臺灣博碩士論文加值系統

結核病的治療需同時使用數種抗結核藥物，且必須持續使用數個月。常用的抗結核藥物皆具有不同程度的肝毒性，而病人使用抗結核藥物之後，肝功能指數監測的必要性及肝毒性的處理方式，尚無統一的標準。據報導，結核病的盛行率在近幾年又有再次爬升的現象，因此，在目前愛滋病毒蔓延及慢性肝炎盛行的情況下，本研究主要在探討台灣抗結核藥物所致肝毒性之現況。
本研究為一回溯性分析研究，研究對象為於民國87年間經台大醫院處方抗結核藥物，且可判讀用藥後肝功能指數變化情形的門診及住院結核病病人。藉由病歷記載資料的記錄與整理，判讀肝毒性發生的種類、分析其發生率及可能的危險因子；並調查醫師對抗結核藥物使用初期的監測及發生肝毒性時的處理方式。
本研究共收入348位病人作肝毒性發生率的資料分析，結果發現有207位病人（59.5%）使用抗結核藥物後發生肝毒性，以嚴重度區分，則肝功能指數異常之發生率為25.0%，肝損傷之發生率為34.5%。若將肝損傷依肝功能指數變化種類細分，則肝細胞型肝損傷之發生率為19.0%，膽汁鬱滯型及混合型肝損傷之發生率均為7.2%，另有4人之肝損傷現象無法作細分類。
本研究發現感染愛滋病毒與C型肝炎病毒為影響肝毒性發生的主要危險因子，且其導致肝損傷發生的風險更高。另外，有每日喝酒習慣的病人亦為肝損傷發生的危險因子。而年齡、性別、使用pyrazinamide等因子，可能受樣本數年齡分佈或其他因子之干擾，並未發現是影響肝毒性發生的危險因子。
在肝毒性發現時間的分析方面，排除發現時間超過270天的3位病人，發生肝功能指數異常或肝損傷的病人的肝毒性平均發現日數，並沒有顯著差異，約為43天左右。在可判讀導致肝毒性的可疑藥品的案例中，可疑的抗結核藥品，以單獨使用pyrazinamide所佔比例最高（32.8%）。發生肝毒性的病人中，醫師未處理且持續用藥的病人佔57%。於可觀察到停藥後肝功能變化情形的病人群中，發現大部分的病人（96.6%）於停藥後肝功能指數均漸漸恢復。停藥後，再重新投與並依次加回抗結核藥物的模式中，以首先加回isoniazid，然後加回rifampin的方式最多（48.4%）。雖然，本研究無法歸納出醫師於肝毒性發生後，處理模式的依據原因，但仍可觀察到大部分醫師，可能由於結核病治療的需要，通常於病人發生較嚴重肝毒性時才會採取停藥的處置。
在所收入研究的病人群中，有218位病人（62.6%）曾監測肝功能指數基礎值，其中有98人的肝功能基礎值不正常。肝功能基礎值不正常的病人或正常的病人，皆有65%的病人發生肝毒性，但用藥前肝功能不正常的病人有較高機會發生較嚴重的肝毒性（即肝損傷，46.9%）。可知用藥前、後監測病人肝功能是有其必要性的。有2.7%病人的醫師在觀察到病人有不正常肝功能指數基礎值時，仍未對病人作用藥後肝功能的監測，可知醫師對於使用抗結核藥物監測肝功能的必要性的認知，仍有待加強。研究者認為，應建立國內的結核病治療指引，加強對肝功能監測與肝毒性處理方式的認知，方能對結核病治療的醫療資源做最合理而有效的運用。

Tuberculosis has to be treated concurrently with several antitubercu-lous agents and lasting for several months. Antituberculous agents are known to be able to induce hepatotoxicity in different degree. There is no consensus on the necessity of liver function monitoring after using antituberculous agents and the management of hepatotoxicity. Due to the spread of human immunodeficiency virus and the endemic of virus hepatitis, the prevalence of tuberculosis increased again in recent years. A retrospective study, therefore, was carried out to investigate the current status of antituberculous agent-induced hepatotoxicity in Taiwan.
The out- and in-patients with a diagnosis of tuberculosis in National Taiwan University Hospital in 1998 and had the prescriptions of antituberculous agents, were included in this study. All the data required were recorded from each patient’s chart. The incidence, type and possible risk factors of antituberculous agent-induced hepatotoxicity were evaluated. The liver function monitoring pattern before and after using antituberculous agents and the management of hepatotoxicity by physicians were elucidated.
We included 348 patients for hepatotoxicity incidence analysis. There were 207 patients (59.5%) developing hepatotoxicity after using antituberculous agents, in which, 25.0% of patients were abnormalities of liver tests, and 34.5% of patients were liver injury. The incidence of hepatocellular, cholestatic and mixed type of liver injury were 19.0%, 7.2%, and 7.2%, respectively. We were not able to classify the type of liver injury in 4 patients due to a shortage of information.
It was found that patients with immunodeficiency virus infection or hepatitis C virus infection were the main risk factors in developing drug-induced hepatotoxicity. Daily alcohol drinker was the risk factor in developing liver injury. After the interference analysis, age, sex and using pyrazinamide, however, were found to be not the main risk factors.
After excluding the data of 3 patients, who had unusual long treatment period, the mean observed onset of hepatotoxicity was about 43 days. For the cases that hepatotoxicity related medication can be evaluated, pyrazinamide alone was the most possible hepatotoxicity related drug (32.8%). There were 57.0% of the patients developing hepatotoxicity who continuously used the antituberculous agents. From part of the patients'' data, it is observed that 96.6% of patients'' liver function gradually recovered after withdrawing the antituberculous agents. The most often used pattern of medication rechallenging was isoniazid first, and then rifampin (48.4%). Although, we were not able to find the management model of physicians while patients has hepatotoxicity developed, but it was observed that most of physicians may not take any action to manage hepatotoxicity until a severe hepatotoxicity developed.
There were 218 patients (62.6%) had baseline liver tests before using antituberculous agents, in which, 98 patients had abnormal initial liver function. Both the patients of normal and abnormal initial liver tests had the drug-induced hepatotoxicity incidence rate of about 65%, however, the abnormal patients had higher possibility of developing severe hepatotoxicity (liver injury, 49.6%). In order to use the antituberculous agents to treat tuberculosis safely and effectively, monitoring patients’ liver function is very important. However, it was found that 2.7% patients did not have liver function monitoring after using antituberculous agents even they had abnormal initial liver tests. It is necessary to develop a guideline for the treatment of tuberculosis and to emphasize the importance of monitoring of liver function and management of hepatotoxicity. Hence, the use of medical source will be more reasonably and effectively.

第一章 前言1
第二章 文獻探討3
第一節 結核病治療的基本原則3
一、 結核菌的特性3
二、 結核病的藥物治療及治療的基本原則3
第二節 藥物引起之肝毒性7
一、 藥物引起之肝毒性的種類及定義7
二、 藥物引起之肝毒性的相關性評估9
第三節 抗結核藥物引起的肝毒性11
一、 抗結核藥物肝毒性個論11
二、 抗結核藥物組合使用的肝毒性13
三、 影響抗結核藥物肝毒性的因素16
第四節 使用抗結核藥物的肝功能監測與肝毒性處理方式19
一、 肝功能監測的建議19
二、 抗結核藥物引起肝毒性之處理方式20
第五節 台灣結核病流行之現況23
一、 死亡率23
二、 盛行率23
三、 台灣地區抗結核藥物肝毒性之相關研究24
第三章 研究目的29
第四章 研究方法30
第一節 研究對象30
第二節 資料收集31
第三節 肝毒性判讀33
第四節 資料處理及分析34
第五章 結果37
第一節 研究對象基本資料分析37
第二節 抗結核藥物相關之肝毒性發生率分析42
第三節 抗結核藥物治療發生肝毒性之危險因子分析44
一、發生肝毒性之危險因子分析44
二、使用HERZ及HER藥物組合病人群之肝毒性危險因子
46
第四節 肝毒性發現時間與各抗結核藥物相關性分析55
一、肝毒性發現時間比較55
二、各抗結核藥物與肝毒性之相關性55
第五節 醫師對使用抗結核藥物病人的肝功能監測及肝毒性發
生後的處理方式59
一、肝功能指數基礎值之監側59
二、使用抗結核藥物後之肝功能指數監測60
三、肝毒性發生後的處理方式65
第六章 討論70
第一節 研究限制70
一、研究假設70
二、研究限制70
第二節 肝毒性發生率的分析72
一、病人的收入條件72
二、藥物引起肝損傷之判定標準73
第三節 發生肝毒性之危險因子75
一、性別75
二、使用PZA77
三、年齡78
四、白蛋白平均值79
第四節 肝毒性發現時間與各抗結核藥物相關性81
一、肝毒性發現時間81
二、肝毒性與抗結核藥物之相關性82
第五節 使用抗結核藥物後的肝功能監測83
第六節 肝毒性發生後的處理88
第七章 結論與建議90
參考文獻92
附錄97

1.Raviglione MC, Dye C, Schmidt S, Kochi A. Assessment of
worldwide tuberculosis control. Lancet 1997;350:624-9.
2.Raviglione MC, Snider DE, Jr, Kochi A. Global epidemiology of
tuberculosis: morbidity and mortality of a worldwide
epidemic. JAMA 1995;273:220-6.
3.World Health Organization. Treatment of tuberculosis:
guidelines for national programmes. 2nd ed. Geneva: WHO
Global Tuberculosis Programme;1997.
4.Durand F, Jebrak G, Pessayre D, Fournier M, Bernuau J.
Hepatotoxicity of antitubercular treatments: rationale for
monitoring liver status. Drug Saf 1996;15:394-405.
5.Thompson NP, Caplin ME, Hamilton MI, et al. Anti-tuberculosis
medication and the liver: dangers and recommendations in
management. Eur Respir J 1995;8:1384-8.
6.Schaberg T. The dark side of antituberculosis therapy:
adverse events involving liver function. Eur Respir Rev
1995;4:1247-9.
7.林雪蓉、嚴幸文。台灣地區愛滋病流行情況。衛生報導 1997;7:29-
34。
8.盧俊良、陳祖裕。B型肝炎之概況。臨床醫學 1994;34:85-98。
9.高嘉宏、陳定信。C型肝炎在台灣。中華衛誌 1998;17:191-7。
10.Ebert SC. Chap. 105 Tuberculosis. In: DiPiro JT, Talbert RL,
editors. Pharmacotherapy: a pathophysiologic approach. 3rd
ed. Stamford: Appleton & Lange; 1997. p. 2101-24.
11.Mitchison DA. Pyrazinamide-on the antituberculosis drug
frontline. Nat Med 1996;2:635-6.
12.Mitchison DA. Basic mechanisms of chemotherapy. Chest 1979;6
suppl:771-81.
13.Starke JR. Multidrug therapy for tuberculosis in children.
Pediatr infect Dis J 1990;9:785-93.
14.Wright PW, Wallace RJ, Jr. Chap. 170 Antimycobacterial
agents. In: Fauci AS, Braunwald E, editors. Harrison’s
principles of internal medicine. 14th ed. New York: McGraw-
Hill; 1998. p. 997-1003.
15.Ward ES, Jr. Chap 59. Tuberculosis. In: Young LY, Koda-
Kimble MA, editors. Applied therapeutics: the clinical use
of drugs. 6th ed. Vancouver: Applied Therapeutics; 1995. p.
1-15.
16.Joint Tuberculosis Committee of the British Thoracic
Society. Chemotherapy and managment of tuberculosis in the
United Kingdom: recommendations 1998. Thorax 1998;53:536-48.
17.American Thoracic Society. Treatment of tuberculosis and
turberculosis infection in adults and children. Am J Respir
Crit Care Med 1994;149:1359-74.
18.Benichou C, for the Council for International Organizations
of Medical Sciences (CIOMS). Criteria of drug-induced liver
disorders: report of an international consensus meeting. J
Hepatol 1990;11:272-6.
19.Danan G, Benichou C. Causality assessment of adverse
reactions to drugs- I. A novel method based on the
conclusions of international consensus meetings:
applications to drug-induced liver injuries. J Clin
Epidemiol 1993;46:1323-30.
20.Benichou C, Danan G, Flahault A. Causality assessment of
adverse reactions to drugs- II. An original model for
validation of drug causality assessment methods: case
reports with positive rechallenge. J Clin Epidemiol
1993;46:1331-6.
21.Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with
isoniazid and rifampin: a meta-analysis. Chest 1991;99:465-
71.
22.McEvoy GK, Litvak K, editors. AHFS drug information.
Bethesda: American Society of Health-System Pharmacists;
1998.
23.Durand F, Bernuau J, Pessayre D, et al. Deleterious
influence of pyrazinamide on the outcome of patients with
fulminant or subfulminant liver failure during
antituberculous treatment including isoniazid. Hepatology
1995;21:929-32.
24.van Aalderen WMC, Knoester H, Knol K. Fulminant hepatitis
during trsatment with rifampicin, pyrazinamide and
ethambutol. Eur J Pediatr 1987;146:290-1.
25.Whittington RM. Fatal hepatotoxiciy of antitubercular
chemotherapy. Lancet 1991;338:1083-4.
26.Gangadharan PRJ. Isoniazid, rifampin, and hepatotoxicity. Am
Rev Respir Dis 1986;133:963-5.
27.Reddy KR, Schiff ER. Hepatotoxicity of antimicrobial,
antifungal, and antiparasitic agents. Gastroenterol Clin
North Am 1995;24:923-36.
28.Jenner PJ, Ellard GA. Isoniazid-related hepatotoxicity: a
study of the effect of rifampicin administration on the
metabolism of acetylisoniazid in man. Tubercle 1989;70:93-
101.
29.Horn DL, Hewlett D, Alfalla C, et al. Limited tolerance of
ofloxacin and pyrazinamide prophylaxis against tuberculosis.
[letter] N Eng J Med 1994;330:1241.
30.O’Brien RJ. Hepatoxic reaction to antituberculous drugs:
adjustments to therapeutic regimen. JAMA 1991;265:3323.
31.Pande JN, Singh SPN, Khilnani GC, Khilnani S, Tandon RK.
Risk factors for hepatotoxicity from antituberculosis drugs:
a case-control study. Thorax 1996;51:132-6.
32.British thoracic association. A controlled trial of six
months chemotherapy in pumonary tuberculosis: first report:
results during chemotherapy. Br J Dis Chest 1981;75:141-53.
33.Medical research council tuberculosis and chest disease
unit. Management and outcome of pulmonary tuberculosis in
adults notified in England and Wales in 1983. Thorax
1988;43:591-8.
34.Pessayre D, Bentata M, Degott C, et al. Isoniazid-rifampin
fulminant hepatitis: a possible consequence of the
enhancement of hepatotoxicity by enzyme induction.
Gastroenterology 1977;72:284-9.
35.Murphy R, Swartz R, Watkins PB. Severe acetaminophen
toxicity in a patient receiving isoniazid. Ann Intern Med
1990;113:799-800.
36.Nolan CM, Sandblom RE. Thummel KE, Slattery JT, Nelson SD.
Hepatotoxicity associated with acetaminophen usage in
patients receiving multiple drug therapy for tuberculosis.
Chest 1994;105:408-11.
37.Yew WW, Chau CH, Leung S. Anti-tuberculosis drugs and liver
toxicity. Eur Respir J 1996;9:389-90.
38.Cross FS, Long MW, Banner AS, Snider DE, Jr. Rifampin-
isoniazid therapy of alcoholic and nonalcoholic tuberculous
patients in a U.S. public health service cooperative therapy
trial. Am Rev Respir Dis 1980;122:349-53.
39.Franks AL, Binkin NJ, Snider DE, et al. Isoniazid hepatitis
among pregnant and postpartum Hispanic patients. Public
Health Rep 1989;104:151-5.
40.Wu J-C, Lee S-D, Yeh P-F, et al. Isoniazid-rifampin-induced
hepatitis in hepatitis B carriers. Gastroenterology
1990;98:502-4.
41.Amarapurkar DN, Prabhudesai PP, Kalro RH, Desai HG.
Antituberculosis drug-induced hepatitis and HBsAg carriers.
Tuber Lung Dis 1993;74:215-6.
42.Hwang S-J, Wu J-C, Lee C-N, et al. Drug-induced liver
disease: a prospective clinical study of isoniazid-
rifampicin-pyrazinamide-induced liver injury in an area
endemic for hepatitis B. J Gastroenterol Hepatol 1997;12:87-
91.
43.McGlynn KA, Lustbader ED, Sharrar RG, Murphy EC, London WT.
Isoniazid prophylaxis in hepatits B carriers. Am Rev Respir
Dis 1986;134:666-8.
44.Ungo JR, Jones D, Ashkin D, et al. Antituberculosis drug-
induced hepatotoxicity: the role of hepatitis C virus and
human immunodeficiency virus. Am J Respir Crit Care Med
1998;157:1871-6.
45.Dossing M, Wilcke JTR, Askgaard DS, Nybo B. Liver injury
during antituberculosis treatment: an 11-year study. Tuber
Lung Dis 1996;77:335-40.
46.Ormerod LP, Horsfield N. Frequency and type of reactions to
antituberculosis drugs: observations in routine treatment.
Tuber Lung Dis 1996;77:37-42.
47.Mitchell JR, Thorgeirsson UP, Black M, et al. Increased
incidence of isoniazid hepatitis in rapid acetylator:
possible relation to hydrazine metabolite. Clin Pharmacol
Ther 1975;18:70-9.
48.Parthasarathy R, Raghupati S, Janardhanam B, et al. Hepatic
toxicity in south Indian patients during treatment of
tuberculosis with short-course regimens containing
isoniazid, rifampicin and pyrazinamide. Tubercle 1986;67:99-
108.
49.Singh J, Arora A, Garg PK, Thakur VS, Pande JN, Tandon RK.
Antituberculosis treatment-induced hepatotoxicity: role of
predictive factors. Postgrad Med J 1995;71:369-62.
50.Ozick LA, Jacob L, Comer GM, et al. Hepatotocixity from
isoniazid and rifampin in inner-city AIDS patients. Am J
Gastroenterol 1995;90:1978-80.
51.American Academy of Pediatrics. Chemotherapy for
tuberculosis in infants and children. Pediatrics 1992;89:161-
5.
52.Dossing M, Sonne J. Drug-induced hepatic disorders:
incidence, management and avoidance. Drug Saf 1993;9:441-9.
53.Schaberg T, Rebhan K, Lode H. Risk factors for side-effects
of isoniazid, rifampin and pyrazinamide in patients
hospitalized for pulmonary tuberculosis. Eur Respir J
1996;9:2026-30.
54.Singh J, Garg PK, Tandon RK. Hepatotoxicity due to
antituberculosis therapy: clinical profile and
reintroduction of therapy. J Clin Gastroenterol 1996;22:211-
4.
55.van den Brande P, van Steenbergen W, Vervoort G, Demedts M.
Aging and hepatotoxicity of isoniazid and rifampin in
pulmonary tuberculosis. Am J Respir Crit Care Med
1995;152:1705-8.
56.行政院衛生署。中華民國86年台灣地區衛生統計（一）公務統計。
57.行政院衛生署。中華民國公共衛生概況。87年6月。
58.Practice Management Information Corporation. International
classification of diseases 9th revison: clinical
modification 4th edition. Los Angeles; 1994.
59.Naranjo CA, Busto U, Seller EM, et al. A method for
estimating the probabiblity of adverse drug reactions. Clin
Pharmcol Ther 1981;30:239-45.
60.Jim LK, Gee JP. Chap. 26 Adverse effects of drugs on the
liver. In: Young LY, Koda-Kimble MA, editors. Applied
therapeutics: the clinical use of drugs. 6th ed. Vancouver:
Applied Therapeutics; 1995. p. 1-15.
61.Hunt CM, Sharara AL. Liver disease in pregnancy. Am Fam
Physician 1999;59:829-35.
62.Younossi ZM, Guyatt G. Quality-of-life assessments and
chronic liver disease. Am J Gastroenterol 1998;93:1037-41.
63.Turktas H, Unsal M, Tulek N, Oruc O. Hepatotoxicity of
antituberculosis therpay (rifampicin, isoniazid and
pyrazinamide) or viral hepatitis. Tuber Lung Dis 1994;75:58-
60.
64.Kumar A, Misra PK, Mehotra R, Govil YC, Rana GS.
Hepatotoxicity of rifampin and isoniazid: is it all drug-
induced hepatitis? Am Rev Respir Dis 1991;143:1350-2.