| Abstract|| |
Hepatitis B virus [HBV] affects almost five per cent of the total population worldwide and majority of the affected population are detected incidentally without any symptoms. This mammoth pool of Hepatitis B virus infected population needs to be properly assessed and followed up to minimize morbidity and mortality in them. This article reviews literature related to this subset of HBV patients and attempts to provide a rational guideline to approach and manage them.
Keywords: Chronic hepatitis B, Hepatitis B virus, incidentally detected asymptomatic HBsAg positive subjects, HBeAg, HBsAg, IDAHS
|How to cite this article:|
Dixit VK, Jena SK. Incidentally detected asymptomatic HBsAg positive subjects. Hep B Annual 2008;5:95-101
| Introduction|| |
Hepatitis B virus (HBV) is a small DNA containing virus that may cause persistent infection of the liver. Approximately 400 million people comprising five per cent of the total population are affected worldwide with chronic hepatitis B virus infection, with India having about 45 million of them. Chronic HBV infection is a dynamic process with a wide spectrum of afflictions - on one extreme is the incidentally detected asymptomatic HBsAg positive subject (IDAHS) with no clinical evidence of liver disease, the other extreme being end stage cirrhosis and hepatocellular carcinoma (HCC). For many decades these IDAHS' were considered to have a benign non progressive infection and referred to as "inactive HBsAg carrier". The prognosis of the inactive HBsAg carrier is considered primarily benign in the West, where majority of HBV infection is acquired during adulthood. However, it is remarkably different in follow-up studies from Asian countries where most chronic HBV infection is acquired during infancy or childhood.
| Incidentally Detected Asymptomatic HBsAg Positive Subjects (IDAHS)|| |
Definition and classification
By definition these subjects have no present / past symptoms or signs of liver disease and have HBsAg positivity on two occasions more than six months apart.
Typically, this subgroup seeks medical attention because HBsAg is detected either during a routine checkup, blood donation, family screening of contacts of patients with HBV related CLD or a routine test showing abnormal ALT or AST. A large proportion of IDAHS acquire the infection through perinatal exposure or horizontal transmission. Although on presentation they are asymptomatic and look healthy, a large proportion of IDAHS show biochemical and histological abnormality and carry the risk of progression to cirrhosis and HCC. According to ALT levels and serum HBeAg status they are classified into two groups.
If any among either group is found to have increased ALT greater than 40 IU/L and/or histological activity index (HAI) greater than three (with other causes of liver disease excluded), the person should be categorized as chronic HBV infection with significant liver disease and considered for further assessment and therapy. In fact among inactive HBsAg carriers, 20-30% may under go reactivation and develop progressive liver disease. 
- HBeAg positive group either with normal or raised ALT
- HBeAg negative group (anti-HBe positive) either with normal or raised ALT
Mode of transmission
HBV is transmitted by contact with blood or body fluids of an infected person. Worldwide, most infections occur from infected mother to child, child-to-child contact in household settings, unprotected sexual activity, blood transfusion, and reuse of unsterilized needles and syringes. In many developing countries, almost all children born from infected mothers become infected with the virus. About 90% of infants infected at birth or during their first year of life, and 30-50% of children infected between one and four years of age develop a chronic infection. This risk of chronic infection declines to ~five per cent for older children and adults. HBV infection from blood transfusion has been almost completely eradicated by routine screening and the use of voluntary blood donors.
Clinical features in IDAHS
Most IDAHS are asymptomatic. The most frequent complaint made by them is fatigue and malaise. Weight loss may occur if the subjects have a mass lesion in liver. Hepatomegaly and vary rarely splenomegaly may be found if the patient have inactive cirrhosis.
Laboratory profile in IDAHS
The results of liver function tests with regard to serum bilirubin, albumin, and globulin are mostly normal in IDAHS, except a raised trans aminses in a small proportion of the subjects.
Following demonstration of HBsAg for more than six months, determination of ALT and HBeAg testing should be done in all these patients. In HBeAg negative individuals, baseline HBV DNA should be tested to determine the replicative status of the virus. Liver biopsy is normally not recommended except in subjects with age more than 40 years having ALT values close to upper limit of normal (one to two times). These tests have to be done in conjunction with clinical assessment including history and physical examination, and an ultrasound examination and endoscopy.
These asymptomatic patients should be followed up closely as there is a constant interplay of host and viral factors that may swing the status of liver towards either side. These patients should be evaluated and managed appropriately whenever there is a rise in trans aminase to control the disease at an early stage.
HBe antigen negative group (HBeAg positive)
From several studies in the West, HBeAg positivity has been found in 10% of IDAHS, and 20-30% of them showed chronic active hepatitis. In a large series of 317 asymptomatic HBsAg subjects in Canada,  65% showed raised ALT greater than 40 IU/L and HBeAg positivity was seen in six per cent of cases. This was similar to another study from Italy by De Franchis et al showing 70% with raised ALT and HBeAg positivity in four per cent of asymptomatic HBsAg carrier with 50% having CAH (HAI greater than three) on liver biopsy. The above studies support the earlier study by Dragosics et al in which HBeAg positivity was found in 7.5% of cases, and among HBeAg positive subjects 26% had histologically CAH (HAI greater than three). A study in India by Chandra et al found HBeAg positivity in 45% of cases, and 76% among them had raised ALT and nearly 70% of HBeAg positive subjects had abnormal liver histopathology with HAI greater than three. This study also revealed that even at normal ALT levels, 27% of HBeAg positive subjects had HAI greater than three.
HBe antigen negative group (Anti-HBe positive):
The prevalence of anti HBe in IDAHS from various studies range from 53-96%: Villeneuve et al.  ( 94%), Dragosis et al.  (93.5%), Chandra et al ( 83%) ; Dixit et al (79%). Hepatic damage which correlates with ALT level, HBV DNA level, and necro inflammatory status of liver is present in 2-20% of anti HBe group. In anti HBe positive group, raised ALT is found in 10-20% of cases (12% - De Franchis et al , 14% - Villeneuve et al , 1994, 10% by Chang  ) which differs from the Asian experience where it is 57% by Chandra et al , and 69% by Chan et al.  HBV DNA was positive in 20% of subjects in the study by De Franchis et al.  which is different from the Asian experience where it was found positive in 57% by Sarin et al.  and in 46% by Chan et al . Among DNA positive cases, 50-70% showed HAI greater than three. Although HBV DNA levels correlate with necroinflammatory activity, it is less accurate than raised ALT.
Another study  reported that 45% of anti-HBe hepatitis cases with raised ALT and necroinflammatory changes in liver histology had HBV DNA level less than 10 5 copies/ml casting doubt on the cut-off value. Hence, along with HBV DNA level, ALT level too should be taken into account to differentiate active from truly inactive liver disease.
Risk of progression to cirrhosis
The prognosis of asymptomatic HBsAg carrier state is usually benign; during long term follow-up only a few subjects develop cirrhosis. The progression to severe liver diseases depends upon genotype (genotype C - higher risk of cirrhosis), DNA level, the stage of fibrosis and severity of necro inflammation. The progression to cirrhosis is increased with concurrent infection with HCV, HBV, HIV and alcohol use. A higher rate of cirrhosis occurs in HBeAg negative patients with raised ALT than HBeAg positive patients, because of the longer duration of infection in HBeAg negative subjects.
Risk of hepatocellular carcinoma (HCC)
There is a very low incidence of HCC among IDAHS. Risk factor for HCC among HBV carriers include male sex, family history of HCC, older age, cirrhosis, co infection with HCV and alcohol use.
No treatment is available or recommended for inactive non replicative chronic HBV infection. That means, in subjects who have normal or less than twice ALT levels, absent or minimal necroinflammatory activity antiviral therapy is currently not recommended.
| Recommendations|| |
- No treatment is required for most patients.
- Reassurance should be given to patients.
- Family members should be screened with HBsAg; if negative they should be vaccinated.
- Protected intercourse should be practiced until partner has developed protective antibodies. Eventual offspring needs active and passive vaccination.
- Avoid alcohol.
- Patients should be made aware of possibility of reactivation or super infection by other viruses and advised to consult their physician if there is jaundice, malaise or increased fatigue.
- They should regularly be followed up at every 6-12 months' intervals with trans aminases as fluctuations in ALT and HBV DNA levels are common during the course of chronic HBV infection.
- If person is more than 50 years of age or there is positive family history of HCC, AFP estimation and USG should be performed every 6-12 months.
- They should not be denied employment or hospital treatment. Universal precautions should be taken while treating such patients in the hospital
- They should not be allowed to donate blood, organ or semen
- Close monitoring is required and prophylactic lamivudine therapy should be given if undergoing chemotherapy or receiving immunosuppressive medications
- For pregnant women, vaccinate the newborn at birth with acute and passive immunization within 12 hours of birth.
| Conclusions|| |
HBsAg testing should be mandatory in all routine medical check ups to know the prevalence and appropriate measure to reduce the carrier load in the community. Contacts of HBV related CLD patients should be screened for HBsAg and those who will be negative should be vaccinated. HBeAg testing should be done in all pregnant women who are HBsAg positive to know replicative status and apply measures to prevent vertical transmission. Safe sex and use of sterilized needles and blood product, strict measures for HBsAg detection at blood bank before blood donation are the need of the hour. As IDAHS subjects are more prone to develop alcohol related liver damage it is wise to recommend that such patients abstain from alcohol.
A significant proportion of incidentally detected asymptomatic positive subjects (IDAHS) have biochemical and histological evidence of liver disease in the absence of symptoms. In IDAHS HBeAg status is neither a reliable indicator of CAH/cirrhosis nor of prognosis and in fact HBeAg negative subjects possess a higher risk because of older age and prolonged period of infection. As chronic HBV infection is a dynamic process with fluctuating levels of serum ALT and DNA levels especially in HBe antigen negative subjects, periodic examination of ALT and DNA by PCR assay is required to correctly assess the prognosis.
| References|| |
|1.||McMahon BJ, Alward WL, Hall DB, Heyward WL, Bender TR, Francis DP, et al. Acute hepatitis B virus infection: Relation of age to the clinical expression. J Infect Dis 1985;151:599-603. [PUBMED] [FULLTEXT] |
|2.||Villeneuve JP, Desrochers M, Infante-Rivard C, Willems B, Raymond G, Bourcier M, et al. A long-term follow-up study of asymptomatic hepatitis B surface antigen-positive carriers in Montreal. Gastroenterology 1994;106:1000-5. [PUBMED] [FULLTEXT] |
|3.||de Franchis R, Meucci G, Vecchi M, Tatarella M, Colombo M, Del Ninno E, et al. The natural history of asymptomatic hepatitis B surface antigen carriers. Ann Intern Med 1993;118:191-4. [PUBMED] [FULLTEXT] |
|4.||Dragosics B, Ferenci P, Hitchman E, Denk H. Long-term follow-up study of asymptomatic HBsAg-positive voluntary blood donors in Austria: A clinical and histologic evaluation of 242 cases. Hepatology 1987;7:302-6. [PUBMED] [FULLTEXT] |
|5.||Chandra R, Kapoor D, Agarwal SR, Malhotra V, Sakhuja P, Sarin SK. Profile of asymptomatic chronic HBV infection in India. Indian J Med Res 2002;116:50-7. [PUBMED] [FULLTEXT] |
|6.||Dixit VK, Panda K, Babu AV, Kate MP, Mohapatra A, Vashistha P, et al. Asymptomatic chronic hepatitis B virus infection in northern India. Indian J Gastroenterol 2007;26:159-61. [PUBMED] |
|7.||Chang MH. Natural history of hepatitis B infection in children. J Gastroenterol Hepatol 2000;15:E11-9. |
|8.||Chan HL, Leung NW, Hussain M, Wong ML, Lok AS. Hepatitis B e antigen-negative chronic hepatitis B in Hong Kong. Hepatology 2000;31:763-8. [PUBMED] [FULLTEXT] |
|9.||Chu CJ, Lok AS. HBV genotype B is associated with earlier seroconversion compared to genotype C. Gastroenterology 2002;122:1756-62. [PUBMED] [FULLTEXT] |
Vinod Kumar Dixit
Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi - 221 005
Source of Support: None, Conflict of Interest: None