This is a figure of a map of the world within Module 1 that is meant to assist clinicians in determining whether a patient is from a country of low (less than 2 percent), intermediate (2 percent to 7 percent), or high (greater than or equal to 8 percent) prevalence of hepatitis B infection. Clinicians are advised that individuals born in regions with intermediate or high endemicity are at particular risk of having chronic hepatitis B infection and that screening populations at high risk of chronic infection is essential to identify anyone who can benefit from monitoring and treatment.
Most of North America has a low prevalence of HBV infection; however, Alaska and the northern-most strip of Canada have an intermediate prevalence of infection. South America is characterized by great regional variability. There are three main zones: a band of high endemicity that spans the northern region from coast to coast; Brazil and the northern coastline with an intermediate prevalence of infection; and south and southwestern South America which have a low prevalence of infection. Most of Western Europe has a low prevalence of hepatitis B infection. However, Greenland has a high prevalence and Spain and neighbouring countries have an intermediate prevalence. In general, Eastern Europe has an intermediate prevalence of infection. Sub-Saharan Africa has a high prevalence of infection, while North Africa is a region of intermediate prevalence. Most of the Middle East has an intermediate prevalence of, except Saudi Arabia, which has a high prevalence. Most of Russia and the Indian Subcontinent have an intermediate prevalence. Central Asia and South-East Asia have a high prevalence. Both Australia and New Zealand have a low prevalence. The figure was reproduced with permission from the New England Journal of Medicine, Volume 359, Issue 14, October 2008(8).
Return to Where is your patient from
There are two figures in this module that provide an overview of hepatitis B serological markers. The first figure is a line graph showing changes in serological markers for acute infection with spontaneous recovery (9) from 0 to 100 weeks after exposure. Hepatitis B surface antigen begins to rise just before 4 weeks after exposure, peaking at less than 12 weeks, after which, it falls to zero at 24 weeks. Hepatitis B e-antigen is present until just after the peak in hepatitis B surface antigen levels at 12 weeks. After this point, hepatitis B e-antigen disappears and hepatitis B e-antibody appears. Symptoms are present when hepatitis B surface antigen reaches its peak and during its decline. The IgM marker of the hepatitis B core antibody begins to rise around 6 weeks after exposure, peaks just before 16 weeks and then declines to zero at 32 weeks. Total hepatitis B core antibody also starts to rise around 6 weeks, then plateaus at about 20 weeks. Hepatitis B surface antibody begins to rise just before 32 weeks, peaks after 36 weeks and then declines.
Chronic Hepatitis B (10)
The second figure is a line graph showing the changes in various hepatitis B serological markers, in the case of chronic hepatitis B infection, from the time of exposure to years later. In chronic infection, hepatitis B surface antigen begins to rise just before 4 weeks after exposure, plateaus at approximately 12 weeks and persists for years. Both the IgM marker of the hepatitis B core antibody and the total hepatitis B core antibody appear at approximately 6 weeks after exposure. The IgM marker peaks at approximately 16 weeks and then gradually declines to zero after 36 weeks, but in chronic hepatitis B infection, may reappear during hepatic flares of activity. The total hepatitis B core antibody plateau’s just after 12 weeks and persists for years. In chronic infection, hepatitis B e-antigen rises at about 4 weeks after exposure and persists for years. In some chronically infected individuals the e-antibody may appear and replace the e-antigen after a period of many years.
Return to Overview of HBV Serological Markers
This table describes 6 possible interpretations of diagnostic test results and subsequent recommended actions for clinicians.
In the first scenario of this table, a patient should be considered to be susceptible to hepatitis B when: hepatitis B surface antigen results are negative; hepatitis B surface antibody results are negative; total hepatitis B core antibody results are negative; and the IgM marker of the hepatitis B core antibody is not available/or not done.
It’s noted that approximately 5 percent to 10 percent of people will not respond to vaccine or else do not produce protective levels of antibody post-vaccination (that is, greater than or equal to 10 international units per millilitre).
The recommended action when a patient is considered to be susceptible to hepatitis B is to vaccinate.
In the second scenario of this table, a patient should be considered to be immune to hepatitis B due to vaccination when: hepatitis B surface antigen results are negative; hepatitis B surface antibody results are positive; total hepatitis B core antibody results are negative; and the IgM marker of the hepatitis B core antibody is not available/or not done. Regarding the hepatitis B surface antibody, clinicians are reminded that about 5 percent to 10 percent of people will not respond to the vaccine or else do not produce a protective level of antibody post-vaccination (that is, greater than or equal to 10 international units per millilitre). Note that in immune individuals, levels of hepatitis B surface antibody may decline over time and become undetectable.
The recommended action when the patient is considered immune due to vaccination is to provide education and counselling as per the recommendations in module 11.
In the third scenario of this table, a patient should be considered immune due to previous infection when: hepatitis B surface antigen results are negative; hepatitis B surface antibody results are positive; total hepatitis B core antibody results are positive; and the IgM marker of the hepatitis B core antibody is not available/or not done. Note that, a small percentage of people with chronic infection will have both hepatitis B surface antigen and hepatitis B surface antibody markers present.
The recommended action when the patient is considered immune due to previous infection is to provide education and counselling as per the recommendations in module 11.
In the fourth scenario of this table, a patient should be considered to have an acute infection when: hepatitis B surface antigen results are positive, hepatitis B surface antibody results are negative, total hepatitis B core antibody results are positive and the results of the IgM marker of the hepatitis B core antibody is positive. When an acute infection is suspected, ordering the IgM marker of the hepatitis B core antibody may be helpful; however this marker may also reappear in a flare of chronic infection.
The recommended action when the patient is considered to have an acute infection is for clinicians to refer to module 4 for guidance on the initial management of patients with hepatitis B surface antigen positive results and to provide education and counselling as outlined in module eleven.
In the fifth scenario of this table, a patient should be considered to have a chronic infection when: hepatitis B surface antigen results are positive; hepatitis B surface antibody results are negative, total hepatitis B core antibody results are positive ; and the results of the IgM marker of the hepatitis B core antibody is negative. Note that, a small percentage of people with chronic infection will have both hepatitis B surface antigen and hepatitis B surface antibody markers present; in addition, the IgM marker of the hepatitis B core antibody may reappear in a flare of chronic infection.
The recommended action when the patient is considered to have a chronic infection is for clinicians to refer to module 4 for guidance on the initial management of patients with hepatitis B surface antigen positive results and to provide education and counselling as outlined in module 11.
The final scenario of this table provides four possible interpretations for the rare occasion when an isolated total hepatitis B core antibody is the only detectable marker and hepatitis B surface antigen results are negative; hepatitis B surface antibody results are and the results of the IgM marker of the hepatitis B core antibody is also negative. The four possible interpretations for when an isolated total hepatitis B core antibody is the only detectable marker are that:
Firstly, that the finding of an isolated total hepatitis B core antibody is more common in immunocompromised people and in those who are co-infected with HIV or hepatitis C.
The recommended action is to provide education and counselling as outlined in module eleven.
Secondly, that the finding of an isolated total hepatitis B core antibody in low prevalence populations, is most often a false positive result or due to lab error.
The recommended action is for clinicians to repeat the test if lab error is suspected.
Less frequently, the third interpretation of a finding of an isolated total hepatitis B core antibody is that it may reflect either resolving acute infection before the appearance of hepatitis B surface antibody or natural immunity with undetectable hepatitis B surface antibody due to decline in antibody over time.
The recommended action is to provide counselling as outlined in Module 11
Finally, the fourth possible interpretation of a finding of an isolated total hepatitis B core antibody is that, rarely, it may represent a chronic infection with undetectable hepatitis B surface antigen.
The recommended action is to consult a specialist for guidance and to provide counselling as outlined in Module 11
This flow chart describes the role of the primary care provider and local public health in the initial management of patients with hepatitis B surface antigen-positive results. The laboratory reports the positive hepatitis B surface antigen result to both the primary care provider and the local public health department as per provincial/territorial legislation. From this point onward, there is ongoing communication for case management and follow-up between the primary care provider and local health department.
The primary care provider
The local public health department as per provincial/territorial legislation
Within module 7 which outlines the natural history of chronic hepatitis B, there is a pictorial diagram. This diagram captures the four phases of chronic hepatitis B virus infection. It illustrates that the natural history and the progression of chronic hepatitis B is complex and non-linear, and varies from person to person. In general, transition from e-antigen positive to e-antigen negative (or e-antibody positive) is not always permanent hepatitis B e-antigen may transition back and forth between positive and negative. Active hepatitis, reactivation, and hepatitis flares increase the risk for cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B.
The diagram also illustrates the fluctuation of hepatitis B DNA and alanine aminotransferase levels during various phases of chronic hepatitis B and the impact these levels can have on histological activity and degrees of fibrosis that can occur in the transition between phases.
In the immune –tolerant phase, hepatitis B e-antigen is always present, the hepatitis B DNA levels are high and alanine aminotransferase levels are low. There is minimal histological activity and scant fibrosis in the liver.
During the immune-active chronic hepatitis B phase the patient can be either hepatitis B e-antigen-positive or –negative. In this phase the levels of hepatitis B DNA and alanine aminotransferase fluctuate. Histology shows active hepatitis and variable degrees of fibrosis, hence, treatment is appropriate.
During the inactive hepatitis B surface antigen phase, the hepatitis B e-antigen is negative and the e-antibody is positive. The hepatitis B DNA and alanine aminotransferase levels are both low. During the inactive phase, there is no histological activity but there may be moderate to severe fibrosis that takes time to resolve.
The diagram shows that there is a 20 percent risk of reactivation to the immune active chronic hepatitis B phase from the inactive hepatitis B surface antigen phase. If this occurs, there will be fluctuating hepatitis B DNA and alanine aminotransferase levels. Histologically, hepatic flares are possible over the lifetime and can result in progressive fibrosis. During reactivation, treatment is appropriate.
Return to Phases of Chronic HBV
This is a table within module 8, which outlines the long-term management of confirmed chronic hepatitis B. It describes the suggested follow-up based on serological and histological findings in each phase of infection.
The first row of the table shows the serological findings and histological activity and degree of fibrosis during the immune tolerant phase. During this phase, hepatitis B e-antigen is positive and alanine aminotransferase is normal; hepatitis B DNA levels are greater than or equal to 200,000 international units per millilitre. In base 10 logarithm, this translates to greater than or equal to 5.3 international units per millilitre; for most patients, the base 10 logarithm level is usually greater than 7 international units per millilitre. During the immune tolerant phase, there is minimal histological activity and scant fibrosis. The degree of fibrosis is close to normal, and biopsy is not indicated.
The suggested follow-up for patients in the immune tolerant phase is to monitor alanine aminotransferase every 6 months. If the alanine aminotransferase level s are elevated for 6 months and there’s no associated drop in hepatitis B DNA, it is important to rule out other causes of liver disease and refer to a specialist, as treatment may be indicated. Refer to module 6 for interpretation of the upper limit of normal for alanine aminotransferase and for guidance on when urgent referral to a hepatologist is indicated.
The second row of the table shows serological findings and histological activity and degree of fibrosis during the hepatitis e-antigen-positive, immune active chronic hepatitis B phase. During this phase, hepatitis B e-antigen is positive and alanine aminotransferase is elevated, usually persistently; hepatitis B DNA levels are greater than or equal to 20,000 international units per millilitre. In base 10 logarithm, this translates to greater than or equal to 4.3 international units per millilitre. Histologically, there is active hepatitis with variable degrees of fibrosis. During the hepatitis e-antigen-positive, immune active chronic hepatitis B phase, treatment may be indicated to prevent severe liver injury. Clinicians are advised that biopsy may also be indicated.
The suggested follow-up for patients in the e-antigen-positive, immune active chronic hepatitis B phase is to monitor alanine aminotransferase every 6 months. If alanine aminotransferase remains elevated after 6 months of follow-up, or if there is any evidence of liver failure, the clinician is advised to refer to or consult a specialist for treatment and monitoring recommendations. Refer to module 6 for interpretation of the upper limit of normal for alanine aminotransferase and for guidance on when urgent referral to a hepatologist is indicated.
The third row of the table shows serological findings and histological activity and degree of fibrosis during the hepatitis e-antigen-negative (or e-antibody positive), immune active chronic hepatitis B phase
During this phase, hepatitis B e-antigen is negative and alanine aminotransferase levels are elevated, though alanine aminotransferase levels may fluctuate between normal and abnormal and may flare intermittently; hepatitis B DNA levels range from 2000 to greater than or equal to 20,000 international units per millilitre. In base 10 logarithm, levels can fluctuate between 3.3 and greater than or equal to 4.3 international units per millilitre. Histologically, there is active hepatitis with variable degrees of fibrosis. During the hepatitis e-antigen-negative (or e-antibody positive), immune active chronic hepatitis B phase, treatment may be indicated to prevent severe liver injury. Biopsy may also be indicated.
The suggested follow-up for patients in the hepatitis e-antigen negative, or e-antibody positive, immune active chronic hepatitis B phase is to monitor alanine aminotransferase every 6 months. If alanine aminotransferase remains elevated after 6 months of follow-up, or if there is any evidence of liver failure, clinicians are advised to refer, or consult a specialist for treatment and monitoring recommendations. Refer to module 6 for interpretation of the upper limit of normal for alanine aminotransferase and for guidance on when urgent referral to a hepatologist is indicated.
The fourth row of the table shows serological findings and histological activity and degree of fibrosis during the inactive hepatitis B surface antigen positive phase when e-antibody is positive. During this phase, hepatitis B e-antigen is negative and alanine aminotransferase is normal; DNA levels are often undetectable or less than or equal to 2000 international units per millilitre. In base 10 logarithm, this translates to less than or equal to 3.3 international units per millilitre. There is no histological activity, but there may be moderate to severe fibrosis that may resolve over time if the disease remains inactive. During this phase, biopsy is not indicated.
The suggested follow-up for patients in the inactive hepatitis B surface antigen-positive phase is to monitor alanine aminotransferase every 6 months. If alanine aminotransferase is greater than 1 to 2 times the upper limit of normal, clinicians are advised to check hepatitis B DNA levels and rule out other causes of liver disease. It is important to check the hepatitis B DNA level annually. If it is elevated, clinicians are advised to refer the patient back to the specialist.
The fifth row in the table shows serological findings and histological activity and degree of fibrosis during the hepatitis B surface antigen clearance phase.
During this phase, hepatitis B e-antigen is negative and alanine aminotransferase is normal; DNA is undetectable in serum, but low levels may be present in the liver. There is no histological activity, but the patient may already have fibrosis and/or cirrhosis that may resolve slowly. During this phase, biopsy is not indicated.
The suggested follow-up for patients in the inactive hepatitis B surface antigen clearance phase is to monitor alanine aminotransferase every 6 months. The patient should also be monitored every six months for the development of hepatitis B surface antibody; once surface antibody is detected, repeat the test one time. Patients in the hepatitis B surface antigen clearance phase should undergo hepatocellular carcinoma surveillance every 6 months. This is important in those who do not develop hepatitis B surface antibody and in those who were cirrhotic prior to hepatitis B surface antigen clearance.
This table is within module 10 which provides guidance on prevention and vaccination. In individuals who are susceptible, the recommended action is to vaccinate. In individuals who are susceptible and recently exposed, the recommended action is to refer to the Canadian Immunization Guide or to their provincial or territorial immunization guidelines for post-exposure prophylaxis recommendations. In individuals who are hepatitis B surface antigen-positive, the recommended action is to refer to a specialist. In individuals who are immune, no action is required.