Hepatitis B, C Virus Infection and Anti-Tuberculosis Drug- Related Hepatitis

B、C型肝炎病毒感染者與肺結核藥物治療時發生肝炎之關連

許雯雁(Wen-Yen Hsu)；江榮人(Jung-Rern Jiang)；顏效禹(Shiao-Yu Yen)

Drug-related hepatitis ； Hepatitis B ； Hepatitis C ； Tuberculosis ； 型肝炎 ； C型肝炎 ； 結核病 ； 藥物性肝炎

若瑟醫護雜誌

11卷1期（2017 / 04 / 01）

17 - 29

英文

Background and purpose: Owing to an aging population, high prevalence rates of tuberculosis, hepatitis B virus (HBV) and hepatitis C virus (HCV) and hereditary factors, the incidence of anti-tuberculosis drug-induced hepatitis (DIH) is high in Taiwan. We conducted this study to compare the incidence of DIH in patients with and without HBV/HCV. Clinical factors associated with DIH were also investigated. Methods: This is a retrospective cohort study. We recruited patients with a diagnosis of mycobacterium or tuberculosis and culture-confirmed pulmonary tuberculosis over a 10-year period at a single centre. The patients were divided into viral hepatitis and control groups, and the viral hepatitis group was further classified into HBV and HCV groups. Baseline data, imaging patterns, comorbidities, and drug adverse effects during the initial 2 months of tuberculosis treatment were analysed. Multinomial regression analysis was performed to investigate the risk factors for anti-tuberculosis DIH. Results: Of 394 included patients, 42 (10.7%) had viral hepatitis, including 17 with HBV, 20 with HCV, and five with HBV and HCV concurrently. The incidence rate of anti-tuberculosis DIH was significantly higher in the viral hepatitis group (p＜0.001), especially in the HCV group (p=0.014). The HBV group had higher incidence rates of optic neuropathy (p=0.001) and peripheral neuropathy (p=0.029). Multinomial regression analysis showed that HCV and HBV were independent predictors (OR=4.15, 95% CI=1.73-9.97) and borderline independent predictors (OR=3.31, 95% CI=1.28-8.54) of anti-tuberculosis DIH. Conclusion: HBV and HCV were risk factors for anti-tuberculosis DIH. Closely monitoring liver function and adjusting anti-tuberculosis therapy is mandatory during treatment.

背景及目的：台灣由於人口老化、病毒性肝炎盛行及遺傳因素，結核病治療藥物引起肝炎的發生率高，本研究目的主要是探討B 及C 型肝炎與治療結核病過程中發生肝功能異常的關連性。方法：採回溯性世代研究，收案時段為10 年，針對痰液培養確診為肺結核者，藉由瀏覽病歷資料與影像學檢查，分析B/C 肝組與對照組之臨床、影像學表現、慢性合併症之差異，比較使用抗結核藥物治療前兩個月內發生藥物副作用之差異，之後針對肝功能惡化部分，使用多變向迴歸分析探討影響發生肝功能異常之可能因素。結果：共394 位個案被分析，包含42 位（10.7%）有B 或C 型肝炎之肺結核患者，其中B 型肝炎患者有17 位，C 型肝炎患者有20 位，同時具有B 及C 肝炎患者有5 位。分析顯示B 或C 型肝炎之肺結核患者，發生肝功能惡化之機率明顯高於對照組，尤其是C 型肝炎與其關連性最大；而B 型肝炎帶原者有較高發生視神經病變及周邊神經病變之機率，多變向迴歸分析發現C 型肝炎達到顯著相關，B 型肝炎則位於顯著相關邊緣。結論： B 及C 型肝炎病毒感染為抗結核藥物引起肝功能惡化的獨立相關因子，此類患者於治療肺結核過程必須規則追蹤肝功能，必要時給予調整治療藥物。

1. Araújo-Mariz, C,Lopes, EP,Ximenes, RA,Lacerda, HR,Miranda-Filho, DB,Montarroyos, UR,Barreto, S,Salustiano, DM,Albuquerque, MF(2016).Serological markers of hepatitis B and C in patients with HIV/AIDS and active tuberculosis.J. Med. Virol,88,996-1002.
2. Baghaei, P,Tabarsi, P,Chitsaz, E,Saleh, M,Marjani, M,Shemirani, S,Pooramiri, MV,Kazempour, M,Farnia, P,Fahimi, F,Mansouri, D,Masjedi, M(2010).Incidence, clinical and epidemiological risk factors, and outcome of drug-induced hepatitis due to antituberculous agents in new tuberculosis cases.Am. J. Ther,17,17-22.
3. Camus, G,Herker, E,Modi, AA,Haas, JT,Ramage, HR,Farese, RV, Jr,Ott, M(2013).Diacylglycerol acyltransferase-1 localizes hepatitis C virus NS5A protein to lipid droplets and enhances NS5A interaction with the viral capsid core.J Biol Chem,288,9915-9923.
4. Centers for Disease Control, Ministry of Health and Welfare, R.O.C.(2015).Taiwan Guidelines for TB Diagnosis & Treatment 5E.
5. Centers for Disease Control, R.O.C. (Taiwan). Hepatitis B. Retrieved October 15, 2016, from http://www.cdc.gov.tw/professional/ThemaNet.aspx?treeid=beac9c103df952c4&nowtreeid=7296679902209942&did=656
6. Centers for Disease Control, R.O.C. (Taiwan). Hepatitis C. Retrieved October 15, 2016, from http://www.cdc.gov.tw/professional/themanet.aspx?did=657&treeid=AC81BE2A11A0FCEF&nowtreeid=AC81BE2A11A0FCEF
7. Chang, FY,Chou, JH,Chuang, JH,Chen, YH,Liu, DP,Chen, CH,Yang, SL,Huang, SY,Wang, JS(2014).Taiwan Tuberculosis Control Report 2013,3-4.
8. Kadka, J,Malla, P,Jha, SS,Poudel, SR(2009).The study of drug induced hepatotoxicity in ATT patients attending in national tuberculosis center in Bhaktapur.SAARC. J Tuberculosis Lung Dis. HIV/AIDS,6,17-21.
9. Kaneko, Y,Nagayama, N,Kawabe, Y,Shimada, M,Suzuki, J,Kunogi, M,Matsui, Y,Kawashima, M,Suzuki, J,Ariga, H,Oshima, N,Masuda, K,Matsui, H,Nagai, H,Tamura, A,Akagawa, S,Toyoda, E,Machida, K,Kurashima, A,Yotsumoto, H(2008).Drug-induced hepatotoxicity caused by antituberculosis drugs in tuberculosis patients complicated with chronic hepatitis.Kekkaku,83,13-19.
10. Lomtadze, N,Kupreishvili, L,Salakaia, A,Vashakidze, S,Sharvadze, L,Kempker, RR,Magee, MJ,del Rio, C,Blumberg, HM(2013).Hepatitis C virus co-infection increases the risk of antituberculosis drug-induced hepatotoxicity among patients with pulmonary tuberculosis.PLoS One,8(12),e83892.
11. McColl, KE,Thompson, GG,El Omar, E,Moore, MR,Park, BK,Brodie, MJ(1987).Effect of rifampicin on haem and bilirubin metabolism in man.Br J Clin Pharmacol,23,553-559.
12. Sharma, SK,Balamurugan, A,Saha, PK,Pandey, RM,Mehra, NK(2002).Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment.Am. J Respir Crit Care Med,166,916-919.
13. Wang, H,Liu, K,Fang, BA,Wu, H,Li, F,Xiang, X,Tang, W,Zhao, G,Lin, L,Bao, S,Xie, Q(2015).Identification of acetyltransferase genes (HAT1 and KAT8) regulating HBV replication by RNAi screening.Cell Biosci,5,66.
14. Wattanapokayakit, S,Mushiroda, T,Yanai, H,Wichukchinda, N,Chuchottawon, C,Nedsuwan, S,Rojanawiwat, A,Denjanta, S,Kantima, T,Wongyai, J,Suwankesawong, W,Rungapiromnan, W,Kidkeukarun, R,Bamrungram, W,Chaiwong, A,Suvichapanich, S,Mahasirimongkol, S,Tokunaga, K(2016).NAT2 slow acetylator associated with anti-tuberculosis drug-induced liver injury in Thai patients.Int J Tuberc Lung Dis,20,1364-1369.
15. Wu, PH,Lin, YT,Hsieh, KP,Chuang, HY,Sheu, CC(2015).Hepatitis C Virus Infection Is Associated With an Increased Risk of Active Tuberculosis Disease: A Nationwide Population-Based Study.Medicine,94,e1328.
16. Yang, KC,Huang, YS(2009).Anti-tuberculosis induced hepatic injury.Clinical Medicine,64,182-187.