OJGas  Vol.5 No.12 , December 2015
Antituberculosis Drug-Induced Liver Injury: An Ignored Fact, Assessment of Frequency, Patterns, Severity and Risk Factors
ABSTRACT
Background/Aims: Antituberculosis drug-induced liver injury (TB DILI) is a frequent medical problem in Pakistan. Critical understanding of various aspects of TB DILI is not only important to manage liver injury but may also prevent unnecessary discontinuation of antituberculosis treatment. The study is aimed to determine the frequency, types, severity and patterns of TB DILI. Study further evaluates various risk factors of TB DILI. Materials and Methods: This is a prospective cohort study of two seventy-eight patients with the diagnosis of tuberculosis, where patients were followed during tuberculosis treatment. TB DILI was defined in accordance to international DILI expert working group. Results: Out of two seventy eight-patients, ninety-five (34.14%) had TB DILI. The most common pattern of TB DILI was hepatocellular (63.15%) followed by mixed (23.15%) and Cholestatic (13.68%). Most of the patients had mild DILI (43.15%) followed by moderate (30.52%), severe (20.01%) and very severe (5.26%). Age > 35 years, concomitant hepatotoxic drugs, extrapulmonary TB and malnutrition are important risk factors for TB DILI. Conclusion: All patterns of TB DILI with varying severity were present. Age > 35 years, malnutrition, extrapulmonary TB and concomitant use of hepatotoxic drugs were risk factors for TB DILI.

Cite this paper
Naqvi, I. , Mahmood, K. , Talib, A. and Mahmood, A. (2015) Antituberculosis Drug-Induced Liver Injury: An Ignored Fact, Assessment of Frequency, Patterns, Severity and Risk Factors. Open Journal of Gastroenterology, 5, 173-184. doi: 10.4236/ojgas.2015.512027.
References
[1]   World Health Organization (2010) Global Tuberculosis Control: WHO Report 2010. WHO Press, Geneva, 5 p.

[2]   World Health Organization (2012) Global Tuberculosis Control: WHO Report 2012.
http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf

[3]   Corbett, E.L., Watt, C.J., Walker, N., et al. (2003) The Growing Burden of Tuberculosis: Global Trends and Interactions with the HIV Epidemic. Archives of Internal Medicine, 163, 1009-1021.
http://dx.doi.org/10.1001/archinte.163.9.1009

[4]   Huang, Y.-S., Chern, H.-D., Su, W.-J., et al. (2002) Polymorphism of the N-Acetyltransferase 2 Gene as a Susceptibility Risk Factor for Antituberculosis Drug-Induced Hepatitis. Hepatology, 35, 883-889.
http://dx.doi.org/10.1053/jhep.2002.32102

[5]   Sharma, S.K., Balamurugan, A., Saha, P.K., Pandey, R.M. and Mehra, M.K. (2002) Evaluation of Clinical and Immunogenetic Risk Factors for the Development of Hepatotoxicity during Antituberculosis Treatment. American Journal of Respiratory and Critical Care Medicine, 166, 916-919.
http://dx.doi.org/10.1164/rccm.2108091

[6]   Marrary, W.C. (2012) Alcohol and Drug Induced Liver Injury. In: Shiff, E.R., Maddrey, W.C., Sorell, M.F., Eds., Schiff’s Diseases of Liver, John Wiley & Sons Ltd., 653-784.

[7]   Saukkonen, J.J., Cohn, D.L., Jasmer, R.M., et al. (2006) An Official ATS Statement: Hepatotoxicity of Antituberculosis Therapy. American Journal of Respiratory and Critical Care Medicine, 174, 935-952.
http://dx.doi.org/10.1164/rccm.200510-1666ST

[8]   Tostmann, A., Boeree, M.J., Aarnoutse, R.E., de Lange, W.C., van der Ven, A.J. and Dekhuijzen, R. (2008) Antituberculosis Drug-Induced Hepatotoxicity: Concise Up-to-Date Review. Journal of Gastroenterology, 23, 192-202.
http://dx.doi.org/10.1111/j.1440-1746.2007.05207.x

[9]   Baghaei, P., Tabarsi, P., Chitsaz, E., Saleh, M., et al. (2010) Incidence, Clinical and Epidemiological Risk Factors, and Outcome of Drug-Induced Hepatitis Due to Antituberculous Agents in New Tuberculosis Cases. American Journal of Therapeutics, 17, 17-22.
http://dx.doi.org/10.1097/MJT.0b013e31818f9eae

[10]   Chitturi, S. and Farrell, G. (2002) Drug-Induced Liver Disease. In: Schiff, E.R., Sorrell, M.F., Maddrey, W.C., Eds., Schiff’s Diseases of the Liver, Lippincott, Williams &Wilkins, 1059-1128.

[11]   Larrey, D. (2002) Epidemiology and Individual Susceptibility to Adverse Drug Reactions Affecting the Liver. Seminars in Liver Disease, 22, 145-155.
http://dx.doi.org/10.1055/s-2002-30101

[12]   Senousy, B.E., Belal, S.I. and Draganov, P.V. (2010) Hepatotoxic Effects of Therapies for Tuberculosis. Nature Reviews Gastroenterology & Hepatology, 7, 543-556.
http://dx.doi.org/10.1038/nrgastro.2010.134

[13]   Kumar, R., Shalimar, B.V., Khanal, S., Sreenivas, V., Gupta, S.D., et al. (2010) Antituberculosis Therapy-Induced Acute Liver Failure: Magnitude, Profile, Prognosis, and Predictors of Outcome. Hepatology, 51, 1665-1674.
http://dx.doi.org/10.1002/hep.23534

[14]   Kaona, F.A., Tuba, M., Siziya, S. and Sikaona, L. (2004) An Assessment of Factors Contributing to Treatment Adherence and Knowledge of TB Transmission among Patients on TB Treatment. BMC Public Health, 4, 68.
http://dx.doi.org/10.1186/1471-2458-4-68

[15]   Hussain, Z., Kar, P. and Hussain, S.A. (2003) Antituberculosis Drug-Induced Hepatitis: Risk Factors, Prevention and Management. Indian Journal of Experimental Biology, 41, 1226-1232.

[16]   Breen, R.A., Miller, R.F., Gorsuch, T., et al. (2006) Adverse Events and Treatment Interruption in Tuberculosis Patients with and without HIV Co-Infection. Thorax, 61, 791-794.

[17]   National Guidelines for Control of Tuberculosis in Pakistan, January 2015.
http://ntp.gov.pk/uploads/NATIONAL_GUIDELINE_ON_TB_CASE_MANAGEMENT_REV_JAN_2015.pdf

[18]   Aithal, G.P., Watkins, P.B., Andrade, R.J., et al. (2011) Case Definition and Phenotype Standardization in Drug- Induced Liver Injury. Clinical Pharmacology & Therapeutics, 89, 806-815.
http://dx.doi.org/10.1038/clpt.2011.58

[19]   Detsky, A.S., McLaughlin, J.R., Baker, J.P., et al. (1987) What Is Subjective Global Assessment of Nutritional Status? Journal of Parenteral and Enteral Nutrition, 11, 8-13.
http://dx.doi.org/10.1177/014860718701100108

[20]   Mahmood, K., Hussain, A., Jairamani, K.L. and Talib, A. (2007) Hepatotoxicity with Antituberculosis Drugs: The Risk Factors. Pakistan Journal of Medical Sciences, 23, 33-38.

[21]   Hno, M., Yamaguchi, I., Yamamoto, I., et al. (2000) Slow N-Acetyltransferase 2 Genotype Affects the Incidence of INH and RMP-Induced Hepatotoxicity. International Journal of Tuberculosis and Lung Disease, 4, 256-261.

[22]   Khalili, H., Dashti-Khavidaki, S., Rasoolinejad, M., et al. (2009) Anti-Tuberculosis Drugs Related Hepatotoxicity; Incidence, Risk Factors, Pattern of Changes in Liver Enzymes and Outcome. DARU, 17, 163-167.

[23]   Steele, M.A., Burk, R.F. and Des Prez, R.M. (1991) Hepatitis with INH and RMP: A Meta-Analysis. Chest, 99, 465- 471.
http://dx.doi.org/10.1378/chest.99.2.465

[24]   Makhlouf, H.A., Helmy, A., Fawzy, E., El-Attar, M. and Rashed, H.A. (2008) A Prospective Study of Antituberculous Drug-Induced Hepatotoxicity in an Area Endemic for Liver Diseases. Hepatology International, 2, 353-360.
http://dx.doi.org/10.1007/s12072-008-9085-y

[25]   Shang, P., Xia, Y., Liu, F., Wang, X., et al. (2011) Incidence, Clinical Features and Impact on Anti-Tuberculosis Treatment of Anti-Tuberculosis Drug Induced Liver Injury (ATLI) in China. PLoS ONE, 6, e21836.
http://dx.doi.org/10.1371/journal.pone.0021836

[26]   Shaikh, M.A., Yakta, D.E. and Shaikh, D. (2012) Frequency of Hepatotoxicity during Anti-Tuberculous Treatment at Medical Unit of Lumhs Sindh. Medical Channel, 18, 20-23.

[27]   Wagan, M.A., Shah, S., Khokar, G.N. and Memon, A.R. (2008) A Study on Hepatic Dysfunction during Dots Therapy for Pulmonary Tuberculosis. Pakistan Journal of Pharmacology, 25, 7-12.

[28]   Sharma, S.K., Singala, R., Sadra, P., et al. (2010) Safety of 3 Different Reintroduction Regimens of Antituberculosis Drugs after Development of Antituberculosis Treatment-Induced Hepatotoxicity. Clinical Infectious Diseases, 50, 833-839.
http://dx.doi.org/10.1086/650576

[29]   Tahaoelu, K., Atao, G., Sevim, T., et al. (2001) The Management of Anti-Tuberculosis Drug-Induced Hepatotoxicity. International Journal of Tuberculosis and Lung Disease, 5, 65-69.

[30]   Saukkonen, J. (2010) Challenges in Reintroducing Tuberculosis Medications after Hepatotoxicity. Clinical Infectious Diseases, 50, 840-842.
http://dx.doi.org/10.1086/650577

[31]   Singla, R., Sharma, S.K., Mohan, A., et al. (2010) Evaluation of Risk Factors for Antituberculosis Treatment Induced Hepatotoxicity. Indian Journal of Medical Research, 132, 81-86.

[32]   Smith, C.A., Wadelius, M., Gough, A.C., Harrison, D.J., Wolf, C.R. and Rane, A. (1997) A Simplified Assay for the Arylamine N-Acetyltransferase 2 Polymorphism Validated by Phenotyping with Isoniazid. Journal of Medical Genetics, 34, 758-760.
http://dx.doi.org/10.1136/jmg.34.9.758

[33]   Dufour, D.R., Lott, J.A., Nolte, F.S., Gretch, D.R., Koff, R.S. and Seeff, L.B. (2000) Diagnosis and Monitoring of Hepatic Injury: I. Performance Characteristics of Laboratory Tests. Clinical Chemistry, 46, 2027-2049.

[34]   Steele, M.A., Burk, R.F. and Des Prez, R.M. (1991) Toxic Hepatitis with Isoniazid and Rifampin. A Meta-Analysis. Chest, 99, 465-471.
http://dx.doi.org/10.1378/chest.99.2.465

[35]   Shakya, R., Rao, B.S. and Shrestha, B. (2004) Evaluation of Risk Factors for Anti-Tuberculosis Drug Induced Hepatotoxicity in Nepalese Population. Annals of Pharmacotherapy, 38, 1074-1079.
http://dx.doi.org/10.1345/aph.1D525

[36]   Younossian, A.B., Rochat, T., Ketterer, J.P., Wacker, J. and Janssens, J.P. (2005) High Hepatotoxicity of Pyrazinamide and Ethambutol for Treatment of Latent Tuberculosis. European Respiratory Journal, 26, 462-464.
http://dx.doi.org/10.1183/09031936.05.00006205

[37]   Papastavros, T., Dolovich, L.R., Holbrook, A., Whitehead, L. and Loeb, M. (2002) Adverse Events Associated with Pyrazinamide and Levofloxacin in the Treatment of Latent Multidrug-Resistant Tuberculosis. Canadian Medical Association Journal, 167, 131-136.

[38]   Devarbhavi, H., Dierkhising, R. and Kremers, W.K. (2010) Antituberculosis Therapy Drug-Induced Liver Injury and Acute Liver Failure. Hepatology, 52, 798-799.
http://dx.doi.org/10.1002/hep.23805

[39]   Devarbhavi, H., Dierkhising, R., Kremers, W.K., Sandeep, M.S., Karanth, D. and Adarsh, C.K. (2010) Single-Center Experience with Drug-Induced Liver Injury from India: Causes, Outcome, Prognosis, and Predictors of Mortality. American Journal of Gastroenterology, 105, Article ID: 2396404.
http://dx.doi.org/10.1038/ajg.2010.287

[40]   Fountain, F.F., Tolley, E., Chrisman, C.R. and Self, T.H. (2005) Isoniazid Hepatotoxicity Associated with Treatment of Latent Tuberculosis Infection: A 7-Year Evaluation from a Public Health Tuberculosis Clinic. Chest, 128, 116-123.
http://dx.doi.org/10.1378/chest.128.1.116

[41]   Srivastava, R.K., Sharma, S., Verma, S., Arora, B. and Lal, H. (2008) Influence of Diabetes on Liver Injury Induced by Antitubercular Drugs and on Silymarin Hepatoprotection in Rats. Methods and Findings in Experimental and Clinical Pharmacology, 30, 731-737.
http://dx.doi.org/10.1358/mf.2008.30.10.1316824

[42]   De Leve, L. and Kaplowitz, N. (2000) Prevention and Therapy of Drug-Induced Hepatic Injury. In: Wolfe, M., Ed., Therapy of Digestive Disorders, WB Saunders, Philadelphia, 334-348.

[43]   Zimmerman, H. (1999) Drug-Induced Liver Disease. In: Schiff, E., Sorell, M. and Madding, W., Eds., Schiff’s Diseases of the Liver, Lippincott-Raven Publishers, Philadelphia, 973-1064.

[44]   Makhija, S. and Baker, J. (2008) The Subjective Global Assessment: A Review of Its Use in Clinical Practice. Nutrition in Clinical Practice, 23, 405-409.
http://dx.doi.org/10.1177/0884533608321214

[45]   Warmelink, I., ten Hacken, N.H., van der Werf, T.S. and van Altena, R. (2011) Weight Loss during Tuberculosis Treatment Is an Important Risk Factor for Drug-Induced Hepatotoxicity. British Journal of Nutrition, 105, 400-408.
http://dx.doi.org/10.1017/S0007114510003636

[46]   Yew, W.W. and Leung, C.C. (2006) Anti-Tuberculosis Drugs and Hepatotoxicity. Respirology, 11, 699-707.
http://dx.doi.org/10.1111/j.1440-1843.2006.00941.x

[47]   Marzuki, O.A., Fauzi, A.R.M., Ayoubm, S. and Kamarul Imran, M. (2008) Prevalence and Risk Factors of Antituberculosis Drug-Induced Hepatitis in Malaysia. Singapore Medical Journal, 49, 688-693.

[48]   Ambreen, K., Sharma, R., Singh, K.P., Khan, F.H. and Kumar, S. (2012) Risk Factors for Antituberculosis Drug-Induced Hepatotoxicity and Its Association with Oxidative Stress in North Indian Population. Annals of Tropical Medicine and Public Health, 5, 574-580.
http://dx.doi.org/10.4103/1755-6783.109278

 
 
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