6.0 Clinical assessment of patients with hepatitis B virus infection

KEY POINTS
  • Determining the phase of hepatitis B virus (HBV) infection is essential to the clinical assessment of the patient with HBV.
  • HBV DNA, liver function testing and fibrosis assessment (non-invasive liver imaging +/– biopsy) are all key components of this assessment.
  • HBV DNA is an important parameter in informing treatment decision. Testing is Medicare rebatable for one test annually for monitoring and up to four tests annually for those on treatment.
  • All patients should be evaluated for possible fibrosis. Non-invasive methods of assessing hepatic fibrosis, such as transient elastography (FibroScan®), are increasingly becoming available and being used.
  • Normal alanine aminotransferase (ALT) ranges are being revised downwards (<19 for females and <30 for males), and normal liver function tests do not rule out significant hepatic disease.
  • Transmission risks, lifestyle modification, cultural factors and long-term complications associated with chronic hepatitis B (CHB) infection are important components of patient education.
  • When a person is diagnosed with hepatitis B, testing and assessment should be offered to their household and sexual contacts.
  • All patients with CHB require regular monitoring for liver damage and disease progression.

For a summary on acute hepatitis B virus (HBV) infection, see Figure 6.4 (at the end of this chapter).

6.1.1 History and physical examination

The assessment of patients with chronic hepatitis B (CHB) should commence with a thorough clinical history and physical examination. Language interpreters are required when patients are not proficient in English. Aspects of the history that deserve close attention are:

  • any risk factors for the acquisition of CHB; for example, ethnic background, family history of CHB and family history of hepatocellular carcinoma (HCC)
  • host or viral factors that are associated with an increased risk of cirrhosis; for example, older age (longer duration of infection), heavy alcohol consumption, cigarette smoking, and co-infection with other viruses such as hepatitis C virus (HCV), hepatitis D virus (HDV) and human immunodeficiency virus (HIV).

The severity of the underlying liver disease should be clinically evaluated by examining for peripheral signs of chronic liver disease, hepatic encephalopathy, splenomegaly, ascites and peripheral oedema (1, 2).

Extrahepatic manifestations of CHB occur in 10–20% of patients, and effective antiviral therapy is pivotal in such patients. An example of such a manifestation is polyarteritis nodosa involving multiple organ systems, including the gastrointestinal tract (colitis), kidney (glomerulonephritis), neurological (neuropathy) and dermatological (vasculitic skin rashes, palpable purpura) systems. Conversely, about 50% of patients with polyarteritis nodosa are positive for hepatitis B surface antigen (HBsAg). Hepatitis B virus infection-associated glomerulonephritis usually presents with nephrotic range proteinuria, which may progress to renal failure in the absence of effective antiviral therapy (3).

6.1.2 Laboratory investigations

Complete HBV serology – HBsAg, antibody to surface antigen (anti-HBs), antibody to hepatitis B core antigen (anti-HBc), hepatitis B e antigen (HBeAg), antibody to hepatitis B e antigen (anti-HBe) (Table 6.1) – and measurement of HBV DNA level should be performed initially to evaluate HBV replication status (1). HBsAg is the first serological marker to appear, and its presence for more than 6 months indicates CHB infection. HBsAg appears in serum 4–10 weeks after exposure, preceding the onset of symptoms of acute hepatitis and alanine aminotransferase (ALT) elevation. HBsAg will become undetectable 4–6 months after acute exposure in those patients who achieve successful immune clearance (see Chapter 3) (1, 2, 4).

Anti-HBs indicates immunity to HBV when the antibody emerges following the disappearance of HBsAg. Anti-HBs usually persists for life, conferring long-term immunity (1, 2, 4).

HBcAg is only expressed in liver tissue and is therefore not used in routine clinical practice. Anti-HBc is a marker of exposure. Anti-HBc immunoglobulin M (IgM) is seen in high titres in acute HBV infection, and at lower levels in patients with CHB undergoing a flare in disease activity.

Table 6.1 Tests used in the initial assessment of patients with chronic hepatitis B
TestWhy the result is important

HBeAg / anti-HBe
HBV DNA

HAV, HCV, HDV, +HIV serology

Quantify replication, identify phase of infection and consider treatment

Ascertain co-infection, evidence of immunity to hepatitis A (need to offer vaccination)

LFTs
FBC
PT, INR
Alpha fetoprotein
Necroinflammatory activity, synthetic function
Thrombocytopenia may indicate cirrhosis
Assessing the liver’s synthetic function
HCC
anti-HBe, antibodies to envelope antigen; FBC, full blood count; HAV, hepatitis A virus; HBeAg, hepatitis B envelope antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HDV, hepatitis D virus; HIV, human immunodeficiency virus; INR, international normalisation ratio; LFT, liver function test; PT, prothrombin time

HBeAg is considered a marker of HBV replication and infectivity. Seroconversion (i.e. loss of HBeAg and development of anti-HBe) often signals transition from an active phase (immune clearance) of the disease to an immune control phase (HBeAg negative, anti-HBe positive, low HBV DNA level). Patients can fluctuate between the active (HBeAg positive, anti-HBe negative, high HBV DNA level) and immune control phases of the disease over time. The absence of HBeAg, however, does not necessarily preclude active viral replication, since specific mutations in the HBV genome can prevent HBeAg synthesis – the so-called precore and core promoter mutants. Patients with these HBV mutants have elevated HBV DNA and ALT despite the absence of HBeAg (HBeAg-negative CHB). In Australia, the frequency of HBeAg-negative CHB is increasing, representing 20–40% of CHB infection (5).

HBV DNA level is a measure of viral replication, used as a criterion for commencing antiviral therapy in patients with CHB in conjunction with evidence of ongoing liver damage. In population studies, a HBV DNA level greater than 2,000 IU/mL was found to be a strong predictor of increased risk of cirrhosis and HCC (6). Results of HBV DNA levels were previously expressed as copies/mL, but the current standard is to convert them to international units (IU)/mL. The conversion factor ranges from 5.2 to 5.8, depending on the laboratory. Currently, most HBV DNA assays are based on real-time polymerase chain reaction (PCR), which provides increased sensitivity and greater dynamic range quantification than hybridisation assays. An earlier version of the hybridisation assay, used commonly until a few years ago, has a threshold of detection greater than 20,000 IU/mL (>141,500 copies/mL). Hence, the clinical status for some patients may need to be reinterpreted using the results obtained with the newer assays. In particular, patients with HBeAg-negative CHB might be erroneously diagnosed as ‘inactive’
or being in the immune control phase, because of the inability of older assays to demonstrate viraemia below the assay detection threshold.

The threshold of HBV DNA level associated with liver disease is unknown. However, treatment is usually considered in HBeAg-positive patients with HBV DNA level of at least 20,000 IU/mL, and in HBeAg-negative patients with HBV DNA of at least 2,000 IU/mL (1, 2, 4). HBV DNA levels may fluctuate widely in CHB. More accurate assessment of the patient’s clinical status requires serial measurements of HBV DNA.

Laboratory evaluation should also include an assessment of liver enzymes, hepatic synthetic function (including coagulation profile), and liver ultrasound and alpha fetoprotein estimation. A complete laboratory screen for other causes of liver dysfunction and testing for co-infection with other viruses (e.g. hepatitis C and D) is also recommended (1, 2, 4).

6.2.1 Liver biopsy

Liver biopsy should only be performed on the recommendation of a specialist clinician. It provides an accurate assessment of the degree of necroinflammatory activity and extent of hepatic fibrosis, and excludes other liver diseases. Such information can be vital in informing the need for antiviral therapy. The two histological features of liver biopsy used in the assessment of HBV are fibrosis (stage of disease) and necroinflammation (grade of disease). Liver fibrosis is usually graded from 0 to 4 (1=limited portal fibrosis; 2=periportal fibrosis; 3=septal fibrosis linking portal tracts or central vein; and 4=cirrhosis with development of nodules and thick fibrous septa). Liver biopsy may be performed percutaneously or – in those with ascites or significant coagulopathy – via the transjugular route. It has been the gold-standard investigation for determining the stage of fibrosis or liver disease. A number of different scoring systems have been developed to stage fibrosis and grade inflammation. Prominent among these are the Scheuer Score, Histological Activity Index (HAI), the Ishak modified HAI and the METAVIR system, which is used mainly for hepatitis C (7-9).

The development of significant fibrosis (stage 2 or greater) implies progressive disease and the need for treatment. Inflammation is graded using necroinflammatory scores.

Liver biopsy has a number of disadvantages. It is an invasive, uncomfortable, costly and time-consuming procedure that carries a small but significant risk of complications. For these reasons, some patients are unwilling to undergo the procedure. Liver biopsy also suffers from sampling bias, because scarring and necroinflammation may be heterogeneously distributed in the liver. The absolute requirement for a biopsy before commencing treatment was removed by the Pharmaceutical Benefits Advisory Committee (PBAC) in November 2011. However, in some patients, biopsy remains the best investigation for determining the true nature of the liver disease, especially in patients with co-morbidities associated with liver injury (e.g. obesity, alcohol use disorders and iron storage disorders). The unique value of biopsy needs to be carefully explained to patients.

6.2.2 Non-invasive assessment of hepatic fibrosis

Non-invasive measures of hepatic fibrosis are increasingly becoming available; the most commonly used being transient elastography (TE) or FibroScan®. This uses ultrasound elastography to measure liver stiffness. Shear waves are generated and measured in kPa, which correlate with fibrosis score as determined by biopsy. Cut-offs are given that can accurately place the patient in different stages of fibrosis (Figure 6.1). A meta-analysis of the use of TE in CHB found that it performed well in detecting cirrhosis (sensitivity 85% and specificity 82%), but was less specific at detecting severe fibrosis (sensitivity 74% and specificity 64%). (10). Some international consensus guidelines have begun to include TE as an acceptable alternative to biopsy for fibrosis staging (11). Currently, FibroScan® is available through liver and hepatitis clinics, but its availability in other settings is likely to increase. There is no Medicare rebate for these services, and access is usually offered as part of a specialist review.

A number of other means of assessing fibrosis non-invasively have been reported; they include acoustic radiation force impulse, magnetic resonance imaging (MRI)-based elastography and serum blood algorithms, such as those used
to derive the Fibrotest and hepascore results. These methods are not routinely available in Australia at present. Further research into non-invasive assessment of hepatic fibrosis is required.

Figure 6.1 FibroScan® suggested cut-off

Adapted with permission from: Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. Journal of Hepatology. 2008;48(50):835-847.

The need for treatment is based on assessment of HBV DNA and liver function tests (to determine the phase of infection), and assessment of fibrosis. Candidates for treatment are those in the immune clearance and escape phases, and all patients with cirrhosis. Pharmaceutical Benefits Scheme (PBS) criteria for initiating therapy are given in Table 7.2 (Chapter 7). All patients with CHB require some form of monitoring, the frequency of which is determined by their clinical state (Figure 6.2).

Figure 6.2 Monitoring patients with CHB

*HBV DNA only Medicare rebatable once/year in patients not on treatment, 4 times/year on antiviral treatment

anti-HBe, antibodies to envelope antigen; CHB, chronic hepatitis B; HBeAg, hepatitis B envelope antigen; HBV, hepatitis B virus; LFT, liver function test

 Monitoring for those not on treatment consists of liver function tests 6-monthly and HBV DNA annually (Medicare rebatable once per 12 months). The monitoring is needed to determine if and when the disease phase has changed and when treatment may be indicated.

CHB can be a life-long disease, and it is important to counsel patients as carefully as possible about the disease, the risks of transmission, and the role of therapy and its limitations. The epidemiology of CHB indicates that most patients will come from culturally and linguistically diverse (CALD) backgrounds. Aboriginal and Torres Strait Islander people also have a high prevalence of CHB. It is important to ensure that counselling patients about CHB is done in a culturally appropriate and safe manner. Health practitioners need to be sensitive about the cultural beliefs of specific patient groups, and aware of the implications of a diagnosis of CHB in various patient populations. When there are language barriers, an accredited interpreter is essential to ensure that information is properly understood and that the patient has an opportunity to ask questions. Family members can be of great support to the patient, but should never be used in place of a qualified interpreter. The Translating and Interpreting Service (TIS) has a number of services, including the Doctors’ Priority Line 1300 131 450 (which is freely available, 24 hours/7 days). For more information on TIS, and links to HBV information packages in other languages, see Appendix 2.

Various lifestyle issues need to be addressed: alcohol consumption should be avoided or minimised, and cigarette smokers or cannabis users should be strongly encouraged to quit. Weight reduction should be encouraged for those who are overweight or obese (based on body mass index), and sound nutritional advice should be provided. Vaccination and transmission issues should be addressed (see Chapter 5).

All patients should understand the aims of treatment (with the assistance of language interpreters where necessary), namely:

  • to achieve prolonged suppression of HBV replication
  • to arrest (or reverse) the progression of liver damage, with the ultimate goal of preventing cirrhosis, HCC and liver failure.

Patients need to have an understanding of the key factors, including the role of liver biopsy, that influence the decision to commence treatment. Figure 6.3 provides some examples of when to seek urgent advice or referral.

Figure 6.3 Critical situations and the need for referral

 

Identifying a patient with cirrhosis
The following may be indicators of advanced disease, and referral  should be considered:
  • low or borderline-low albumin level for age and gender
  • low platelet count
  • reversed ratio of ALT and aspartate aminotransferase (AST)
  • elevated prothrombin time
  • reverse portal flow on ultrasound
  • firm nodular liver edge
  • splenomegaly
  • stigmata of chronic liver disease (e.g. spider naevi, caput medusae, Dupuytren’s contractures).

Remember, patients with advanced disease may have normal liver function test results.

An important element in the assessment of a patient with CHB is HCC screening; this is recommended for patients with CHB who are at high risk of HCC (Table 6.2). Screening is recommended every 6 months, using ultrasound and alpha fetoprotein estimation (1, 2, 4, 12).

The incidence of HCC is lower in patients receiving nucleos(t)ide analogues (based mainly on data from treatment with lamivudine or adefovir) or interferon than in untreated patients, even in those without cirrhosis (5, 6). However, screening for HCC needs to continue, regardless of treatment outcome, because the risk is not completely eliminated.

Table 6.2 Recommended screening for hepatocellular carcinoma (HCC) screening in patients with chronic hepatitis B
Ongoing surveillance, including 6-monthly ultrasound (US) tests and alpha fetoprotein (AFP) level tests, is recommended for the following patients with CHB.
• Any patient with cirrhosis
• Asian men over 40 years of age
• Asian women over 50 years of age
• African people over 20 years of age
• Aboriginal and Torres Strait Islander people over 50 years of age
• those with a family history of HCC.

 

Figure 6.4 Acute hepatitis B virus (HBV) infection
ALT, alanine aminotransferase; anti-HBc, antibodies to core antigen; anti-HBs, antibodies to surface antigen; AST, aspartate aminotransferase; CHB, chronic hepatitis B; HBeAg, hepatitis B envelope antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; IgM, immunoglobulin; IU, international units

The incidence of acute HBV infection has been decreasing in Western countries for a number of years, due to widespread vaccination and routine blood testing. Acute HBV infection is characterised by the onset of symptoms 1–4 months after exposure. A serum sickness-like syndrome may occur, followed by an illness characterised by anorexia, nausea, jaundice and right upper quadrant pain. Symptoms usually disappear after 1–3 months, but some patients have prolonged fatigue even after liver function tests have normalised.

Elevated ALT/AST with values up to 1,000–2,000 IU/L are characteristic of acute HBV. Prothrombin time is the best guide to prognosis. In the early phase of infection, HBsAg, anti-HBc IgM and HBeAg are all positive. The disappearance of HBsAg is usually followed by the appearance of anti-HBs. However, the appearance of this antibody may be delayed, creating a window period where the diagnosis of recent HBV infection can only be made by the detection of anti-HBc IgM.

A small proportion of patients (0.1–0.5%) will develop fulminant hepatic failure, believed to be caused by massive immune-mediated lysis of infected hepatocytes. Such patients may have no evidence of active viral replication at the time of presentation.

The management of acute HBV is symptomatic care. Bed rest and nutritional support are central. Anti-nausea medications may be of benefit, and limited doses of paracetamol (<2 g/day) or codeine may be cautiously administered for abdominal pain or fevers. Since most patients recover, antiviral therapy is not generally recommended. However, case reports and results from a small series of patients suggest some benefits of early therapy. Current recommendations support the use of nucleos(t)ide analogues at the first sign of severe liver injury or impending hepatic failure. Patients should be monitored regularly with laboratory tests during the acute phase of their illness, and referred for specialist review if they have a prolonged prothrombin time, elevated serum bilirubin concentration, and signs of encephalopathy, or if the illness is uncharacteristically lengthy. Continued serological assessment following recovery from the icteric illness is important to identify the small proportion of patients who develop CHB.

The assessment of patients with CHB infection is complex because it requires an intimate knowledge of the natural history of the disease. Current understanding of CHB has improved dramatically, and new therapeutic agents have altered the management of patients in recent years. Treatment paradigms of CHB are constantly changing. Primary-care doctors will need to keep abreast of these developments to properly advise their patients of the most appropriate management plan. Imparting current knowledge is particularly relevant because the current migration patterns suggest that the prevalence of disease in Australia will continue to increase.

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Darrell HG Crawford, School of Medicine, University of Queensland, Greenslopes Private Hospital, and Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD

& Nghi Phung, Department of Addiction Medicine, Department of Gastroenterology and Hepatology, Westmead Hospital, Westmead, NSW