| Abstract|| |
Alanine transaminase (ALT) levels have been routinely used in assessment of patients with chronic HBV infection for making the treatment decisions. ALT is traditionally considered to be marker of hepatocellular injury. Various studies using interferon, peg interferon, Lamivudine, Adefovir have shown the importance of elevated ALT levels in predicting the response rate to therapy. Various guidelines have recommended treating the patients of chronic hepatitis B with elevated transaminases and suggested that patients with normal ALT should not be treated. This approach needs a reappraisal. Information available to us in last decade compels to us reevaluate importance of ALT in management of chronic hepatitis B infection. With the help of available information it is reasonable to conclude that the ALT levels have poor predictability for progression of liver disease and planning treatment in patients with CHB. To conclude, patients with CHB infection with normal ALT should be considered for treatment based on the HBV DNA levels assessed by sensitive real time PCR and histological activity. Patients age and family history of liver cancer are two important parameters in considering aggressive approach in these patients.
|How to cite this article:|
Amarapurkar D. Management of hepatitis B viral infection with normal ALT. Hep B Annual 2006;3:155-64
Around 2 billion people are infected by hepatitis B virus (HBV) worldwide of which 360 million persons suffer chronic infection with HBV. Raised ALT is found in 38% where as 62% have normal ALT. Although most of carriers will not develop hepatic complications from chronic hepatitis B, 15-40% will develop serious complications during lifetime like cirrhosis, decompensated liver disease or HCC. Around 5, 20, 000 deaths/year are due to HBV - 50,000 from acute hepatitis B and 4,70,000 from cirrhosis or HCC. 0.3 to 1 million cases of HCC occur annually throughout the world.
| Natural history of hepatitis B|| |
Infections acquired perinataly or in early childhood are usually asymptomatic. Approximately 30% of infection amongst adults presents as icteric hepatitis of which 0.1-0.5% result in FHF and > 95% resolve. Risk of developing chronic HBV infection after acute exposure is dependant on age of the patient and ranges from 90% in newborns of HBeAg Positive mothers to 25%-30% in infants and children < than 5 years to < 10% in adults.,, Such risk is more in immunocompromized persons. In HIV infected adults risk of chronicity increase up to 20% than in HIV negative subjects (6%). Most commonly if HBsAg persists for more than six months it is considered a chronic infection, but some individuals may take up to one year to clear HBsAg after acute HBV infection.
Chronic Hepatitis B infection evolves in four different phases [Table - 1]
1. Immune tolerant, 2. Immune clearance, 3. Residual- nonreplicative, 4. Reactivation
- Immune tolerant phase- HBsAg and HBeAg are detectable, HBVDNA levels are high, but aminotransferase are normal or minimally elevated and mostly asymptomatic. It is during the replication of virus that the liver suffers injury; usually it lasts for 20-30 years with very low spontaneous HBsAg clearance rate of 2-3% per year and annual risk for HCC 0.5%.,
- Immune clearance phase- during second or third decades of chronic infection, HBVDNA levels decrease and aminotransferase levels increase, patient becomes symptomatic and experiences flares of aminotransferase. In some, this is followed by HBeAg seroconversion and very low HBVDNA levels that are suppressed by host immune reasonably, this evolve as inactive carriers or may lead to resolution of HBV infection with spontaneous HBeAg clearance rate up to 10-20% per year. In some (1-5%), seroconversion is accompanied by selection of HBV mutants and results in HBeAg negative hepatitis B.,
- Residual phase- inactive carrier stage with HBeAg negativity, antiHBe positivity, undetectable HBVDNA and normal ALT. Histology depends on duration of disease prior to seroconversion.
- Reactivation: In some, liver disease may relapse after period of inactivity.
Differential progression rate with HBV infection may be related to various clinical serological and histological markers.,,,, Recognized risk factors for progression are presence of hepatitis B e-antigen, advanced stage, increased alanine transaminase levels (ALT), co-infection with other hepatitis viruses and diabetes mellitus. Hence ALT levels have been routinely used in assessment of patients with chronic HBV infection and making the treatment decisions.
ALT is traditionally considered to be a marker of hepatocellular injury. Various studies using interferon, peg interferon, Lamivudine, Adefovir have shown the importance of elevated ALT levels in predicting the response rate to therapy. Various guidelines have recommended treating the patients of chronic hepatitis B with elevated transaminases and suggested that patients with normal ALT should not be treated., Does this approach need a change. The answer is emphatic yes. Information available to us in the last decade forces us to reevaluate importance of ALT in management of chronic hepatitis B infection.
In a prospective cohort study - Kim et al. demonstrated that ALT values above 20 Iu/L are associated with increased risk of death from liver disease. In addition, recent data suggest ALT values may be related to body mass index (BMI), gender, abnormal lipids, carbohydrate metabolism and patients receiving haemodialysis. Currently recommended upper limit of normal ALT values are 30 Iu/L for men and 19 Iu/L for women. These values are almost half of the values traditionally accepted values of the upper limit of normal ALT.
ALT patterns in chronic HBV infection
ALT levels are normal in patients with immune tolerant phase of HBV infection. Immune tolerant patients have high viral load. Patients with e-antigen negative chronic HBV infection have fluctuating ALT levels and one point estimation of ALT may not be reliable. Elevated ALT was considered to be associated with active liver disease on histology while normal ALT was considered to be associated with inactive histology. Current findings suggest that patients with normal ALT may be associated with significant fibrosis in 12-43% patients especially in patients with a negative chronic HBV infection ALT elevation in chronic hepatitis B patients may occur spontaneous or drug induced seroconverions or due to superadded insult with other viruses or drug.
With the help of the above mentioned information, it is reasonable to conclude that the ALT levels have poor predictability for progression of liver disease and planning treatment in patients with CHB.
Majority of the studies predicting the liver disease in patients with CHB infection came from tertiary reference centers. Many of the studies demonstrated association between chronic viral replication and liver injury, disease complications in patients with CHB., Serum HBV DNA levels have been shown to co-relate directly with the histological grading and staging of the disease and response to antiviral therapy reduces progression of fibrosis. Iloeje et al. in a population-based prospective cohort study demonstrated that HBV viral load was the strongest predictor of progression to cirrhosis with relative risk of (95% confidence interval) 2.5 (1.6-3.8) for HBVDNA levels ≥ 10 4 - < 10 5 , 5.6 (3.7-8.5) for HBVDNA levels ≥ 10 5 - < 10 6 and 6.5 (4.1-10.2) for HBVDNA levels >10 6 . The risk of progression to cirrhosis was independent of ALT values and e-antigen status.
In prospective cohort study Chen et al. demonstrated relation between the development of hepatocellular carcinoma (HCC) and base line HBVDNA levels. Patients with high DNA levels had a increased chance of developing HCC. Patients with HBV DNA levels lower than 10 5 copies/ml have been traditionally not offered treatment but in both the studies by Chen and Iloeje, patients with DNA levels < 10 5 copies/ml have been shown to have high risk of progression to cirrhosis and HCC.,
With the availability of highly sensitive real time PCR serum HBV DNA assays has become most useful measurement of assessing the disease severity and follow-up of evaluation of patients with CHB. A systemic review of 26 prospective studies done by Mommeja Marin et al. have shown that significant co-relation between viral load or viral-load change and various markers of disease activity like histological grading, ALT and serological response. Currently exact levels of HBV DNA cut off limits for deciding the treatment are not available. Still for optimal management of CHB requires the use of sensitive real time PCR assays. Therapeutic goals in the management of CHB are 1) to prevent cirrhosis, 2) liver failure 3) HCC 4) improve survival as CHB related disease progression has been shown to be associated with viral load, it is logical to consider prolong suppression of HBV will lead to achieving these goals. Effective antiviral treatment with Lamivudine has shown that in patients who have suppressed viral replication have decreased chance of cirrhosis and HCC. Real concern on antiviral therapy lies in patients who develop resistance to antiviral drug.
Strategies to reduce antiviral resistance are: 1) use highly potent antiviral agents 2) use combination and antiviral agents. Rational use of antivirals comes from the clinical trials which suggests that if viral suppression to the level of less than 300 Iu/ml is achieved at the end of six months treatment. Chance of development of drug resistance is low and efficacy of sustained response is high.,
Sustained viral inhibition can modify the natural history of CHB and prevent disease progression. Maximal early viral suppression is associated with improved treatment outcomes. Early viral suppression may be a useful tool to tailor individual therapy and can be explored as a predictor for treatment efficacy. Emerging potent antiviral therapies provide the prospect for more effective treatment response and individualized treatment algorithms.
All patients with CHB should be evaluated for HBV DNA levels, real time PCR, ALT levels, e-antigen status and if possible liver biopsy and genotype of HBV. Recommendations for treatment of HBe positive patients: Patients with HBV DNA levels < 20,000 Iu/ml and normal ALT should not receive treatment but should be monitored carefully depending on the patient's age and family history of liver cancer. If liver histology showing significant disease progression more than stage II, these patients can be treated with antiviral therapy in spite of low viral load and normal ALT. Patients with viral load more than 20,000 Iu/ml with normal ALT the treatment decisions should be based on age of the patient and histological disease state. Chances of successful treatment and having e-seroconversion are low. Younger patients who are immune tolerant and near normal histology one can observe these patients carefully. If a patient is beyond the age of 35 it is important to have histological evaluation and the patient should be treated if histological activity is significant. Patients who have HBV DNA more than 20,000 Iu/ml and elevated ALT should be treated.
In patients with HBe negative disease HBV DNA levels are less than 2,000 Iu/ml and have normal ALT, no treatment is required and they need a regular follow- up. Only in patients with established cirrhosis, therapy should be considered. Patients with HBV DNA more than 2,000 Iu/ml and normal ALT should be considered for liver biopsy and treatment decisions should be made on histological findings. Patients HBV DNA more 2,000 Iu/ml and elevated liver enzymes should be considered for antiviral treatment. Patients with decompensated liver disease irrespective of e-antigen status and DNA levels more 200 Iu/ml irrespective of ALT status.
In summary, patients with CHB infection with normal ALT should be considered for treatment based on the HBV DNA levels assessed by sensitive real time PCR and histological activity. Patient's age and family history of liver cancer are two important parameters in considering aggressive approach in these patients.
| References|| |
|1.||EASL jury. EASL International Consensus Conference on Hepatitis B. 13-14 September, 2002: Geneva, Switzerland. Consensus statement (short version). J Hepatol 2003;38:533-40. |
|2.||McMahon BJ. Hepatocellular carcinoma and viral hepatitis. In : Wilson RA, editor. Viral Hepatitis. Marcel Dekker: New York; 1997. p. 315-30. |
|3.||Lok AF, Mc Mahon BJ; Practice Guidelines Committee, American Association for the Study of Liver Diseases. Chronic hepatitis B. Hepatology 2001;34:1225-41. |
|4.||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. [PUBMED] |
|5.||McMahon BJ, Alward WL, Hall DB, Heyward WL, Bender TR, Francis DP, et al . Acute hepatitis B viraus infection: Relation of age to the clinical expression of disease and subsequent development of the carrier state. J Infect Dis 1985;151:599-603. [PUBMED] |
|6.||Liaw YF, Leung N, Guan R, Lau GK, Merican I, McCaughan G, et al . Asian Pacific Consensus Statement on the management of chronic hepatitis B a 2005 update. Liver Int 2005;25:472-89. [PUBMED] [FULLTEXT]|
|7.||Sarin SK, Singal AK. Hepatitis B in India: Therapeutic options and prevention strategies-consensus statements-INASl. Indian J Gastroenterol 2000;19:C54-66. |
|8.||Chang MH. Natural history of hepatitis B virus infection in children. J Gastroenterol Hepatol 2000;15:E16-9. [PUBMED] |
|9.||Fattovich G, Brollo L, Giustina G, Noventa F, Pontisso P, Alberti A, et al . Natural History and prognostic factors for chronic hepatitis type B. Gut 1991;32:294-8. [PUBMED] |
|10.||Huo T, Wu JC, Hwang SJ, Lai CR, Lee PC, Tsay SH, et al . Factors predictive of liver cirrhosis in patients with chronic hepatitis B: A multivariate analysis in a longitudinal study. Eur J Gastroenterol Hepatol 2000;12:687-93. [PUBMED] |
|11.||Tamura I, Kurimura O, Koda T, Ichimura H, Katayama S, Kurimura T, et al . Risk of liver cirrhosis and hepatocellular carcinoma in subjects with hepatitis B and delta virus infection: a study from Kure, Japan. J Gastroenterol Hepatol 1993;8:433-6. [PUBMED] |
|12.||Realdi G, Fattovich G, Hadziyannis S, Schalm SW, Almasio P, Sanchez-Tapias J, et al . Survival and prognostic factors in 366 patients with compensated cirrhosis type B: A multicenter study. The Investigators of the European Concerted Action on Viral Hepatitis (EUROHEP). J Hepatol 1994;21:656-66. |
|13.||Fattovich G, Pantalena M, Zgni I, Realdi G, Schalm SW. Christensen E, et al . Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: A cohort study of 297 patients. Am J Gastroenterol 2002;97:2886-95. |
|14.||Perrillo RP, Wright T, Rakela J, Levy G, Schiff E, Gish R, et al . A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology 2001;33:424-32. [PUBMED] [FULLTEXT]|
|15.||Keeffe EB, Dieterich DT, Han SH, Jacobson RM, Martin P, Schiff ER, et al . A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an Update. Clin Gastroenterol Hepatol 2006;4:936-62. |
|16.||Lok AS, McMahon BJ Chronic Hepatitis B: Update of recommendations. Hepatology 2004:39:857-61. |
|17.||Kim HC Nam CN, Jee SH, Han KH, Oh DK, Suh I. Normal serum aminotransferase concentration and risk of mortality from liver disease: Prospective cohort study. BMJ 2004;328:983. |
|18.||Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del Vecchio E, et al . Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002;137:1-10. [PUBMED] [FULLTEXT]|
|19.||Perrilo RP. Acute flares in chronic hepatitis B: The natural and unnatural history of an immunologically mediated liver disease. Gastroenterology 2001;120:1009-22. |
|20.||Perrillo R. Hepatitis B Virus replication x time equals trouble. Gastroenterology 2006;130:989-91. [PUBMED] [FULLTEXT]|
|21.||Yuen MF, Ng IO, Fan ST, Yuan HJ, Wong DK, Yuen JC, et al . Significance of HBV DNA levels in liver histology of HBeAg and anti-HBe positive patients with chronic hepatitis B. Am J Gastroenterol 2004;99:2032-7. [PUBMED] [FULLTEXT]|
|22.||Mommeja-Marin H, Mondou E, Blum MR, Rousseau F. Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: Analysis and review of the literature. Hepatology 2003;37:1309-19. [PUBMED] [FULLTEXT]|
|23.||Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ, et al . The risk evaluation of viral load elevation and associated liver disease/cancer. Gastroenteroly 2006;130:678-86. |
|24.||Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al . Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295:65-73. [PUBMED] [FULLTEXT]|
|25.||Liaw YF, Sung JJ, Chow WC, Farell G, Lee CZ, Yuen H, et al . Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:1521-31. |
|26.||Gauthier J, Bourne EJ, Lutz MW, Crowther LM, Dienstag JL, Brown NA, et al . Quantitation of hepatitis B viremia and emergence of YMDD variants in patients with chronic hepatitis B treated with lamivudine. J Infect Dis 1999;180:1757-62. [PUBMED] [FULLTEXT]|
|27.||Yuen MF, Sablon E, Hui CK, Yuan HJ, Decraemer H, Lai CL. Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy. Hepatology 2001;34:785-91. [PUBMED] [FULLTEXT]|
|28.||Maynard JE. Hepatitis B: Global importance and need for control. Vaccine 1990;8:S18-20. [PUBMED] |
|29.||Beasley RP, Hwang LY, Lin CC, Leu ML, Stevens CE, Szmuness W, et al . Incidence of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 1983;1:1099-102. |
|30.||Torresi J, Lokarnini S. Antiviral chemotherapy for the treatment of hepatitis B virus infections. Gastroenterology 2000:118:S83-103. |
|31.||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. |
|32.||Hadziyannis SJ, Tassopoulas NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al . Adefovir dipivoxil for the treatment of hepatitis B e-antigen negative chronic hepatitis B. N Engl J Med 2003;348:800-7. |
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[Figure - 1]
[Table - 1]