Hepatitis B Workup

Updated: May 26, 2017
  • Author: Nikolaos T Pyrsopoulos, MD, PhD, MBA, FACP, AGAF; Chief Editor: BS Anand, MD  more...
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Workup

Approach Considerations

Laboratory evaluation of hepatitis B disease generally consists of liver enzyme tests, including levels of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGT), as well as liver function tests (LFTs) that include total and direct serum bilirubin, albumin, and measurement of the international normalized ratio (INR). [37] Hematologic and coagulation studies also include a platelet count and a complete blood count (CBC). Ammonia levels may be obtained, but the results often create diagnostic confusion in clinicians. [38]

Serologic tests for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) immunoglobulin M (IgM) are required for the diagnosis of acute hepatitis B virus (HBV). [1, 39, 40]  HBsAg is positive in both acute and chronic HBV infection; however, the presence of IgM anti-HBc is diagnostic of acute or recently acquired infection. [39] Antibody to HBsAg (anti-HBs) is produced after a resolved infection and is the only HBV antibody marker present after vaccination. The presence of HBsAg and total anti-HBc, with a negative test for IgM anti-HBc, indicates chronic HBV infection; the absence of IgM anti-HBc or the persistence of HBsAg for 6 months indicates chronic HBV infection. The presence of anti-HBc alone might indicate acute, resolved, or chronic infection or a false-positive result. [39]

To evaluate the patient’s level of infectivity, quantification of hepatitis (HBV) DNA is essential, and the presence of hepatitis B e antigen (HBeAg) should be determined. Indeed, the best indication of active viral replication is the presence of HBV DNA in the serum. Hybridization or more sensitive polymerase chain reaction (PCR) assay techniques are used to detect the viral genome in the serum, as well as specific genotypes, mutants resistant to oral nucleoside and nucleotide analogues, and core and precore mutations.

A positive result suggests not only the likelihood of active hepatitis but also that the disease is much more infectious, as the virus is actively replicating. [40]

HBV DNA testing is also recommended when occult HBV is suspected (positive anti-HBc and negative antibody to anti-HBs and HBsAg) or in cases in which all of the serologic tests are negative. [41]

American Association for the Study of Liver Diseases (AASLD) recommendations

The current AASLD recommendations for the initial evaluation of HBsAg-positive patients is summarized below. [37]

All patients

History and physical examination: Thoroughly evaluate for the following:

  • Alcohol, metabolic, and other risk factors for HBV infection
  • Patient's HBV vaccination status
  • Family history of HBV infection and hepatocellular carcinoma
  • The presence of symptoms/signs of cirrhosis

Routine laboratory studies

  • CBC, platelet count; INR
  • Levels of AST, ALT, total bilirubin, ALP, and albumin

Serologic/virologic studies

  • Hepatitis B e antigen (HBeAg)/anti-HBe
  • HBV DNA level
  • Anti-hepatitis A virus (anti-HAV) (to determine need for vaccination)

Imaging/staging studies 

  • Abdominal ultrasonography
  • Vibration-controlled transient elastography (eg, FibroScan) or a serum fibrosis marker panel (APRI [AST-to-platelet ratio index], FIB-4 [platelet count, ALT, AST, age], or FibroTest [gamma-2 macroglobulin, gamma-2 globulin, gamma globulin, apolipoprotein A1, gamma-GGT, total bilirubin])

Select patients

Routine laboratory studies: In the setting of elevated liver function test results, obtain tests to exclude other causes of chronic liver disease. Obtain levels of alpha-fetoprotein (AFP) and GGT.

Serologic/virologic studies

  • HBV genotyping
  • Tests for coinfection with hepatits C virus (HCV), hepatitis D (delta) virus (HDV), and/or human immunodeficiency virus (HIV) in at-risk individuals aged 13-64 years who have not undergone one-time screening 

Screening

HBV

In June 2014, the US Preventive Services Task Force (USPSTF), which had previously recommended against screening asymptomatic persons for HBV infection, issued a recommendation in favor of screening of asymptomatic, nonpregnant adolescents and adults at high risk for HBV infection, including the following [42, 43, 44, 45] :

  • Those born in countries and regions where prevalence of HBV infection is at least 2%
  • Individuals born in the United States who were not vaccinated as infants and whose parents were born in regions with a high prevalence of HBV infection, such as sub-Saharan Africa and southeast and central Asia
  • HIV-positive individuals
  • Injection drug users
  • Men who have sex with men
  • Household contacts of individuals with HBV infection

Testing should be performed with a HBsAg test followed by a licensed, neutralizing confirmatory test for initially reactive screening results. [42, 43, 44, 45]

The United States currently screens foreign-born residents for HBV infection if their country of origin has an HBV prevalence of 2% or greater. According to a model developed by Eckman et al, although this threshold for screening is cost-effective, a broader screening program with a threshold of 1.3% or even 0.3% country-of-origin prevalence would be cost-effective as well, suggesting a reconsideration of current policy. [46]

HCV

As previously mentioned, the prevalence of hepatocellular carcinoma (HCC) among patients with HBV and HCV coinfection is higher than in those with a single infection.

Some controversy exists regarding screening for HCV infections in adults. In August 2012, the Centers for Disease Control and Prevention (CDC) expanded their existing, risk-based testing guidelines to recommend a 1-time blood test for HCV infection in baby boomers—the generation born between 1945 and 1965, who account for approximately three fourths of all chronic HCV infections in the United States—without prior ascertainment of HCV risk (see Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945-1965.) [47]

The recommendations noted that 1-time HCV testing in baby boom population could identify nearly 808,600 additional people with chronic infection; thus, the CDC recommended that all individuals identified with HCV should be screened and/or managed for alcohol abuse, followed by referral to preventative and/or treatment services, as appropriate. [47]

However, in a systematic review for the US Preventive Services Task Force (USPSTF), Chou et al noted that despite the accuracy of screening tests in identifying asymptomatic adults with chronic HCV infection, screening strategies that target multiple risk factors can miss some of these patients. [48] They recommended further investigation to determine the effects of different HCV screening strategies on diagnostic yield and clinical outcomes.

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Diagnostic Tests

Laboratory studies will be discussed according to the stage of disease.

Acute hepatitis B disease

High levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), within a range of 1000-2000 IU/mL, is the hallmark of this stage of HBV disease, although values 100 times above the upper limit of normal (ULN) can be also be identified. Higher values are found in patients with icteric hepatitis. ALT levels are usually higher than AST levels.

Gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) levels may be elevated, but they are usually not more than 3 times the ULN.

Albumin levels can be slightly low, and serum iron levels may be elevated as an acute phase reactant. In the preicteric period (ie, before the appearance of jaundice), leukopenia (ie, granulocytopenia) and lymphocytosis are the most common hematologic abnormalities and are accompanied by an increase in the erythrocyte sedimentation rate (ESR).

Anemia due to a shortened red blood cell survival period is an infrequent finding, although hemolysis may be noted. Thrombocytopenia is a rare finding. Patients with severe hepatitis experience a prolongation of the international normalized ratio (INR).

Several viral markers can be identified in the serum and the liver. Hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) (marker of infectivity) are the first markers that can be identified in the serum in acute disease. Hepatitis B core antibody (anti-HBc) immunoglobulin M (IgM) follows.

For patients who recover, seroconversion to hepatitis B surface antibody (anti-HBs) and hepatitis B e antibody (anti-HBe) is observed. The anti-HBc is of the IgG class. Patients with persistent HBsAg lasting more than 6 months are considered to have chronic hepatitis.

Inactive hepatitis B disease

The term “healthy carriers” is no longer used due to the fact that a person who is positive for HBsAg has a high risk of cirrhosis and hepatocellular carcinoma (HCC) and, therefore, cannot be defined as healthy. Such individuals have normal AST and ALT levels, with markers of infectivity, such as HBeAg, being negative and HBV DNA going undetected or being detected at very low levels (usually below 2,000 IU/ml). HBsAg, anti-HBc of IgG type, and anti-HBe are present in the serum. A minimum follow-up of these patients for 1 year with laboratory evaluation every 3 to 4 months is recommended.

Chronic active hepatitis B disease

Chronic active HBV disease is categorized into HBeAg-positive and HBeAg-negative disease.

Subtype “wild type” or HBeAg-positive disease

Patients have mild to moderate elevation of the aminotransferases (≤5 times the ULN). The ALT levels are usually higher than the AST levels. Extremely high levels of ALT can be observed during exacerbation or reactivation of the disease, and they can be accompanied by impaired synthetic function of the liver (ie, decreased albumin levels, increased bilirubin levels, and prolonged prothrombin time [PT]).

HBV DNA levels are high during this phase. HBsAg and anti-HBc of IgG or IgM type (in case of reactivation) are identified in the serum.

If the AST levels are higher than the ALT levels, the diagnosis of cirrhosis must be considered. Hyperglobulinemia is another finding, predominantly with an elevation of the IgG globulins. Tissue-nonspecific antibodies, such as anti–smooth muscle antibodies (ASMAs) (20-25%) or antinuclear antibodies (ANAs) (10-20%), can be identified. Tissue-specific antibodies, such as antibodies against the thyroid gland (10-20%), can also be found. Mildly elevated levels of rheumatoid factor (RF) are usually present, indicating the presence of cryoglobulins on further assessment.

Subtype chronic HBV HBeAg-negative disease

Note that although the HBeAg result is negative in this stage, HBeAg negativity can be associated with greater HBV DNA replication and more rapid disease progression in patients who carry mutations in either the precore or the basic core promoter region of the HBV genome. [41]

Cirrhosis

In early stages of cirrhosis, findings of chronic viral hepatitis can be found. Later, as the disease progresses, low albumin levels, hyperbilirubinemia, prolonged PT, low platelet and white blood cell counts, and AST levels higher than ALT levels can be identified. Alkaline phosphatase (ALP) and GGT levels can be slightly elevated.

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Radiologic Studies

Findings on imaging studies are briefly reviewed according to the disease stage.

Acute and chronic hepatitis B disease

Performing abdominal ultrasonography, computed tomography (CT) scanning, or magnetic resonance imaging (MRI) in patients with hepatitis B is important to help exclude biliary obstruction (see the following images). Nonspecific findings include increased echogenicity of the liver parenchyma.

Radiologic studies may be useful in all stages of Radiologic studies may be useful in all stages of hepatitis B infection. Ultrasonography, computed tomography (CT) scanning, or magnetic resonance imaging (MRI) may exclude biliary obstruction in acute infection. In chronic disease, ultrasonograms may show nonspecific increased echogenicity of the liver parenchyma. In patients with long-standing disease, CT imaging may be used to detect cirrhosis or hepatocellular carcinoma (as shown).
Long-standing cirrhosis leads to progressive repla Long-standing cirrhosis leads to progressive replacement of liver parenchyma with fibrotic tissue. Over time, the liver contracts and develops a lobulated contour. These changes are readily apparent on cross-sectional imaging. This contrast-enhanced computed tomography (CT) scan demonstrates extensive cirrhosis, as well as malignant hepatocellular lesions (arrow).

Cirrhosis

Imaging findings in cirrhosis include coarse echogenicity of the liver, with a nodular appearance, and findings compatible with portal hypertension (eg, varices, splenomegaly, ascites, pleural effusion [ie, hepatic hydrothorax]).

Neoplastic lesions can also be detected but may be very difficult to evaluate because they can be mistaken for regenerating nodules. In such cases, highly sophisticated techniques, such as MRI with superparamagnetic iron oxide (ferumoxides), should be considered. Ferumoxides (negative contrast material) are phagocytosed by the reticuloendothelial cells of the normal liver, producing predominant T2 imaging on MRI. Therefore, a marked decrease in the signal in the normal liver parenchyma occurs, effectively permitting the identification of tumors.

In a trial that compared ultrasonographic surveillance at 3- or 6-month intervals to detect hepatocellular carcinoma (HCC) in 1278 patients with cirrhosis due to hepatitis B virus (12.5%), hepatitis C virus (44.1%), or alcohol (39.2%), investigators reported that ultrasonographic surveillance at 3-month intervals detected more small focal lesions (≤10 mm) than at 6-month intervals; however, the shorter interval did not improve detection of small HCC. [49]

On December 17, 2014, the FDA gave marketing approval for the Hepatiq radiologic image processing system. [50, 51] The software application uses quantitative analysis of nuclear medicine liver-spleen images to determine the severity of liver disease and to predict clinical outcomes. [51] The developer notes that Hepatiq "automates the Quantitative Liver Spleen Scan (QLSS) that has been proven to be an accurate predictor of clinical outcomes in the recently concluded HALT-C [epatitis C ntiviral ong-term reatment against irrhosis] trial." [51] The HALT-C trial was a multicenter, randomized controlled study that evaluated whether long-term interferon would suppress HCV, prevent progression to cirrhosis, prevent liver cancer, and reduce the need for liver transplantation. [52]

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Liver Biopsy and Histologic Features

Liver biopsy, percutaneous or laparoscopic, is the standard means of assessing the severity of disease in patients with features of chronic active liver disease (ie, abnormal aminotransferase levels and detectable levels of hepatitis B virus [HBV] DNA).

Although liver biopsy is not indicated for patients with acute hepatitis B disease, the findings in the acute phase are predominantly lobular, with degenerative and regenerative hepatocellular changes, as well as accompanying inflammation. Necrosis may be predominantly centrilobular.

Acute vs chronic histologic findings

Acute hepatitis B

The hallmark of acute hepatitis B is liver cell death. Scattered within the lobule are small, individual clusters of dying hepatocytes in apoptosis. (When the nucleus is extruded, it is an eosinophilic, or Councilman, body). Many of the surviving hepatocytes show hydropic swelling known as ballooning degeneration. Lymphocytes diffusely infiltrate the lobule, with macrophages and neutrophils seen occasionally.

Chronic hepatitis B

The hallmark of chronic hepatitis B infection is lymphoid inflammation, mostly involving the portal tracts. However, occasional Councilman bodies are seen in the lobule. Hepatocytes that are distended with viral particles may acquire an unusual “ground-glass” appearance on the hematoxylin and eosin (H&E) stain (see the following image). Ground-glass cells are seen in approximately 50-75% of livers affected by chronic HBV infection, and they stain positive for hepatitis surface B antigen (HBsAg). Immunohistochemical staining of the specimen can help to identify the presence of HBsAg or hepatitis B core antigen (HBcAg) (ie, chronic infection).

Under higher-power magnification, ground-glass cel Under higher-power magnification, ground-glass cells may be visible in chronic HBV infection. Ground-glass cells are present in 50% to 75% of livers with chronic HBV infection. Immunohistochemical staining is positive for HBsAg.

As the severity of the histologic changes advance, interface hepatitis (piecemeal necrosis) appears, with erosion of the limiting plate by chronic inflammation from the portal side of the lobule. Over time, this ongoing type of inflammation may lead to increasing degrees of fibrosis that spreads out from that portal tract to connect with other nearby portal tracts (bridging fibrosis). When the fibrosis advances further in severity, regenerating nodules of hepatocytes appear; this constitutes cirrhosis (see the image below).

Liver biopsy with hematoxylin stain showing stage Liver biopsy with hematoxylin stain showing stage 4 fibrosis (ie, cirrhosis) in a patient with hepatitis B.
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Staging

Liver damage is graded according to the inflammatory component and is described as follows:

  • Grade 0 – Portal inflammation only, no activity
  • Grade 1 – Minimal portal inflammation and patchy lymphocytic necrosis, with minimal lobular inflammation and spotty necrosis
  • Grade 2 – Mild portal inflammation and lymphocytic necrosis involving some or all portal tracts, with mild hepatocellular damage
  • Grade 3 – Moderate portal inflammation and lymphocytic necrosis involving all portal tracts, with noticeable lobular inflammation and hepatocellular change
  • Grade 4 – Severe portal inflammation and severe lymphocytic bridging necrosis, with severe lobular inflammation and prominent, diffuse hepatocellular damage

Liver damage staging (ie, fibrosis) is described as follows:

  • Stage 0 – No fibrosis
  • Stage 1 – Portal fibrosis
  • Stage 2 – Periportal fibrosis
  • Stage 3 – Septal, bridging fibrosis
  • Stage 4 – Cirrhosis
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