第五章 結論與建議
5.2 建議
We emphasize that the present study found some important clinical effects. First, physicians shall not worry about a higher likelihood of DIH in their chronic viral hepatitis patients during anti-TB therapy whose baseline liver biochemistry tests are normal. Second, physicians should take the onset of liver function impairment and whether the patient had chronic hepatitis into consideration to decide whether the potential hepatotoxic drug should be stopped. In patients with chronic viral hepatitis developing abnormal liver function test during anti-TB therapy, continue anti-tuberculosis medication is a rational approach unless hepatitis symptoms occur. Because the chance of TLI is approximately twice of DIH regardless of the onset time of abnormal liver function test according to our observation. In patients without chronic hepatitis who experienced liver function, the onset time is an important factor for clinical decision. If liver function impairment occurred after 2 months, we suggested hepatotoxic agents shall be stopped instantly and rechallenge the drug separately to
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determine the culprit medication. Third, in patients with chronic hepatitis, we suggested follow up liver biochemistry test intensely even after 2 months of initializing anti-TB therapy owing to half of HCV patients developed DIH during this period.
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參考文獻
1.Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC:
Consensus statement. Global burden of tuberculosis: Estimated incidence, prevalence, and mortality by country. Who global surveillance and monitoring project. JAMA : the journal of the American Medical Association 1999;282:677-686.
2.Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, Fujiwara P, Grzemska M, Hopewell PC, Iseman MD, Jasmer RM, Koppaka V, Menzies RI, O'Brien RJ, Reves RR,
Reichman LB, Simone PM, Starke JR, Vernon AA: American
thoracic society/centers for disease control and prevention/infectious diseases society of America: Treatment of tuberculosis. American journal of respiratory and critical care medicine 2003;167:603-662.
3.Dossing M, Wilcke JT, Askgaard DS, Nybo B: Liver injury during antituberculosis treatment: An 11-year study. Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 1996;77:335-340.
29
4.Pande JN, Singh SP, Khilnani GC, Khilnani S, Tandon RK:
Risk factors for hepatotoxicity from antituberculosis drugs: A case-control study. Thorax 1996;51:132-136.
5.Schaberg T, Rebhan K, Lode H: Risk factors for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis. The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology 1996;9:2026-2030.
6.Amarapurkar DN, Prabhudesai PP, Kalro RH, Desai HG:
Antituberculosis drug-induced hepatitis and HBsAg carriers. Tubercle and lung disease : the official journal of the International Union
against Tuberculosis and Lung Disease 1993;74:215-216.
7.Hwang SJ, Wu JC, Lee CN, Yen FS, Lu CL, Lin TP, Lee SD:
A prospective clinical study of
isoniazid-rifampicin-pyrazinamide-induced liver injury in an area endemic for hepatitis B. Journal of gastroenterology and hepatology 1997;12:87-91.
8.Lee BH, Koh WJ, Choi MS, Suh GY, Chung MP, Kim H, Kwon
30
OJ: Inactive hepatitis B surface antigen carrier state and hepatotoxicity during antituberculosis chemotherapy. Chest 2005;127:1304-1311.
9.Wong WM, Wu PC, Yuen MF, Cheng CC, Yew WW, Wong PC, Tam CM, Leung CC, Lai CL: Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology
2000;31:201-206.
10.Wu JC, Lee SD, Yeh PF, Chan CY, Wang YJ, Huang YS, Tsai YT, Lee PY, Ting LP, Lo KJ: Isoniazid-rifampin-induced
hepatitis in hepatitis B carriers. Gastroenterology 1990;98:502-504.
11.Ungo JR, Jones D, Ashkin D, Hollender ES, Bernstein D, Albanese AP, Pitchenik AE: Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human
immunodeficiency virus. American journal of respiratory and critical care medicine 1998;157:1871-1876.
12.Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D: Incidence of serious side effects from first-line
antituberculosis drugs among patients treated for active tuberculosis.
31
American journal of respiratory and critical care medicine 2003;167:1472-1477.
13.Yew WW, Leung CC: Antituberculosis drugs and hepatotoxicity.
Respirology 2006;11:699-707.
14.Chemotherapy and management of tuberculosis in the United Kingdom: Recommendations 1998. Joint Tuberculosis Committee of the British Thoracic Society. Thorax 1998;53:536-548.
15.Turktas H, Unsal M, Tulek N, Oruc O: Hepatotoxicity of
antituberculosis therapy (rifampicin, isoniazid and pyrazinamide) or viral hepatitis. Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease
1994;75:58-60.
16.Tost JR, Vidal R, Cayla J, Diaz-Cabanela D, Jimenez A,
Broquetas JM: Severe hepatotoxicity due to anti-tuberculosis drugs in spain. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 2005;9:534-540.
17.Whittington RM: Fatal hepatotoxicity of anti-tubercular
32
chemotherapy. Lancet 1991;338:1083-1084.
18.Kumar R, Shalimar, Bhatia V, Khanal S, Sreenivas V, Gupta SD, Panda SK, Acharya SK. Antituberculosis therapy-induced acute liver failure: magnitude, profile, prognosis, and predictors of outcome.
Hepatology 2010;51:1665-1674.
19.Devarbhavi H, Dierkhising R, Kremers WK. Antituberculosis therapy drug-induced liver injury and acute liver failure. Hepatology 2010;52:798-799.
20.Devarbhavi H, Singh R, Patil M, Sheth K, Adarsh CK, Balarajuet G. Outcome and determinants of mortality in 269 patients with
combination anti-tuberculosis drug-induced liver injury. Journal of Gastroenterol Hepatol 2013;28 (1):161-7
21.Girling DJ: Adverse effects of antituberculosis drugs. Drugs 1982;23:56-74.
22.Sun HY, Chen YJ, Gau CS, Chang SC, Luh KT: A prospective study of hepatitis during antituberculous treatment in Taiwanese patients and a review of the literature. Journal of the Formosan Medical Association 2009;108:102-111.
33
23.Chien JY, Huang RM, Wang JY, Ruan SY, Chien YJ, Yu CJ, Yang PC: Hepatitis C virus infection increases hepatitis risk during anti-tuberculosis treatment. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 2010;14:616-621.
24.Wang JW, Liu CH, Hu FC, Chang HC, Liu JL, Chen JM, Yu CJ, Lee LN, Kao JH, Yang PC. Risk factors for hepatitis during
antituberculous treatment and implications of hepatitis viral load. J infection 2011;62:448-55
25.Senior JR. Monitoring for hepatotoxicity: what is the predictive value of liver "function" tests? Clin Pharmacol Therapeu
2009;85:331-334
26.Lee SD, Wang YJ, Lu RH, Chan CY, Lo KJ, Moeckli R:
Seroprevalence of antibody to hepatitis E virus among Chinese subjects in Taiwan. Hepatology 1994;19:866-870.
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Table 1. Baseline characteristics of patients with chronic viral hepatitis and cont subjects
Baseline bilirubin(mg/dL) Baseline creatinine
(mg/dL)
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Data are presented as mean ± standard error or n (%)
2P value: 1-way ANOVA.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; HBV, HBV = surface antigen positive and anti-HCV antibody negative; HCV = HBV surface antigen negative and HCV antibody positive; HBV + HCV = both HBV surface antigen positive and anti-HCV antibody positive; HER = isoniazid, ethambutol, and rifampicin; HERZ = isoniazid,
ethambutol, rifampicin, and pyrazinamide; HR, isoniazid and rifampicin; IU = International Unit; NS = not significant.
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1Data are presented as n (%)
2P value compared with the control group
DIH = drug-induced hepatotoxicity; HBV = HBV surface antigen positive and anti-HCV antibody negative; HBV + HCV = HBV surface antigen positive and anti-HCV antibody positive; HCV = HBV surface antigen negative and HCV antibody positive; LFI = liver function impairment; NS = not significant; TLI = transient liver function impairment.
Table 2. Incidences of hepatitis during anti-TB treatment in different patien
groups
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Table 3. The association between jaundice and the drug induced hepatotoxicity
Total
TLI and jaundice/
All TLI patients
DIH and jaundice/
All DIH patients
OR 95% CI P value
Control 392 3/9 16/32 5.5 1.6–19.1 0.004 Any hepat 161 2/20 8/11 4.7 1.0–22.1 0.061 All 553 5/29 25/43 5.2 2.0–13.7 <0.001
CI = confidence interval; DIH = drug-induced hepatitis; OR = odds ratio; TLI = transient liver function impairment.
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Table 4. Incidence of jaundice in different group of patients
NO Jaundice1
2P value compared with the control group
DIH = drug-induced hepatotoxicity; HBV = HBV surface antigen positive and anti-HCV antibody negative; HBV + HCV = HBV surface antigen positive and anti-HCV antibody positive; HCV = HBV surface antigen negative and HCV antibody positive; NS = not significant; TLI = transient liver function impairment.
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Table 5. The onset of liver function impairment
Control HBV HCV
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<4 months 32 (100) 5 (100) 5 (83) NS NS P value: 1HBV group compared with the control group; 2HCV group compared with the control group.
DIH = drug-induced hepatitis; NS = not significant; TLI = transient liver function impairment
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Table 6. Number of patients developed liver func impairment in different periods
<=2 month1 >2 month1 With chronic hepatitis
TLI 13(65) 7(64)
DIH 7(35) 4(36)
Without chronic hepatitis
TLI 9(24) 0(0)
DIH 29(76) 3(100)
1Data presented as No. (% of patients in definite period)
TLI = Transient liver function impairment; DIH = Drug induced hepatitis
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Table 7. Days of onset of DIH in different drugs
Control1 HBV1 HCV1
All
patients1
No Range
INH 40.7±30.4 42.7±67.0 49.0±51.2 46.5±40.7 13 3-120
RIF 46.5±30.6 24.0±29.7 70.8±41.5 47.7±32.9 23 3-128
PZA 35.8±30.8 35.8±30.8 14 3-115
1Data presented as mean ± standard error
No PZA related DIH is observed in HBV or HCV patients
INH = isoniazid; PZA = pyrazinamide; RIF = rifampicin
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Table 8. Significance of the effect of drugs on the onset of DIH
All patients Control HBV HCV
INH vs. RIF 0.925 0.961 0.745 0.56
INH vs. PZA 0.897 0.998
RIF vs. PZA 0.968 0.949
No PZA related DIH is observed in HBV or HCV patients
INH = isoniazid; PZA = pyrazinamide; RIF = rifampicin