA is essential for diagnosis and to determine the phase of infection, although it may be undetectable in some patients.[38]​​ HBV DNA is commonly used to assess viral load and candidacy for antiviral therapy, and to monitor response to therapy.[38][64][71]​​

  • A positive HBsAg result establishes the diagnosis and indicates active infection. HBsAg will be detected an average of 4 weeks (range 1-9 weeks) after exposure to the virus. Patients who are HBsAg-positive and IgM anti-HBc-positive in the presence of HBV DNA are diagnosed with acute infection or reactivation. Patients who are HBsAg-positive for at least 6 months (with negative anti-HBs and positive anti-HBc) are diagnosed with chronic infection. The phase of chronic infection is determined by serum HBV DNA levels, HBeAg and anti-HBe status, and ALT levels (See Criteria section).[2][38]​​

  • A few patients may have an acute reactivation of asymptomatic carrier state, or a flare up of chronic HBV infection, and show IgM anti-HBc-positive status. This is particularly likely in patients with a known history of being HBsAg-positive, and in those who are receiving chemotherapy or other immunosuppressive agents.[72][73] Obtaining HBsAg and total anti-HBc in this population, and vaccinating those individuals with HBV-seronegative status prior to initiating chemotherapy or immunosuppressive therapy is recommended. It should be noted that an increased dose may be needed in immunosuppressed patients to achieve immunity to hepatitis B.[38]

Genotype and resistance testing

  • HBV genotype may play a role in HBV-related liver disease progression and response to interferon therapy, 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 HBV infection. However, it may be useful for selecting patients to be treated with peginterferon.[2][38]

  • 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]

Rapid diagnostic tests

  • HBsAg rapid diagnostic tests have excellent specificity and good sensitivity compared with laboratory immunoassays.[74]

Testing for co-infections

  • Check the patient’s HIV, hepatitis C, and hepatitis D status as this affects management options.

  • Testing for tuberculosis may be recommended as co-infection can occur. Patients on anti-tuberculosis multi-drug regimens are at increased risk of drug-induced liver injury, particularly those with underlying liver disease.[75][76]

Imaging

Order a baseline abdominal ultrasound in all patients to evaluate the liver for advanced fibrosis, cirrhosis, and portal hypertension, and for HCC.[38] 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).

The American Association for the Study of Liver Diseases (AASLD) guidelines recommend ultrasound of the liver (with or without AFP) every 6 months in patients with cirrhosis, or in adults at high risk for HCC (e.g., Asian or black men >40 years of age, Asian women >50 years of age, patients with a first-degree family member with a history of HCC).[2]

Liver disease staging

Staging of liver disease severity using liver biopsy or non-invasive methods (e.g., transient elastography, fibrosis biomarkers) is recommended to guide surveillance and assist with treatment decisions.[2]

Liver biopsy may be required in some patients with chronic HBV infection to grade and stage liver disease before initiating therapy, and to rule out other causes of liver disease. Patients with chronic HBV infection have varying degrees of fibrosis and/or inflammation. AASLD guidelines recommend biopsy in patients with persistent borderline normal, or slightly elevated, ALT levels, particularly in patients >40 years of age who have been infected from a young age.[2] European guidelines recommend a liver biopsy when biochemical and HBV markers reveal inconclusive results.[38] In general, liver biopsy is indicated if it is likely to influence subsequent treatment decisions. The size of the liver biopsy is of paramount importance, because 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 4000-10,000 procedures.[77]

In individuals who are reluctant to undergo the risks of an invasive procedure, non-invasive options to evaluate liver disease severity include transient elastography and serum liver fibrosis markers (e.g., FIB-4®, FibroTest®).[2][38][78][79][80][81][82][83][84][85]​ Transient elastography is preferred over liver fibrosis markers, and may be the preferred non-invasive test in settings where it is available and cost is not an issue.[2][64]​ In Europe, transient elastography is popular in identifying cirrhosis; however, its use has been limited by false positive results secondary to marked liver inflammation and a lack of uniform standard to calculate liver stiffness.[38][86][87]​ Magnetic resonance elastography has been shown to be more accurate than Fibroscan® in diagnosing liver fibrosis in patients with chronic HBV infection.[88]​ Blood-based and imaging-based non-invasive tests may be combined, particularly for the detection of significant and advanced fibrosis.[89]​​

In resource-limited settings, aspartate aminotransferase-to-platelet ratio index (APRI) is recommended as the preferred non-invasive test to assess for significant fibrosis or cirrhosis.[64][90]

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