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Abstract

  1. Top of page
  2. Abstract
  3. Initial Evaluation
  4. Monitoring
  5. Screening and Surveillance for HCC
  6. Special Populations
  7. Conclusion and Needs for Future Research
  8. References

The initial evaluation of a patient with hepatitis B virus infection should attempt to assess the disease activity and stage in the context of the known natural history of this infection and to properly assess the needs for treatment and surveillance. In addition to a medical history and focused physical examination, the initial evaluation usually requires serological, biochemical, and virological tests to confirm the diagnosis as well as an imaging study to establish a baseline for future monitoring. A liver biopsy is generally not needed but can provide useful information on prognosis, need for surveillance for hepatocellular carcinoma (HCC), and whether to recommend therapy. Follow-up monitoring is aimed at determining disease progression, development of complications, and reassessing the need for treatment. Monitoring frequency should be determined based on the activity and stage of disease. Initiation of screening for HCC should be based on age, race, sex, family history, and stage and duration of disease. The current recommended method of screening and surveillance for HCC is by ultrasonography and alpha-fetoprotein measurements every 6–12 months. Prospective studies are needed to evaluate the role of longitudinal application of noninvasive assays of fibrosis, such as serum fibrosis markers and transient elastography. Better biomarkers and imaging modalities are needed for early detection of HCC. Finally, studies are needed to better refine the indications and to balance the risks and benefits of antiviral therapy. (HEPATOLOGY 2009;49:S22–S27.)


Initial Evaluation

  1. Top of page
  2. Abstract
  3. Initial Evaluation
  4. Monitoring
  5. Screening and Surveillance for HCC
  6. Special Populations
  7. Conclusion and Needs for Future Research
  8. References

The initial evaluation of the patient found to have hepatitis B surface antigen (HBsAg) in serum should attempt to establish the diagnosis and assess the grade (activity) and stage of disease in relation to the complex and dynamic natural history of hepatitis B. Hepatitis B virus (HBV) infection evolves through several phases, the pattern of which may vary by viral strain, mode of infection, ethnicity, and presence of comorbidities.1, 2 These phases include (1) an early, immune-tolerant phase that typically occurs in children and is marked by high levels of HBV DNA, presence of hepatitis B e antigen (HBeAg), but normal serum aminotransferase levels and absence of disease activity; (2) immune-activation phase of chronic hepatitis B, marked by moderate to high levels of HBV replication, continued or fluctuating disease activity, and aminotransferase elevations and during which progressive liver damage can occur; and (3) an inactive carrier state, marked by low levels of HBV replication, absence of HBeAg, and normal serum aminotransferase levels with inactive liver disease. Chronic hepatitis B is a dynamic disease, and patients can pass from one phase to another and back, from disease activity to inactivity. During periods of activity, progressive liver damage can occur, resulting in cirrhosis and its complications, as well as hepatocellular carcinoma (HCC). Thus, the presence of HBsAg in serum may have a range of implications, indicating acute or chronic hepatitis B that can be mild or severe and progressive. The goals of the initial evaluation should be to determine the phase of HBV infection, the severity of disease, and the need for monitoring and treatment.

An initial evaluation should include a thorough medical history with specific focus on possible modes of infection and their timing. Important elements of the history should be any exposure to blood or blood products, injection drug abuse, sexual exposure, occupational exposure, and family history of hepatitis B.3 If acute hepatitis B is suspected, recent history of medical procedures should be elicited, particularly if done in outpatient surgical suites.4 Immigrants from countries with a high prevalence of HBV infection should be questioned about family history of hepatitis, cirrhosis, or liver cancer, as well as about other exposure modes such as ritual scarification, piercing, and traditional or unsafe medical procedures.5

The time of onset of infection in patients presenting with chronic hepatitis B is often difficult to define. Most patients with chronic hepatitis B do not report a history of acute, symptomatic onset, and the timing of exposure may be unclear. A history of blood donation can be useful in that all blood donations in the United States have been screened for HBsAg since 1972 and for antibodies to hepatitis B core antigen (anti-HBc) since 1987. As in all patients with liver disease, a detailed medication history including past and present medications with specific attention to over-the-counter, herbal, and alternative medications should be elicited. Personal habits regarding smoking, alcohol consumption, drug abuse, and sexual activity need to be documented. A history of previous treatment for HBV infection is important, and in patients coinfected with human immunodeficiency virus (HIV), the exact antiretroviral regimens used in the present and past should be determined, because these can promote viral resistance and affect treatment choices.

The initial physical examination should document the presence or lack of signs of chronic liver disease. For most patients with chronic hepatitis B, the results of physical examination are normal. Findings such as jaundice, hepatomegaly or a shrunken liver, splenomegaly, palmar erythema, spider angiomata, Dupuytren's contracture, gynecomastia, ascites, peripheral edema, caput medusae, or asterixis are indicative of advanced disease. Signs of other disorders that could affect treatment decision (such as heart failure, renal function impairment, or thyroid disease) should be sought, as well as evidence of extrahepatic manifestations of HBV infection (rash, arthritis, and neuropathy).

Laboratory tests on the initial visit (Table 1) should include a chemistry panel of serum enzymes, direct and total bilirubin, albumin, total protein and creatinine, complete blood count, coagulation tests, and alpha-fetoprotein (AFP). HBV markers including HBsAg, HBeAg and antibody to HBeAg (anti-HBe), and HBV DNA will confirm the diagnosis and help determine the phase of disease (Table 2). Repeating the test for HBsAg is useful, because patients are sometimes told that they have hepatitis B based on the presence of antibody to HBsAg (anti-HBs) or anti-HBc alone. Tests for anti-HBs and anti-HBc are usually not needed, although immunoglobulin M anti-HBc testing may be appropriate if acute hepatitis B is considered possible.

Table 1. Laboratory and Imaging Studies on Initial Visit
Hepatitis B surface antigen (HBsAg)
Hepatitis B e antigen (HBeAg) and antibody (anti-HBe)
Hepatitis B virus DNA
IgM antibody to hepatitis B core antigen (anti-HBc IgM) (if acute hepatitis B is suspected)
Routine chemistry panel (including alanine and aspartate aminotransferase, alkaline phosphatase, creatine phosphokinase, lactate dehydrogenase, total and direct bilirubin, albumin, total protein, blood urea nitrogen, and creatinine)
Complete blood count
Prothrombin time
Quantitative immunoglobulin levels
Alpha fetoprotein
Antibody to hepatitis C virus (anti-HCV)
Antibody to hepatitis A virus (anti-HAV)
Antibody to hepatitis D virus (anti-HDV)
Antibody to human immunodeficiency virus (anti-HIV)
Abdominal ultrasound
Table 2. Interpretation of Serologic Testing
Disease PhaseHBsAgAnti-HBsHBeAgAnti-HBeAnti-HBcHBV DNA (Copies/mL)ALTHistory
  1. Adapted from Lok et al.26

Inactive HBsAg carrier+++Negative-104Normal 
Immune-tolerant+++>107Very normal (24, 25)Younger age (2nd–3rd decades), infected in infancy
Chronic hepatitis B (HBeAg-positive)+++>105ElevatedDistant infection
Chronic hepatitis B (HBeAg-negative)+++>104Elevated (persistently or intermittently)Distant infection (more common in Mediterranean and Asian patients), older age
Acute hepatitis B++IgMPositiveElevatedEvidence of recent exposure
Resolved infection+/−+/−+/−Negative (or very low levels)NormalPast exposure
Immunized+NegativeNormalHistory of vaccination

Chronic hepatitis B cannot be correctly classified with reliability on the basis of a single assessment, and serial testing for serum enzymes and HBV DNA is almost always helpful. This is particularly true for HBeAg-negative chronic hepatitis B, which is often marked by a fluctuating course of serum aminotransferase levels in response to fluctuating levels of HBV DNA.2 A single normal alanine aminotransferase (ALT) value is often thought to imply an inactive carrier or the immune-tolerant state and can affect the decision to perform a liver biopsy or to initiate therapy. However, a single normal level cannot be viewed in isolation. Serial testing should be done before it is assumed that the ALT levels are persistently normal; furthermore, a normal ALT associated with an elevated aspartate aminotransferase (AST) level, elevated serum bilirubin, or decreases in serum albumin values may be indicative of advanced disease and even cirrhosis. It is also important to interpret assay results within the context of the assay characteristics. For example, with the increasing sensitivity of HBV DNA assays, some patients who were previously thought to be negative for HBV DNA can be shown to have low levels of viremia.6, 7 Similarly, the absolute level of ALT may be more important than its relation to the local normal range, because values in the high end of the currently accepted range are associated with a higher risk of histological damage and disease progression,8, 9 and probably should not be accepted as being fully normal in patients presumed to be carriers or immune-tolerant.

Other laboratory studies are important in defining the severity of disease and can provide clues for the presence of fibrosis or advanced liver disease. Laboratory evidence of hepatic decompensation such as low albumin, prolonged prothrombin time, and increased direct bilirubin should be sought. An elevated level of AFP can also hint at advanced disease. Although less accurate than a liver biopsy (see below) in determining actual histological stage, some common laboratory tests can be useful for detecting advanced disease or minimal disease (Table 3). Testing for these “red flags” or “danger signals” should be done routinely at initial evaluation. In addition, testing for coinfection with hepatitis C virus, hepatitis delta virus, and HIV virus is mandated, because these significantly affect therapy and prognosis.

Table 3. Markers of Advanced Liver Disease
AST > ALT27
Decreased platelet count
AST to platelet ratio index (APRI)28
Elevated immunoglobulins or globulins29
Increased alkaline phosphatase or gamma glutamyl transpeptidase30
Elevated alpha fetoprotein

Testing for the genotype of hepatitis B may provide some information on the expected natural history of the disease and on the risk for liver cancer. However, in most scenarios, this assay is not required in clinical practice and should be reserved for selected patients and research protocols. Similarly, testing for mutations conferring resistance to antiviral agents is not applicable to the initial evaluation in routine practice.

An imaging study should be included in the initial evaluation, preferably an abdominal ultrasound. The operator should be directed to assess for signs of advanced liver disease (such as irregular liver contour, splenomegaly, ascites, abnormal portal vein flow) and for liver masses. This will also serve as a useful baseline for future imaging studies, as part of the screening regimen for HCC.

The role of a liver biopsy as part of the evaluation of the patient with HBV is controversial. There is no absolute indication for a biopsy; however, a biopsy is still the gold standard for assessing necroinflammatory activity (grade) and degree of fibrosis (stage) and serves as a useful baseline for future follow-up. The most important role for the biopsy is to assist in deciding on the need for antiviral therapy. Thus, if a biopsy result is going to affect treatment decision, it is clearly indicated. This is especially true in patients with low or normal liver enzymes, in which a biopsy can differentiate active, progressive disease from the inactive carrier or the immune-tolerant state. On the other hand, if the decision to treat is obvious prior to a liver biopsy, then the biopsy serves only as a baseline assessment. The specific indication should be discussed with the patient when the recommendation for a procedure is made.

Noninvasive methods of assessing liver histology are being developed. Combinations of serum markers10 or imaging studies such as transient elastography11 can detect advanced fibrosis with a high degree of accuracy, and to a lesser degree, disease activity. However, the use of these tests to assist in deciding about treatment initiation has yet to be validated. Noninvasive studies may be more useful, when done serially and in combination with a baseline liver biopsy, to assess disease progression over time.12 It is advisable to utilize the available studies at the initial assessment, even if a biopsy is performed, as this could serve s a baseline for longitudinal assessment.

The initial evaluation appointment should also be used to educate patients on their disease, the prognosis, and lifestyle recommendations. Alcohol use should be discouraged. Vaccination against hepatitis A should be offered. Signs and symptoms of disease flares should be discussed. Specific inquiry should be made regarding testing and vaccination of family members or sexual partners and disclosure of infectious status to them. It is important to discuss child-bearing plans with female patients and to recommend monitoring during pregnancy. The risk of disease reactivation during, and after, treatment with immune-suppressant agents13, 14 should be conveyed to all patients and reinforced periodically. Patients should be advised to contact their hepatologist immediately if the need for such a treatment arises. With the currently available treatment options, one can realistically provide patients with hope that their illness can be controlled, enabling them to lead long and normal lives. Patient fears, both cultural and individual, need to be addressed in an objective and honest manner. Finally, patients should be encouraged to educate themselves and keep up to date on the understanding of hepatitis B and its treatment. Several excellent websites are available with reliable information about hepatitis B (Table 4).

Table 4. Internet Resources for Patients
OrganizationWeb Site
American Liver Foundationwww.liverfoundation.org
American Association for the Study of Liver Diseaseswww.aasld.org
Asian Liver Center at Stanford Universityhttp://liver.stanford.edu
Centers for Disease Control and Preventionwww.cdc.gov/hepatitis/HBV.htm
Hepatitis B Foundationwww.hepb.org
Hepatitis B Research Networkwww.hepbnet.org
Hepatitis Foundation Internationalwww.hepfi.org
Immunization Action Coalitionwww.hepprograms.org
National Institutes of Healthwww.digestive.niddk.nih.gov

Monitoring

  1. Top of page
  2. Abstract
  3. Initial Evaluation
  4. Monitoring
  5. Screening and Surveillance for HCC
  6. Special Populations
  7. Conclusion and Needs for Future Research
  8. References

After an initial evaluation (which may require serial assessments), the goals of patient follow-up visits are to reassess disease activity and the need for treatment, to monitor for progression of liver disease and its complications, and to screen for liver cancer. Patients should be reminded that they have a chronic disease; long-term, if not lifelong, monitoring is required.

The frequency of patient monitoring for disease activity should be based on the temporal pattern of disease, on the importance of early detection, and the potential change in management as a result of follow-up (Table 5). Carriers and patients with normal liver enzymes and without HBeAg can develop intermittent and transient flares of disease that typically last for a few weeks to several months. Monitoring liver enzymes every 3 months would detect most of the flares at a relatively early stage, although there is no evidence that early detection of a flare affects treatment success. Thus, monitoring patients every 3–6 months with serum aminotransferase determinations should be sufficient. Patients in the immune-tolerant phase do not typically develop hepatitis until the third or fourth decade of life, and again, early detection may not affect management. Thus, in children with the immune-tolerant state, monitoring every 6–12 months is probably adequate. In contrast, patients who have cirrhosis can decompensate abruptly and spontaneously and may not have the liver reserve to tolerate a disease flare, mandating early intervention. If not being treated, these patients should be monitored every 3 months (Table 5).

Table 5. Monitoring Disease Activity
Disease PhaseMonitoring Frequency (Months)Comments
Immune-tolerant6 to 12Serum enzymes, less frequently HBeAg and HBV DNA
Carrier or normal ALT3 to 6Serum enzymes, less frequently HBsAg and HBV DNA
Elevated ALT, untreated6 to 12Serum enzymes, less frequently HBV DNA
Cirrhosis3Serum enzymes, less frequently HBV DNA and markers for HCC
Treated patients3Serum enzymes and HBV DNA regularly

The routine tests to accompany monitoring have not been fully established. Ideally, measuring HBV DNA levels concomitantly with liver enzymes would be optimal; however, this has to be balanced with cost and test availability. Most patients can be monitored using serum aminotransferase levels as a guide to disease activity. Nonviremic carriers should be tested occasionally for loss of HBsAg, a phenomenon that can occur spontaneously at an annual rate of 0.5%–1.4%15–17 as well as for the development of anti-HBs. In patients with known chronic hepatitis who are not being treated, monitoring HBV DNA levels and enzymes is less important because it is not likely to affect management. Naturally, all patients should be educated on symptoms of disease flares or exacerbations and should be instructed to contact their physician if these occur.

Monitoring of patients during antiviral therapy depends on the agent used and the initial disease severity and is discussed elsewhere in these proceedings. HBV DNA testing is more important during therapy because of the need to assess the possibility of antiviral resistance: genotypic and virological breakthrough precedes biochemical breakthrough, and early intervention with salvage therapy appears to improve long-term response rates.18

To assess disease progression during follow-up visits, apart from liver enzymes, routine monitoring of synthetic function (albumin, prothrombin time), bilirubin, and complete blood count is required. Changes over time in these parameters, and especially a gradual decline in platelet count, may be more sensitive markers of progressing liver fibrosis than one-time measurements, especially for the parameters described in Table 2. One example may be the AST-to-platelet ratio index (APRI = [AST value/upper limit of the normal range] ÷ [Platelet count/1000] × 100); although this index is only moderately accurate at predicting fibrosis on a single occasion, longitudinal monitoring may serve to detect progression of disease. Values above 1.5 are considered suspicious and above 2.0 highly suggestive of the presence of cirrhosis or advanced fibrosis. Continuously rising levels may be an early indication of progressive disease. This approach has not been validated specifically in hepatitis B, but was shown to be useful in patients with HCV-HIV coinfection.19 Similarly, repeated application of serum fibrosis marker panels12 or transient elastography can detect progression of fibrosis. Repeating these assays is especially relevant when monitoring for disease activity is infrequent, and disease flares may have been missed. If these noninvasive markers suggest progression of disease, even in a patient with normal ALT, a decision to treat may ensue. In this situation, a repeat liver biopsy may also be considered.

Screening and Surveillance for HCC

  1. Top of page
  2. Abstract
  3. Initial Evaluation
  4. Monitoring
  5. Screening and Surveillance for HCC
  6. Special Populations
  7. Conclusion and Needs for Future Research
  8. References

Patients with hepatitis B infection are at risk for development of liver cancer. Specific risk factors are age, male sex, African or Asian origin, family history of liver cancer, genotype, core promoter mutations, necroinflammatory activity, and high viral load.20 However, the major risk factor is cirrhosis. Thus, all patients with cirrhosis, as well as patients with advanced necroinflammatory activity, should be screened. The current guidelines recommend initiating screening in all other chronically infected patients on the basis of age, sex, and race (Table 6). Recently, a risk score for the development of HCC in patients with chronic hepatitis B was described.21 If validated, especially in non-Asian patients, this score may serve as a guide for screening initiation. For specific patients, diversion from these guidelines may be justified based on individual risk factors. The recommended screening and surveillance method is by abdominal ultrasonography every 6–12 months.20 AFP should not be used as a single screening test because its performance characteristics are markedly inferior to imaging studies. It can be used in combination with sonography to increase sensitivity, albeit specificity is decreased concomitantly. However, repeated sonography and AFP measurement can also provide information on progression of disease beyond their applicability for cancer screening.

Table 6. Screening Indications for HCC in Patients with HBV
  1. Adapted from Bruix and Sherman.20

Asian males aged ≥ 40 years
Asian females aged ≥ 50 years
Africans aged ≥ 20 years
Family history of HCC
Patients with cirrhosis
Patients with high HBV DNA (probably does not apply to patients in the immune-tolerant phase)
Patients with increased necroinflammatory activity

Special Populations

  1. Top of page
  2. Abstract
  3. Initial Evaluation
  4. Monitoring
  5. Screening and Surveillance for HCC
  6. Special Populations
  7. Conclusion and Needs for Future Research
  8. References

Pregnant patients should be followed at least once per trimester. It is advisable to maintain contact with the patient's obstetrician and recommend passive and active immunization of the newborn,22 especially in mothers who are positive for HBeAg. In patients with a high viral load, the benefits and hazards of treatment with a nucleoside analog during the third trimester, to reduce the risk of vertical transmission, should be discussed with the patient, although the data to favor such an approach is limited.23

Patients who are undergoing, or are about to undergo, profound immune-suppression should be evaluated, preferably prior to treatment initiation. A full serologic panel and HBV DNA level should be repeated for baseline. The decision to initiate prophylactic therapy should be individualized and should be based on the patient's status of hepatitis B infection and projected degree and duration of immune suppression. The patient and the treating physician should be educated about potential signs and symptoms of disease reactivation or exacerbation. Close monitoring of liver enzymes and HBV DNA is mandated, whether or not prophylaxis is given.

Conclusion and Needs for Future Research

  1. Top of page
  2. Abstract
  3. Initial Evaluation
  4. Monitoring
  5. Screening and Surveillance for HCC
  6. Special Populations
  7. Conclusion and Needs for Future Research
  8. References

The initial approach and subsequent monitoring of patients with hepatitis B should focus on assessing disease activity, severity, and need for treatment. Often, more than a single visit is required for correct diagnosis of disease status. Although much is still to be learned about the natural history of hepatitis B, the main focus of future research should be to determine the optimal timing to initiate the modern-day effective, albeit costly and potentially lifelong, antiviral medications. The usefulness of repeated longitudinal measurements of noninvasive assays of liver fibrosis (such as serum marker panels or transient elastography) for monitoring disease progression should be evaluated formally. Improving the sensitivity and specificity of screening methods for HCC should be attempted, and validated across races and geographic regions.

References

  1. Top of page
  2. Abstract
  3. Initial Evaluation
  4. Monitoring
  5. Screening and Surveillance for HCC
  6. Special Populations
  7. Conclusion and Needs for Future Research
  8. References