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ORIGINAL ARTICLE  
Year : 2012  |  Volume : 9  |  Issue : 1  |  Page : 4-15
Spectrum of hepatitis B infection in Southern India: A cross-sectional analysis


Department of Gastroenterology and Hepatology, Stanley Medical College and Hospital, Chennai, Tamil Nadu, India

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Date of Web Publication2-Nov-2016
 

   Abstract 

Background and Aim: Hepatitis B virus (HBV)-related liver disease is not an uncommon problem in India. There are very few reports on pattern of chronic HBV infection from South India. The aim of the present study was to determine the spectrum of chronic HBV infection among patients attending the liver clinic in a tertiary referral center.
Materials and Methods: Hepatitis B surface antigen (HBsAg) positive patients registered in the liver clinic between July 2010 and March 2011 were included in the study. All patients had baseline liver function tests, serological markers for HBV infection (hepatitis B e antigen [HBeAg], anti-HBe, anti-HBc total, and anti-HBc IgG, and HBV DNA quantification), serum alpha-fetoprotein, and ultrasound. Based on the viral profile and transaminase levels and ultrasound findings, patients were categorized as immunotolerant, inactive carriers, immune clearance and reactivation phase, and chronic liver disease with or without hepatocellular carcinoma.
Results: Majority of the patients were asymptomatic and incidentally detected during blood donation camps, master health checkup (MHC), or during initial screening. Almost 40% of patients were either in immune inactive phase or had features of chronic liver disease. In the immunotolerant phase (24 patients), women were a decade younger than their male counterparts. Alanine aminotransferase (ALT) levels were similar in both HBeAg-positive and negative patients. The mean HBV DNA values were significantly high in HBeAg-positive men and women. In the immune inactive phase (58 patients), there were only three patients who were HBeAg positive. The ALT levels were in the normal range. HBV DNA values were low or not detectable. Among patients with elevated ALT and HBV DNA levels (immune clearance/immune reactive) (fifty patients), the mean ALT levels were higher in HBeAg-negative patients. HBV DNA quantity was significantly high in patients who were HBeAg positive.
Conclusion: A significant proportion of HBsAg-positive patients is in inactive or in immunotolerant phase and do not require treatment. Patients with elevated ALT and HBV DNA levels need further evaluation to categorize them into immune clearance or immune reactive phase.

Keywords: Chronic hepatitis B, hepatitis B e antigen, hepatitis B virus, hepatitis B virus DNA, immune clearance, immunotolerance

How to cite this article:
Balasubramanian S, Velusamy A, Krishnan A, Venkatraman J. Spectrum of hepatitis B infection in Southern India: A cross-sectional analysis. Hep B Annual 2012;9:4-15

How to cite this URL:
Balasubramanian S, Velusamy A, Krishnan A, Venkatraman J. Spectrum of hepatitis B infection in Southern India: A cross-sectional analysis. Hep B Annual [serial online] 2012 [cited 2017 May 27];9:4-15. Available from: http://www.hepatitisbannual.org/text.asp?2012/9/1/4/193288



   Introduction Top


Hepatitis B is a global health problem that affects over four hundred million people worldwide and causes over a million deaths every year. In India, hepatitis B virus (HBV) is an important cause of hepatocellular carcinoma (HCC).[1],[2],[3]

Following an acute HBV infection, the rate of progression from acute to chronic hepatitis B is approximately 90% for a perinatally acquired infection,[4] 20–50% for infections acquired between the age of 1 and 5 years,[5],[6] and <5% for an adult-acquired infection.[7]

The natural course of chronic HBV infection is determined by the interplay between virus replication and the host immune response. Other factors that may play a role in the progression of HBV-related liver disease include gender, alcohol consumption, and concomitant infection with other hepatitis virus (es). The outcome of chronic HBV infection depends on the severity of liver disease at the time when HBV replication is arrested.

Chronic HBV infection consists of two phases: an early replicative phase with active liver disease and a late or low replicative phase with remission of liver disease.[8],[9] In patients with a perinatally acquired HBV infection, there is an additional immunotolerance phase, in which virus replication is not accompanied by active liver disease.[10] In some patients, reactivation of HBV replication occurs after a varying period of quiescence. The treatment options [11],[12],[13] include interferon and oral antivirals (nucleotide and nucleoside analogs).

There are very few reports on the spectrum of chronic HBV infection from different regions of the Indian subcontinent.[14],[15] The aim of the present study was to do a cross-sectional analysis of various phases of chronic HBV infection and to determine its sequel at the time of registration at a tertiary referral center for liver disease and liver transplantation.


   Materials and Methods Top


The Department of Gastroenterology and Hepatology caters to a large population from North Madras and referrals from other centers for the management of liver disease as well as for registration for liver transplantation. All patients referred to the Department of Gastroenterology or if directly referred to the liver clinic with a liver disease were routinely screened for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) antibody, and for retroviral infection. Pregnant women were also routinely screened for HBsAg. Further evaluation for those found to be HBsAg positive included baseline liver function tests, hepatitis B e antigen (HBeAg), anti-HBe, anti-Hbc (total and anti-HBc IgG), HBsAg and HBV DNA quantification, ultrasound examination, and serum alpha-fetoprotein (S. AFP). Liver biopsy was not considered mandatory for analysis, but when available were included in the analysis.

Individuals who were positive for HBsAg for at least 6 months were included in the final analysis. Anti-HBc, anti-HB IgM, and anti-HBc IgG were done when considered appropriate. Patients positive for anti-HBc IgM were excluded from the study and were followed by for a further 6 months for viral clearance. Alanine aminotransferase (ALT) levels >45 U/L were considered as elevated for both men and women.

Based on the viral profile and transaminase levels and ultrasound findings, patients were categorized as immunotolerant, immune clearance/reactive, and inactive carriers. Based on the clinical presentation, the sequel of chronic HBV infection was categorized as asymptomatic/incidental, chronic hepatitis, cirrhosis liver with or without decompensation, and HCC.

Patient information included age, gender, date of detection and duration of HBsAg positivity, family history of liver disease including HCC, past history of tattoo, blood transfusion, jaundice, and surgery. All family members including children of index HBsAg-positive patients were screened for HBsAg and further evaluated, if found positive. HBsAg-negative patients were vaccinated against HBV infection.

Definition

In HBV immunotolerance phase (replicative phase) (perinatal acquired infection), HBeAg is positive, HBV DNA levels are high, and ALT levels are normal. Patients are asymptomatic, and liver biopsy changes are often minimal in this phase. Treatment is not routinely recommended during this phase except under research protocol.

In HBV immune clearance phase (active phase), the HBV DNA and ALT levels (active liver disease) are both elevated with evidence of chronic hepatitis on liver biopsy. Patients are often asymptomatic or occasionally present with chronic liver disease with decompensation. Treatment may be recommended during this phase in the absence of advanced fibrosis or cirrhosis irrespective of HBeAg status.

In HBV inactive phase or low or nonreplicative phase, patients are HBeAg is negative, anti-HBe is positive, and HBV DNA levels are either not detectable or are low (<2000 IU/mL). ALT levels are normal. Liver biopsy shows resolution of necroinflammation. Treatment is routinely not recommended during this phase.

HBeAg-negative chronic hepatitis: ALT and HBV DNA levels show fluctuations or a sustained biochemical remission and liver biopsy shows chronic inflammation. These patients fail to produce HBeAg due to precore or core promoter gene variation. Patients are older with advanced liver disease.

In HBV reactive phase, there is histological evidence of liver damage and more rapid disease progression. Treatment for HBV infection is absolutely indicated in reactivation of chronic HBV after chemotherapy or immunosuppression.


   Results Top


Majority of patients were asymptomatic and incidentally detected to be positive during blood donation camps, during MHC, or during initial screening in the Gastroenterology Department at the time of registration. [Table 1] shows the risk factors for HBV transmission and spectrum of chronic liver disease amongst the different category of study subjects. Almost 40% of patients were either in immune inactive phase or had features of chronic liver disease. Five of seven pregnant women and three of the five family members were in the immune inactive phase. There were an equal number of cirrhotic patients in the immune inactive, immunotolerant, and immune clearance/reactive phase. One patient in the entire series was positive for both HBV and retrovirus, and three were positive for HBV and HCV. Two asymptomatic patients were on immunosuppressants and required prophylactic antivirals.
Table 1: Risk factors for HBV transmission and spectrum of chronic liver disease amongst the different category of study subjects

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There were seven patients who had HBV-related HCC during the study period. The mean age was 55 years. Except for one female patient all were men. Serum AFP was significantly elevated in all the patients. Mean ALT level was 96.6 IU/L. Five of the seven patients had very low HBV DNA levels, three were HBeAg positive, and remaining negative. Two of the three patients underwent liver transplantation, and one had hepatic resection of the affected lobe.

In the immun tolerant phase [Table 2], women were a decade younger than their male counterparts. ALT levels were similar in both HBeAg positive and negative patients. The mean HBsAg quantity was significantly higher among HBeAg-positive men than for HBeAg-negative women. The mean HBV DNA values were significantly high for HBeAg-positive men and women, indicating greater infectivity and transmission.
Table 2: Immune tolerant phase: Comparison of HBeAg positive and Negative cases

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In the immune inactive phase [Table 3], there were only three patients who were HBeAg positive. The mean age for men and women was similar. The ALT levels were in the same normal range. Quantitatively, the HBsAg was more among men than women. HBV DNA values were low or not detectable in both men and women.
Table 3: Immune inactive phase: Gender Comparison

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Among patients with elevated ALT and HBV DNA levels (immune clearance/immune reactive) [Table 4], the mean age for men and women in HBeAg-positive patients was similar. In HBeAg-negative patients, women were slightly younger. The mean ALT levels were higher in HBeAg-negative patients. HBV DNA quantity was significantly high in men and women who were HBeAg positive indicating higher infectivity and transmissibility rates. There was no correlation between HBsAg and HBV DNA quantity with HBeAg positivity.
Table 4: Comparison between HBeAg positive and negative subjects with high ALT [>45 IU/L]and high HBV DNA

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   Discussion Top


HBV infection is the most common cause of chronic liver disease in the Asia-Pacific region. Nearly 40 million people out of the global HBV infection pool of 350 million are from India. So far, studies on HBV epidemiology and estimates of the burden of infection due to HBV in India have included patient populations as well as arbitrarily chosen population samples that have been small in size. Such studies often fail to reflect the demographic heterogeneity of the general population.[16],[17]

The goals of hepatitis B therapy are to prevent disease progression and improve patient survival and quality of life. Treatment protocol for an individual depends on the phase of HBV infection. Currently, treatment is recommended for patients in the immune clearance, immune reactive phase, during pregnancy, those on immunosuppressants/immunosuppressed, with liver cirrhosis, and patients with HBV-related HCC awaiting for liver transplantation.[13]

In the present study, a significant number of patients were in the inactive/immunotolerant phase not requiring treatment. However, there are at least two reports [18],[19] stressing on the need to treat patients in immunotolerant phase with high HBV DNA load. Significant fibrosis and inflammation have been reported in 37% of patients with persistently normal ALT and HBV DNA levels >10,000 copies/ml. Contradictory to this, two further reports concluded that in immunotolerant phase of chronic HBV infection, most patients had no or minimal fibrosis, despite elevated HBV DNA levels. Age and duration of illness possibly predict severity of liver injury in the presence of high HBV DNA levels.[20],[21]

Patients in immune clearance and reactive phase need to be treated. A significant proportion of our patients despite being asymptomatic had high ALT and HBV DNA levels. The study, however, could not differentiate the immune clearance from the reactive group of patients as in the majority of the patients, the cause for the flare was not discernible.

In the present series, clinically, five of the seven pregnant women, six of nine patients in chronic hepatitis, and five of seven patients with HCC had low ALT and HBV DNA levels (<2000 IU/L). Among cirrhotic patients, there were almost an equal number of patients with biochemical and serological markers suggestive of immune inactive, immunotolerant, and immune clearance/reactive phase, respectively [Table 1].

Shanmugam et al.[22] from Chennai, in an analysis of 560 HBV DNA samples, 26% (146/560) of samples showed evidence of viremia. Among the 154 HBeAg-positive cases, HBV DNA was positive in 118 cases (77%), significantly (P < 0.001) higher than the anti-HBe positive (7%) (28/406) cases. Significant increase in liver disease (P < 0.01) with ALT enzyme elevation (P < 0.001) was observed in both HBe and anti-HBe viremic cases.


   Conclusion Top


A significant number of HBsAg-positive patients belong to either immune inactive or immunotolerant phase, not requiring treatment. Patients with elevated ALT and HBV DNA levels need an in-depth evaluation to categorize these patients into immune clearance and immune reactive phase, which was not possible in the present study, due to financial constraints.

Financial support and sponsorship

Nil.

Conflict of interest

There are no conflicts of interest.

 
   References Top

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2.
Fattovich G, Giustina G, Schalm SW, Hadziyannis S, Sanchez-Tapias J, Almasio P, et al. Occurrence of hepatocellular carcinoma and decompensation in Western European patients with cirrhosis type B. The EUROHEP study group on hepatitis B virus and cirrhosis. Hepatology 1995;21:77-82.  Back to cited text no. 2
    
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Alward WL, McMahon BJ, Hall DB, Heyward WL, Francis DP, Bender TR. The long-term serological course of asymptomatic hepatitis B virus carriers and the development of primary hepatocellular carcinoma. J Infect Dis 1985;151:604-9.  Back to cited text no. 3
    
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Stevens CE, Beasley RP, Tsui J, Lee WC. Vertical transmission of hepatitis B antigen in Taiwan. N Engl J Med 1975;292:771-4.  Back to cited text no. 4
    
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Tassopoulos NC, Papaevangelou GJ, Sjogren MH, Roumeliotou-Karayannis A, Gerin JL, Purcell RH. Natural history of acute hepatitis B surface antigen-positive hepatitis in Greek adults. Gastroenterology 1987;92:1844-50.  Back to cited text no. 7
    
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Hoofnagle JH, Dusheiko GM, Seeff LB, Jones EA, Waggoner JG, Bales ZB. Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis. Ann Intern Med 1981;94:744-8.  Back to cited text no. 8
    
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Realdi G, Alberti A, Rugge M, Bortolotti F, Rigoli AM, Tremolada F, et al. Seroconversion from hepatitis B e antigen to anti-HBe in chronic hepatitis B virus infection. Gastroenterology 1980;79:195-9.  Back to cited text no. 9
    
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Lok AS. Natural history and control of perinatally acquired hepatitis B virus infection. Dig Dis 1992;10:46-52.  Back to cited text no. 10
    
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Papatheodoridis GV, Manolakopoulos S, Dusheiko G, Archimandritis AJ. Therapeutic strategies in the management of patients with chronic hepatitis B virus infection. Lancet Infect Dis 2008;8:167-78.  Back to cited text no. 11
    
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Lok AS, McMahon BJ. Chronic hepatitis B: Update 2009. Hepatology 2009;50:661-2.  Back to cited text no. 12
    
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Li Z, Jennifer P. Hepatitis B – Recent developments in therapy. Eur Gastroenterol Hepatol Rev 2009;5:38-42.  Back to cited text no. 13
    
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Tandon BN, Acharya SK, Tandon A. Epidemiology of hepatitis B virus infection in India. Gut 1996;38 Suppl 2:S56-9.  Back to cited text no. 14
    
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Choudhury A. Epidemiology of hepatitis B virus infection in India. Hep B Annual 2004;1:17-24.  Back to cited text no. 15
    
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Chowdury A, Santra A, Chakravorty A, Bannerji A, Pal S, Dhali G, et al. Community-based epidemiology of hepatitis B virus infection in West Bengal, India: Prevalence of hepatitis B e antigen-negative infection and associated viral variants. J Gastroenterol Hepatol 2005;20:1712-20.  Back to cited text no. 16
    
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Murhekar MV, Murhekar KM, Sehgal SC. Epidemiology of hepatitis B virus infection among the tribes of Andaman and Nicobar Islands, India. Trans R Soc Trop Med Hyg 2008;102:729-34.  Back to cited text no. 17
    
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Lai M, Hyatt BJ, Nasser I, Curry M, Afdhal NH. The clinical significance of persistently normal ALT in chronic hepatitis B infection. J Hepatol 2007;47:760-7.  Back to cited text no. 18
    
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Kumar M, Sarin SK, Hissar S, Pande C, Sakhuja P, Sharma BC, et al. Virologic and histologic features of chronic hepatitis B virus-infected asymptomatic patients with persistently normal ALT. Gastroenterology 2008;134:1376-84.  Back to cited text no. 19
    
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Andreani T, Serfaty L, Mohand D, Dernaika S, Wendum D, Chazouillères O, et al. Chronic hepatitis B virus carriers in the immunotolerant phase of infection: Histologic findings and outcome. Clin Gastroenterol Hepatol. 2007;5:636-41.  Back to cited text no. 20
    
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Hui CK, Leung N, Yuen ST, Zhang HY, Leung KW, Lu L, et al. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase. Hepatology 2007;46:395-401.  Back to cited text no. 21
    
22.
Shanmugam S, Velu V, Nandakumar S, Madhavan V, Shanmugasundaram U, Shankar EM, et al. Low frequency of precore mutants in anti-hepatitis B e antigen positive subjects with chronic hepatitis B virus infection in Chennai, Southern India. J Microbiol Biotechnol 2008;18:1722-8.  Back to cited text no. 22
    

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Correspondence Address:
Sivasubramaniam Balasubramanian
No. 1, Old Jail Road, Stanley Medical College Hospital, Royapuram, Chennai - 600 001, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-9747.193288

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