Patient Description

Mr. C is a 35-year-old male computer programmer. Born in the United States to Chinese parents who emigrated 40 years prior, he has been married for 6 months and has no children. He presented for a routine check-up and reported no health concerns or symptoms. His past medical history was unremarkable with the exception of asthma, which required hospitalization at age 28 years. After discharge, he remained on corticosteroid treatment for 3 months. His family history is significant for a maternal uncle who died from hepatitis-B–related hepatocellular carcinoma. To his knowledge, neither his parents nor his two younger sisters, all living, have reported any health problems. He is a nonsmoker, does not drink alcohol, and has never used recreational or intravenous drugs. An albuterol inhaler, as needed, is his only current medication. When asked about his hepatitis B virus (HBV) vaccination status, he was unable to confirm whether or not he had ever received the vaccine series.

The physical examination was normal. Laboratory results performed 12 months prior showed a normal complete blood count, urinary analysis, lipid profile, and liver panel.

Clinical Decision Point 1: Choosing an HBV Screening Test

Question 1: Which of the following tests should be ordered now?

1. Hepatitis B surface antibody (anti-HBs) only
2. Hepatitis B surface antigen (HBsAg) only
3. HBsAg, anti-HBs, and HBV DNA
4. No HBV test is needed at this time

Discussion

(b) The first widespread hepatitis screening program began in 1969 with HBsAg testing of blood donors, a practice the FDA mandated in 1972.¹ Since then, screening laws and recommendations have changed as knowledge about hepatitis B virology, epidemiology, transmission, and disease burden have evolved. In 2008, the Centers for Disease Control and Prevention (CDC) expanded the list of population groups who are candidates for screening by including, among others, US-born persons not vaccinated as infants whose parents were born in regions with high HBV endemicity (ie, where HBsAg prevalence is ≥8%), regardless of maternal HBsAg status.² Mr. C falls into this group because 1) his parents were born in China, a region that meets this prevalence threshold, and 2) his vaccination status is unknown. Overall, fewer than 25% of Asian Americans with HBV infection have been diagnosed and approximately 40% to 65% of this high-risk population have not been screened.³ The CDC recommends the HBsAg test as the primary screening test for the presence of active HBV infection, either acute or chronic.² This recommendation is based on the typical pattern of circulating serologic markers following exposure to and onset of infection with hepatitis B.

Serologic markers for HBV include viral antigens (HBsAg and HBeAg) and antibodies produced by the host against those antigens (anti-HBs, anti-HBe, and anti-HBc).² All of the above circulate in blood and may be assessed with commercially available assays. Over the course of disease, these serologic markers appear and disappear in a typical pattern, and therefore, may be used to identify the presence of active acute or chronic infection, as well as resolution of active infection and progression of chronic disease.

With new infection, HBsAg is the first marker to appear and may be the only marker for the first 3 to 5 weeks after infection (Figure 1).² HBeAg and anti-HBc IgM are the next markers to appear. As acute infection resolves, HBsAg disappears at about 6 months, followed by the appearance of anti-HBs. Similarly, HBeAg disappears as anti-HBe appears. Total anti-HBc positivity persists for life with the development of IgG antibodies. Anti-HBc IgM antibodies typically disappear in 6 to 8 months.

Figure 1. Typical Serologic Progression of Acute HBV Infection to Resolution²

Abbreviations: anti-HBc, antibody to hepatitis B core antigen; anti-HBe, antibody to hepatitis e antigen; anti-HBs, antibody to hepatitis B surface antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; IgM, immunoglobulin M.

In chronic infection, HBsAg persists at a high titer, as does total anti-HBc. IgM anti-HBc disappears at about the same time as in acute infection (Figure 2).² HBeAg is eventually cleared with the appearance of anti-HBe.

Figure 2. Typical Serologic Progression of Acute to Chronic HBV Infection²

Abbreviations: anti-HBc, antibody to hepatitis B core antigen; anti-HBe, antibody to hepatitis e antigen; anti-HBs, HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; IgM, immunoglobulin M.

Based on these patterns of serologic marker appearance and disappearance, it can be understood why HBsAg is the key marker for identifying the presence of active disease, whether acute or chronic.² Patients who test positive for HBsAg should be referred for medical management. Additional testing distinguishes acute from chronic infection, evaluates chronic disease status, and identifies coinfection with HIV, hepatitis C, or delta hepatitis (Figure 3).^2,4 HBsAg in a person without symptoms of acute hepatitis is suggestive of chronic infection, which is confirmed by the absence of IgM anti-HBc. All HBsAg-positive laboratory results should be reported to the state or local health department, as required by state requirements.² Patients who test negative for HBsAg should be assessed for ongoing risk for hepatitis B and vaccinated, if not immune.

HBV DNA testing is expensive and not necessary to determine HBV infection status. It is, however, integral to the evaluation of chronic disease after initial diagnosis.⁴

Figure 3. Typical Algorithm for Interpretation of HBV Serologic Marker Results ^2,4

Click to Enlarge

Abbreviations: ALT, alanine aminotransferase; anti-HBc, antibody to hepatitis B core antigen; anti-HBe, antibody to hepatitis e antigen; anti-HBs, antibody to hepatitis B surface antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HDV, hepatitis D virus; HIV, human immunodeficiency virus; IgG, immunoglobulin IgG; IgM, immunoglobulin M.

Exceptions to this typical pattern exist. In most cases, anti-HBs does not appear in chronic infection; therefore, its absence points to chronic infection, while its presence points to active infection resolved. It is important to note, however, that anti-HBs positivity alone does not absolutely rule out chronic hepatitis B infection. Some studies have demonstrated a high prevalence of coexisting HBsAg and anti-HBs in Asian patients with chronic hepatitis B, including one study in which 5% of 411 patients had coexisting HBsAg and anti-HBs, and another study of 864 patients in which the prevalence of both was 9%.^5,6 The mechanism is not clearly understood, but it may be due to the selection of HBsAg immune variants or the presence of a mixed viral population, including wild type virus.

Another exception to the typical serologic pattern is that of isolated total anti-HBc, which has been documented in patients with resolved HBV infection and waning of anti-HBs titer over time, and in patients with chronic infection (particularly those coinfected with human immunodeficiency virus or hepatitis C virus) and circulating HBsAg that is undetectable by commercial assays.^2,4 Also an exception is the appearance of IgM anti-HBc during an exacerbation of chronic hepatitis B.²

Why is HBV testing needed in a person who is apparently healthy? Why not just give the vaccine?
Audio commentary from Dr. Pan

Case Continues

An HBsAg test was ordered, and the result was positive. Mr. C was told he had the diagnosis of chronic hepatitis B. He expressed significant concern and asked advice regarding whom in his family should also be screened.

At what point did Mr. C most likely acquire hepatitis B infection? Why might this be important?
Audio commentary from Dr. Pan

Clinical Decision Point 2: HBsAg Screening in Family Members

Question 2: Which of the patient's family members should be screened for hepatitis B?

1. His wife only
2. His mother and two sisters only
3. Both parents, his two sisters, and his wife
4. Only those family members who have symptoms

Discussion

(c) Studies have shown that 14% to 60% of household contacts of individuals with chronic HBV infection have serologic evidence of resolved HBV infection and 3% to 20% have evidence of chronic infection.² Children living with, and sex partners of, chronically infected individuals are at the highest risk. Serologic testing and hepatitis B vaccination, if indicated, for these groups has been recommended since 1982. Therefore, the patient's wife should certainly be screened by HBsAg testing. His sisters should also be screened because they were born to the same parents. His parents, being born in the highly endemic region, should also be screened. Screening prerequisites do not include the presence of symptoms, because chronic hepatitis B infection can be asymptomatic, especially during the stage of compensated liver disease. Screening based on clinical symptoms may delay the diagnosis of chronic hepatitis B.

In total, the CDC recommends routine HBsAg testing for 14 population groups.² These groups are listed below. Of these, six groups were added with the 2008 screening guideline expansion and are indicated with an asterisk. The first three groups are based on geographic factors, whereas the others transcend geography and relate to behavioral, contact, and medical factors. In some cases, additional tests are recommended at the same time as HBsAg testing to identify susceptible at-risk persons who may require the HBV vaccination series.

Persons born in regions of high HBV endemicity. Approximately 45% of the world's population resides in regions where the HBsAg prevalence is ≥8% (Figure 4).^2,7 New infections in these regions occur primarily through perinatal or childhood transmission. All persons born in these areas of high endemicity, including immigrants, refugees, asylum seekers, and internationally adopted children, should be tested for HBsAg, regardless of vaccination status in their country of origin.

Persons born in regions with intermediate HBV endemicity.* Regions where the HBsAg prevalence is 2% to 7% account for 43% of the world's population. Modes of transmission vary, including perinatal, household contact, sexual, injection-drug use, and healthcare-related.² All persons born in these areas of intermediate endemicity, regardless of vaccination status outside the United States, should be tested for HBsAg.

US-born persons not vaccinated as infants whose parents were born in regions with high HBV endemicity.* As discussed previously, regardless of maternal HBsAg status, persons born to parents from highly endemic areas (HBsAg prevalence ≥8%) should be tested for HBsAg, unless they have been vaccinated in the United States.²

Figure 4. Worldwide Prevalence of HBsAg, 2006⁷

Click to Enlarge

Household, needle-sharing, or sex contacts of HBsAg-positive persons. Testing for anti-HBc or anti-HBs should be performed as well to determine susceptibility.²

Infants born to HBsAg-positive mothers. These infants should be tested for HBsAg and anti-HBs at the age of 9 months or older, 1 to 2 months after completion of at least three doses of a licensed hepatitis B vaccine series to assess the effectiveness of postexposure immunoprophylaxis.²

Injection-drug users.* In addition to HBsAg testing, testing for anti-HBc or anti-HBs also should be done to identify nonimmune persons in this group who are candidates for vaccination.²

Men who have sex with men.* As with injection-drug users, HBsAg, anti-HBc or anti-HBs testing is recommended to identify infection and immune status.²

Persons needing immunosuppressive therapy.* This group includes persons needing chemotherapy and immunosuppression related to organ transplantation, or rheumatologic or gastroenterologic disorders.² Serologic testing should include HBsAg, anti-HBc, and anti-HBs.

Persons with elevated alanine transaminase (ALT) or aspartate aminotransferase (AST) of unknown etiology.* HBsAg testing should be included in the overall evaluation of these patients.²

Hemodialysis patients. Serologic testing should include HBsAg, anti-HBc, and anti-HBs.²

HIV-positive persons. Test for HBsAg and anti-HBc and/or anti-HBs to determine susceptibility.²

All pregnant women. Women should be tested for HBsAg early in each pregnancy, preferably in the first trimester, and again at admission for delivery, if indicated.²

Donors of blood, plasma, organs, tissues, or semen. Testing of HBsAg, anti-HBc, and HBV DNA is required by the FDA.²

Persons who are the sources of blood or body fluids for exposures that might require postexposure prophylaxis (eg, needlestick, sexual assault). The source person should be tested for HBsAg.²

What lifestyle modifications should Mr. C make to minimize the risk of transmission to others as well as to promote his own liver health?
Audio commentary from Dr. Pan

Case Continues

Mr. C agreed to discuss his chronic hepatitis B diagnosis with his family and urge them to make appointments for hepatitis B screening and possible vaccination, if appropriate. Additional laboratory tests were ordered to further evaluate his disease status. Results were as shown in Table 1.

Why should HBV-infected persons be tested for hepatitis C, hepatitis D, and HIV?
Audio commentary from Dr. Pan

Clinical Decision Point 3: Assessment of Disease Status

Question 3: Which of the following statements represents the most correct assessment of the patient's disease status?

1. He is an inactive hepatitis B carrier since anti-HBs, anti-HBe, and total anti-HBc were all positive, HBeAg was negative, and ALT levels were persistently normal
2. He has resolved hepatitis B infection since anti-HBs and total anti-HBc were positive and ALT levels were persistently normal
3. He has chronic hepatitis B with HBeAg-negative disease, regardless of persistently normal ALT levels

Discussion

(c) Four clinical phases of chronic HBV infection are recognized, although they do not represent a linear progression characteristic of the natural history in all patients (Table 2).^4,8,9 The immune tolerant phase is characterized by subclinical or mild disease in which the virus is actively replicating. Chronic hepatitis B, divided into HBeAg-positive and -negative disease, represents active liver disease with ongoing viral replication and rising ALT levels. Seroconversion from HBeAg to anti-HBe marks transition to the inactive carrier phase, where ALT and HBV DNA levels fall.

Based on these distinctions, this patient can be diagnosed as chronic HBeAg-negative hepatitis B due to the high level of HBV DNA simultaneous with the absence of HBeAg and the presence of anti-HBe. The pattern of intermittent elevation of ALT has been observed in chronic hepatitis B infected patients, especially with HBeAg-negative disease.^8,9 Frequent follow-up with repeated liver panels may discover the transient elevation of ALT.¹⁰ However, normal ALT does not rule out active disease. Treatment guidelines issued by the American Association for the Study of Liver Diseases and the US Algorithm group recommended regular ALT monitoring for those patients with normal ALT levels and significant viral load who are not yet considered for treatment.^4,9 In fact, recent guidelines also recommend decreasing the upper limit of normal for ALT to 30 IU/mL for men and 19 IU/mL for women to reflect the risk for significant liver disease at levels lower than the routine ALT reference range.

The presence of anti-HBs in a patient with a history of acute or chronic hepatitis B often points to resolved infection, particularly when anti-HBe is also present.² In the case of this patient, however, that would be an incorrect interpretation. The high viral load combined with HBsAg positivity is a strong indicator of active disease. The presence of anti-HBs could be due to an HBsAg mutation or mixed viral population as described previously. Similarly, the inactive carrier state also can be ruled out due to the patient's high viral load.

Table 2. Phases of Chronic Hepatitis B Infection^4,8,9

Why is it necessary to determine the specific phase of chronic infection?
Audio commentary from Dr. Pan

Case Continues

The patient was scheduled to return for a follow-up ALT test in 3 months. A liver biopsy was also discussed with him for the purpose of obtaining detailed information regarding his HBV-related liver injury. He indicated his preference to be referred to a hepatologist for this procedure.

His wife, sisters, and parents were screened for hepatitis B with HBsAg testing. His mother was HBsAg positive and was advised to see her primary care provider for treatment evaluation. All other family members were HBsAg negative and received HBV vaccination.

Should the patient and his family members receive the hepatitis A vaccine if they haven't already? Is it necessary to test for anti-HAV prior to giving the vaccine?
Audio commentary from Dr. Pan

Conclusion

Updated CDC guidelines have extended hepatitis B screening to persons born in regions of high and intermediate HBV endemicity (ie, HBsAg prevalence ≥2%), and to persons born in the United States not vaccinated as infants whose parents were born in regions with high HBV endemicity (ie, HBsAg prevalence ≥8%). Due to the HBV endemicity in China and other parts of Asia, many foreign-born Asian Americans or those with parents who immigrated are candidates for HBV screening. Further HBV screening and consultation should be provided to the family members of any patient with a positive screening result.

The complex myriad of available HBV-related tests may be simplified by considering tests according to their purpose along a continuum of screening to disease evaluation. HBsAg is the primary screening test for hepatitis B. Chronic infection in an HBsAg-positive patient is confirmed with a negative IgM anti-HBc test. Thereafter, another set of tests, while not needed for diagnosis, is needed to evaluate chronic disease status. This set includes: ALT, HBeAg, anti-HBe, and HBV DNA. Additional tests to identify coinfection with HCV, HDV, and HIV also assist in evaluation.

HBV screening costs appear to be comparable to costs associated with screening for other diseases, including HIV and diabetes.² One unpublished study determined it costs $750 to $3752 (2007 data) to identify one person with chronic infection in a population with a chronic infection prevalence of 2%. The cost to identify one chronically infected person would be less in populations with greater prevalence.

Screening can be done individually based on discussion between physician and patient, as part of family screening, particularly when a new patient is found to have hepatitis B, or as part of a community screening program, such as are being offered in many communities around the country now. For individuals who have inadequate medical insurance, the costs of screening may sometimes be borne by state or local health departments or community programs. In the case of community programs, it is probably very useful to have case managers who can work with individuals found to have hepatitis B in order to facilitate further assessment and screening for the family. State and local health departments are often able to provide hepatitis B vaccine to uninfected individuals within the family. Finally, given the ethnic distribution of hepatitis B, it is useful to have caregivers and providers (including physicians, nurses, and case managers) who can communicate with the HBV-infected patient in his or her native language.

References

1. United States General Accounting Office. Blood supply: FDA oversight and remaining issues of safety. February 1997. Available at: www.gao.gov/cgi-bin/getrpt?GAO/PEMD-97-1. Accessed on: February 11, 2010.


2. Centers for Disease Control and Prevention. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Morb Mortal Wkly Rep. 2008;57(RR-8):1-20.


3. Hutton DW, Tan D, So SK, Brandeau ML. Cost-effectiveness of screening and vaccinating Asian and Pacific Islander adults for hepatitis B. Ann Intern Med. 2007;147:460-469.


4. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:1-36.


5. Zhang JM, Xu Y, Wang XY, et al. Coexistence of hepatitis B surface antigen (HBsAg) and heterologous subtype-specific antibodies to HBsAg among patients with chronic hepatitis B virus infection. Clin Infect Dis. 2007;44:1161-1169.


6. Lada O, Benhamou Y, Poynard T, Thibault V. Coexistence of hepatitis B surface antigen (HBs Ag) and anti-HBs antibodies in chronic hepatitis B virus carriers: influence of "a" determinant variants. J Virol. 2006;80:2968-2975.


7. Centers for Disease Control and Prevention. Travelers' Health - Yellow book. Atlanta, GA: US Department of Health and Human Services, CDC; 2008. Available at: http://wwwnc.cdc.gov/travel/content/yellowbook/home-2010.aspx. Accessed on: February 24, 2010.


8. Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. Management of hepatitis B: summary of a clinical research workshop. Hepatology. 2007;45:1056-1075.


9. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol. 2008;6:1315-1341.


10. Hadziyannis SJ, Papatheodoridis GV. Hepatitis B e antigen-negative chronic hepatitis B: natural history and treatment. Semin Liver Dis. 2006;26:130-141.