Title

血管張力素轉化酶抑制劑引起肝臟損傷之回溯性案例系列分析

Translated Titles

A Retrospective Case Series Study of Angiotensin Converting Enzyme Inhibitors-Induced Liver Injury

Authors

江姿宜

Key Words

ACEIs ; 肝臟損傷 ; 肝毒性 ; ACEIs ; liver injury ; hepatotoxicity

PublicationName

中國醫藥大學藥學系博士班學位論文

Volume or Term/Year and Month of Publication

2013年

Academic Degree Category

碩士

Advisor

鮑柏穎

Content Language

繁體中文

Chinese Abstract

未上市藥品在進行臨床實驗時,受限於試驗的時間、人數及受試者條件等限制時,一些特異性肝臟傷害不易察覺。上市後的藥品,肝毒性常是退出市場的主要原因之一。國外的流行病學指出每年藥品引起肝毒性的發生率,每100,000人中約有1.27至40.6件案例;台灣全國藥物不良反應通報系統之藥品導致肝毒性案件每年平均為233 件,發生率約為總人口數的1/100,000,前3名藥理分類分別為抗感染劑(49.4%)、神經系統(14.0%)及心血管系統用藥(13.0%)。在台灣B型肝炎帶原盛行率平均17.3%是美國的40倍;C型肝炎抗體陽性之盛行率平均4.4%。隨著老年人口增加,高血壓、高血糖及高血脂(簡稱三高)等慢性病也有增加的趨勢,以及在國人的用藥市場中,治療三高的藥品為大宗且降血壓用藥量為最多,故在長期服用降血壓藥品下,若病人本身特性含有引起藥品肝毒性之潛在危險因子,則可能增加藥品不良反應之風險。 相較於眾多降血壓藥品中,血管張力素轉化酶抑制劑(angiotensin converting enzyme inhibitors,ACEIs)有較多引起肝臟損傷的報告,因此本研究對一家醫學中心之服用ACEIs的門診病人,進行西元2002年至2011年之回溯性病歷觀察研究,依ACEIs導致肝毒性之ICD-9診斷碼、納入及排除條件進行篩選。最後納入觀察對象就ACEIs之長期使用,進行文獻回顧並探討相關危險因子,如:年齡、性別、飲酒習慣、吸菸、B型或C型肝炎、藥品交互作用、藥品劑量及藥品之化學結構對肝臟損傷之影響。研究結果顯示在服用ACEIs共 21,846位病人中,15人疑似因ACEIs引起肝臟損傷,其中男性9人,平均年齡約60.73±13.45歲,發生率約0.07%。5位病人有B型肝炎病史,1位病人有C型肝炎病史,B、C型肝炎病人占疑似服用ACEIs導致肝臟損傷者中約40%;6位病人有飲酒習慣約占40%,4位病人同時有吸菸及飲酒習慣約占26.67%。依Council for International Organizations of Medical Sciences (CIOMS)定義之肝臟損傷型態分三種:肝細胞損傷型有10人,混合損傷型(肝細胞損傷型和膽汁淤積損傷型)有1人,膽汁淤積損傷型有4人。分析疑似ACEIs引起肝臟損傷案例,起始時間(onset)之中位數為64天,最短為11天,最長為574天。發生肝臟損傷之藥品fosinopril有6人、captopril 有4人、imidapril 有4 人、使用複方amlodipine&benazepril有1人,各案例服用之ACEIs的劑量皆在藥品仿單建議範圍內,且與併用藥品之間無肝臟方面之藥品交互作用。使用 Roussel Uclaf Causality Assessment Method (RUCAM)評估ACEIs與肝臟損傷之間相關性,highly probable有1人,probable有10人,possible有3人,unlikely有1人。 依研究結果顯示老年人為ACEIs引起肝臟損傷之重要危險因子,而性別與過往文獻不同,以男性居多,其他危險因子如:飲酒、吸菸之證據力不足;而B型或C型肝炎與ACEIs引起肝臟損傷相關。除此之外,ACEIs含有phosphoryl、sulfhydryl、carboxyl或proline環之化學結構可能與肝臟損傷相關。本研究希望藉由ACEIs引起肝臟損傷之初探,提高醫療人員對ACEIs引起肝臟損傷的敏感度,設立相關藥品肝毒性之醫囑警訊資料,提高病人的用藥安全,以降低病人因藥品肝毒性導致住院或其它額外醫療成本支出,期許能提供ACEIs引起罕見但可能嚴重之不良反應的本土性數據資料,以供未來台灣 ACEIs引起肝臟損傷之藥物基因學研究參考。

English Abstract

In clinical trials, the study design is generally limited to aspects such as the test duration, number of cases, and inclusion and exclusion criteria. Idiosyncratic liver injury induced by some drugs is not identified during clinical trials, and this is one of the main reasons cited for withdrawal of an approved drug from the market. According to an international drug epidemiology study, the annual incidence of drug-induced hepatotoxicity ranges between 1.27 and 40.6 cases per 100,000 persons. According to the National Reporting System of Adverse Drug Reaction in Taiwan, 233 cases of drug-induced hepatotoxicity are reported every year, with an incidence of 1 per 100,000 persons. With regard to pharmacological classification, the National Reporting System of Adverse Drug Reaction in Taiwan has shown that the 3 major categories of medication associated with the highest incidence of hepatotoxicity are those for infection (49.4%), central nervous system disorders (14.0%), and cardiovascular disorders (13.0%). In Taiwan, the average prevalence of hepatitis B carriers (17.3%) is 40 times higher than that in the United States, and the average incidence of antibody-positive hepatitis C virus-infected patients is 4.4%. With an increase in the elderly population, the prevalence of chronic diseases such as hypertension, hyperglycemia, and hyperlipidemia also tends to increase. In the Taiwan pharmaceutical market, most drugs were used for these three diseases, and in which the antihypertensive agents were the most commonly prescribed. The long-term administration of antihypertensive agents could increase the risk of adverse drug reactions in patients who are at high risk of experiencing drug-induced hepatotoxicity. Angiotensin-converting enzyme inhibitors (ACEIs) have more liver injury reports than other antihypertensive agents. Therefore, we conducted a retrospective study in which we analyzed the medical records of patients who met the eligibility criteria from 2002 to 2011 to assess ACEIs-induced liver injury according to the International Classification of Diseases-9 code. We reviewed the literature and discussed the relationship between ACEIs-induced liver injury and risk factors such as age, gender, alcohol consumption, smoking status, status of hepatitis B or hepatitis C infection, drug interaction, drug dosage, and drug chemical structure in patients who received long-term administration of ACEIs. We found that, of the 21,846 patients taking ACEIs, 15 were suspected of having ACEIs-induced liver injury. Nine of the 15 patients were men, the mean age was 60.73±13.45 years, and the incidence of ACEIs-induced liver injury was approximately 0.07%. Five patients had a history of hepatitis B infection and 1 patient had a history of hepatitis C infection; these patients accounted for 40% of the patients suspected of having ACEIs-induced liver injury. In addition, 6 patients who reported alcohol consumption accounted for approximately 40% and 4 patients with both smoking status and alcohol consumption accounted for approximately 26.67% of the patients suspected of having ACEIs-induced liver injury. According to the Council for International Organizations of Medical Sciences definition, 10 patients experienced hepatocellular injury, 1 patients experienced mixed injury (hepatocellular injury and cholestatic injury), and 4 patients experienced cholestatic injury. We found that the median onset time of the suspected ACEIs-induced liver injury was 64 days (range, 11–574 days). The ACEIs fosinopril, captopril, imidapril, and amlodipine/benazepril induced liver injury in 6, 4, 4, and 1 patient, respectively. The dosage of ACEIs administered to all patients was within the recommended range as identified by the drug label, and no drug interaction due to liver metabolism was noted. According to the Roussel Uclaf Causality Assessment Method to estimate the relationship between ACEIs administration and liver injury, this relationship was highly probable in 1 patient, probable in 10, possible in 3, and unlikely in 1. Elderly patients are a higher risk of ACEIs-induced liver injury. Our study showed a gender-related risk pattern, with men being at a higher risk of experiencing ACEIs-induced liver injury; however, this finding is inconsistent with the literature. Other risk factors, such as alcohol consumption and smoking status, were found to have no obvious effect. Hepatitis B or hepatitis C infection was associated with ACEIs-induced liver injury. Moreover, the chemical structures were associated with liver injury only for ACEIs that contained phosphoryl, sulfhydryl, carboxyl, or proline rings. To the best of our knowledge, this is the first reported ACEIs-induced liver injury study. We believe that the findings will help medical practitioners enhance their understanding of ACEIs-induced liver injury, enable doctor’s to appropriately advice patients on drug hepatotoxicity, and improve drug safety, thereby reducing the proportion of patients who experience drug hepatotoxicity, which would reduce hospitalization costs and other additional medical expenses. We also plan to create a local database for Taiwan, in which cases of rare but potentially serious ACEIs-induced adverse drug reactions would be recorded and which would serve as a reference for pharmacogenetics research in the future.

Topic Category 醫藥衛生 > 藥理醫學
藥學院 > 藥學系碩士班
Reference
  1. 蹤調查研究. 行政院衛生署國民健康局.2012年12月1日索檢自
    連結:
  2. seroprevalence of hepatitis B virus and hepatitis C virus
    連結:
  3. screening participants. J Formos Med Assoc 2007; 106:148-
    連結:
  4. with angiotensin-converting enzyme inhibitors. Ann
    連結:
  5. Pharmacother 1993;27:228-31.
    連結:
  6. potentially hepatotoxic drugs among major US drug
    連結:
  7. compendia. Res Social Adm Pharm 2005; 1:460-79.
    連結:
  8. 10.Andrade RJ, Lucena MI, Fernandez MC, et al. Drug-induced
    連結:
  9. Gastroenterology 2005; 129:512-21.
    連結:
  10. acute idiosyncratic drug-induced liver injury: Long-term
    連結:
  11. 12.ACE INHIBITOR-INDUCED HEPATOTOXICITY. Micromedex.Last
    連結:
  12. clinical trials: as rare as hens' teeth. Am J
    連結:
  13. Gastroenterol 2009; 104:1159-61.
    連結:
  14. 16.Ramaiah SK. Preclinical safety assessment: current gaps,
    連結:
  15. challenges, and approaches in identifying translatable
    連結:
  16. 2011; 31:161-72.
    連結:
  17. hepatotoxicity: data from the Serbian pharmacovigilance
    連結:
  18. and their agreement with clinical judgments in
    連結:
  19. hepatotoxicity. Pharmacoepidemiology and Drug Safety
    連結:
  20. 2011; 20:272-285.
    連結:
  21. assessment methods in drug induced liver injury:
    連結:
  22. strengths and weaknesses. J Hepatol 2011; 55:683-91.
    連結:
  23. definition and phenotype standardization in drug-induced
    連結:
  24. liver injury.Clin Pharmacol Ther 2011; 89:806-15.
    連結:
  25. hepatotoxicity or drug-induced liver injury. Clin Liver
    連結:
  26. 22.Senior JR. Drug hepatotoxicity from a regulatory
    連結:
  27. perspective. Clin Liver Dis 2007; 11:507-24, vi.
    連結:
  28. Hepatology 2008; 47:2003-9.
    連結:
  29. concepts of mechanisms in drug-induced hepatotoxicity.
    連結:
  30. Curr Med Chem 2009; 16:3041-53.
    連結:
  31. of this data organization approach to phase III clinical
    連結:
  32. 26.Lee WM. Drug-induced hepatotoxicity. N Engl J Med 2003;
    連結:
  33. 27.Guidance for Industry ─Drug-Induced Liver Injury:
    連結:
  34. Premarketing Clinical Evaluation. U.S. Department of
    連結:
  35. Health and Human Services,Food and Drug Administration,
    連結:
  36. Center for Drug Evaluation and Research (CDER),Center
    連結:
  37. for Biologics Evaluation and Research (CBER). 2009.
    連結:
  38. 28.Reuben A, Koch DG, Lee WM, Acute Liver Failure Study G.
    連結:
  39. Drug-induced acute liver failure: results of a U.S.
    連結:
  40. induced liver injury: insights from genetic studies.
    連結:
  41. Pharmacogenomics 2009; 10:1467-87.
    連結:
  42. of nomenclature and causality assessment in drug-induced
    連結:
  43. liver injury: summary of a clinical research workshop.
    連結:
  44. Hepatology 2010; 52:730-42.
    連結:
  45. 31.Verma S, Kaplowitz N. Diagnosis, management and
    連結:
  46. prevention of drug-induced liver injury. Gut 2009;
    連結:
  47. Evaluation of naranjo adverse drug reactions probability
    連結:
  48. scale in causality assessment of drug-induced liver
    連結:
  49. injury. Aliment Pharmacol Ther 2008; 27:780-9.
    連結:
  50. 33.Friis H, Andreasen PB. Drug-induced hepatic injury: an
    連結:
  51. on Adverse Drug Reactions between 1978 and 1987. J
    連結:
  52. Intern Med 1992; 232:133-8.
    連結:
  53. cholestasis. Hepatology 2011; 53:1377-87.
    連結:
  54. 35.Pillans PI. Drug associated hepatic reactions in New
    連結:
  55. 37.Benichou C. Criteria of drug-induced liver disorders.
    連結:
  56. Report of an international consensus meeting. J Hepatol
    連結:
  57. 1990; 11:272-6.
    連結:
  58. 38.Danan G, Benichou C. Causality assessment of adverse
    連結:
  59. conclusions of international consensus meetings:
    連結:
  60. Epidemiol 1993; 46:1323-30.
    連結:
  61. 39.Benichou C, Danan G, Flahault A. Causality assessment of
    連結:
  62. 1993; 46:1331-6.
    連結:
  63. clinical features, and outcomes from a prospective study
    連結:
  64. of drug-induced liver injury in the United States.
    連結:
  65. Gastroenterology 2008; 135:1924-34, 1934 e1-4.
    連結:
  66. Induced Liver Injury Network (DILIN) prospective study:
    連結:
  67. rationale, design and conduct. Drug Saf 2009; 32:55-68.
    連結:
  68. Liver Disease Caused by drugs. Feldman: Sleisenger and
    連結:
  69. Fordtran's Gastrointestinal and Liver Disease, 9th ed.
    連結:
  70. 44.Ramachandran R, Kakar S. Histological patterns in drug-
    連結:
  71. induced liver disease. J Clin Pathol 2009; 62:481-92.
    連結:
  72. induced liver injury (DILI) with different drugs in the
    連結:
  73. Spanish Registry: the dilemma of the relationship to
    連結:
  74. autoimmune hepatitis. J Hepatol 2011; 55:820-7.
    連結:
  75. induced autoimmune hepatitis: clinical characteristics
    連結:
  76. and prognosis. Hepatology 2010; 51:2040-8.
    連結:
  77. 48.Liu ZX, Kaplowitz N. Immune-mediated drug-induced liver
    連結:
  78. disease. Clin Liver Dis 2002; 6:755-74.
    連結:
  79. 49.Czaja AJ. Drug-induced autoimmune-like hepatitis. Dig
    連結:
  80. Dis Sci 2011; 56:958-76.
    連結:
  81. 50.Kumari R, Timshina DK, Thappa DM. Drug hypersensitivity
    連結:
  82. syndrome. Indian J Dermatol Venereol Leprol 2011;77:7-15.
    連結:
  83. 51.Pratt DS. CHAPTER 73 Liver Chemistry and Function Tests
    連結:
  84. Liver Disease, 9th ed. 2010.
    連結:
  85. 53.Lee WM. chapter 152 Toxin- and Drug-Induced Liver
    連結:
  86. 54.Watkins PB. Biomarkers for the diagnosis and management
    連結:
  87. of drug-induced liver injury. Semin Liver Dis 2009;
    連結:
  88. 55.Winger J, Michelfelder A. Diagnostic approach to the
    連結:
  89. 56.Temple R. Hy's law: predicting serious hepatotoxicity.
    連結:
  90. Pharmacoepidemiol Drug Saf 2006; 15:241-3.
    連結:
  91. 57.Bjornsson E, Olsson R. Outcome and prognostic markers in
    連結:
  92. of drug-induced liver injury. Hepatology 2010; 52:748-61.
    連結:
  93. drug-induced liver injury. Gastroenterology 2010;
    連結:
  94. 60.Tajiri K, Shimizu Y. Practical guidelines for diagnosis
    連結:
  95. and early management of drug-induced liver injury. World
    連結:
  96. J Gastroenterol 2008; 14:6774-85.
    連結:
  97. suspected adverse drug reactions in VigiBase. Br J Clin
    連結:
  98. Pharmacol 2010; 70:721-8.
    連結:
  99. Characteristics of idiosyncratic drug-induced liver
    連結:
  100. study. J Pediatr Gastroenterol Nutr 2011; 53:182-9.
    連結:
  101. failure-associated liver disease in children. Clin Res
    連結:
  102. Hepatol Gastroenterol 2012; 36:308-10.
    連結:
  103. 64.Triantafyllou K, Vlachogiannakos J, Ladas SD.
    連結:
  104. Gastrointestinal and liver side effects of drugs in
    連結:
  105. elderly patients. Best Pract Res Clin Gastroenterol
    連結:
  106. 2010; 24:203-15.
    連結:
  107. characterization of idiosyncratic drug-induced liver
    連結:
  108. 66.Lucena MI, Andrade RJ, Fernandez MC, et al. Determinants
    連結:
  109. of the clinical expression of amoxicillin-clavulanate
    連結:
  110. Hepatology 2006; 44:850-6.
    連結:
  111. mortality. Am J Gastroenterol 2010; 105:2396-404.
    連結:
  112. coinfection, an important risk factor for hepatotoxicity
    連結:
  113. 69.Tracy TS, Venkataramanan R, Glover DD, Caritis SN.
    連結:
  114. Temporal changes in drug metabolism (CYP1A2, CYP2D6 and
    連結:
  115. 2005; 192:633-9.
    連結:
  116. hypersensitivity syndrome: cross-reactivity with
    連結:
  117. reactivity of enalapril- and captopril-induced
    連結:
  118. hepatotoxicity. Ann Pharmacother 1992; 26:780-1.
    連結:
  119. hepatotoxicity of flutamide and cyproterone acetate.
    連結:
  120. Liver Int 2007; 27:1144-7.
    連結:
  121. induced acute hepatitis with absence of cross-toxicity
    連結:
  122. with simvastatin. Lancet 1999; 353:1763-4.
    連結:
  123. 2010; 52:2216-22.
    連結:
  124. peroxidase in idiosyncratic drug-induced liver injury.
    連結:
  125. Hepatology 2010; 52:303-12.
    連結:
  126. practice: a challenge for gastroenterologists. World J
    連結:
  127. Gastroenterol 2007; 13:329-40.
    連結:
  128. drug-induced liver injury. Clin Gastroenterol Hepatol
    連結:
  129. 2010; 8:463-70.
    連結:
  130. 79.Watanabe M, Shibuya A. Validity study of a new
    連結:
  131. diagnostic scale for drug-induced liver injury in Japan-
    連結:
  132. two clinical scales for causality assessment in
    連結:
  133. hepatotoxicity. Hepatology 2001; 33:123-30.
    連結:
  134. assessment in drug-induced liver injury using a
    連結:
  135. structured expert opinion process: comparison to the
    連結:
  136. 2010; 51:2117-26.
    連結:
  137. hepatotoxic adverse drug reactions. J Hepatol 2000;
    連結:
  138. and their agreement with clinical judgments in
    連結:
  139. 84.Lee WM, Stravitz RT, Larson AM. Introduction to the
    連結:
  140. revised American Association for the Study of Liver
    連結:
  141. Diseases Position Paper on acute liver failure 2011.
    連結:
  142. Hepatology 2012; 55:965-7.
    連結:
  143. 85.Kaplan NM. Systemic Hypertension. Bonow: Braunwald's
    連結:
  144. Heart Disease - A Textbook of Cardiovascular Medicine,
    連結:
  145. 86.Vijayaraghavan K, Deedwania P. Renin-angiotensin-
    連結:
  146. aldosterone blockade for cardiovascular disease
    連結:
  147. prevention. Cardiol Clin 2011; 29:137-56.
    連結:
  148. 89.Sangole NV, Dadkar VN. Adverse drug reaction monitoring
    連結:
  149. with angiotensin converting enzyme inhibitors: A
    連結:
  150. Indian J Pharmacol 2010; 42:27-31.
    連結:
  151. 91.Wilson CO, John M. Beale J, Block JH. Wilson and
    連結:
  152. Health/Lippincott Williams & Wilkins, 2011.
    連結:
  153. drugs: nonsteroidal anti-inflammatory drugs,
    連結:
  154. antihypertensives, antidiabetic agents, anticonvulsants,
    連結:
  155. lipid-lowering agents, psychotropic drugs. Semin Liver
    連結:
  156. 93.Gonzalez de la Puente MA, Calderon E, Espinosa R, et al.
    連結:
  157. Fatal hepatotoxicity associated with enalapril. Ann
    連結:
  158. Pharmacother 2001; 35:1492.
    連結:
  159. subfulminant hepatitis probably due to the combination
    連結:
  160. Gastroenterol Clin Biol 2000; 24:464.
    連結:
  161. hemoglobin and liver function tests in hypertensive
    連結:
  162. hepatotoxicity caused by enalapril: a case report. J
    連結:
  163. Gastrointestin Liver Dis 2010; 19:187-90.
    連結:
  164. of fosinopril-induced severe cholestatic jaundice with
    連結:
  165. plasma exchange. Ann Pharmacother 2008; 42:1887-92.
    連結:
  166. hepatotoxicity. Arch Pathol Lab Med 2003; 127:1493-7.
    連結:
  167. presumed lisinopril-induced hepatotoxicity. Am J Health
    連結:
  168. Syst Pharm 2010; 67:1354-6.
    連結:
  169. failure due to enalapril. Herz 2000; 25:689-93.
    連結:
  170. Hepatol 2008; 23:1327-38.
    連結:
  171. associated with captopril treatment. Br J Clin Pharmacol
    連結:
  172. 1981; 11:105-6.
    連結:
  173. 103.Zimran A, Abraham AS, Hershko C. Reversible cholestatic
    連結:
  174. jaundice and hyperamylasaemia associated with captopril
    連結:
  175. associated cholestatic jaundice. Ann Intern Med 1985;
    連結:
  176. 102:56-8.
    連結:
  177. 105.Nissan A, Spira RM, Seror D, Ackerman Z. Captopril-
    連結:
  178. associated "pseudocholangitis'. A case report and review
    連結:
  179. of the literature. Arch Surg 1996; 131:670-1.
    連結:
  180. hepatotoxicity in a case of renal crisis due to systemic
    連結:
  181. sclerosis. Nephrol Dial Transplant 1997; 12:1717-8.
    連結:
  182. additional reports in the literature. Am J Med Sci 2001;
    連結:
  183. hepatitis related to Enalapril. J Hepatol 2003;39:1091-2.
    連結:
  184. cholestatic jaundice. J R Soc Med 1990; 83:271-2.
    連結:
  185. prolonged cholestatic jaundice and pruritus: first case
    連結:
  186. report. Eur J Gastroenterol Hepatol 2001; 13:279-82.
    連結:
  187. Hepatotoxicity induced by fosinopril. J Hepatol 2001;
    連結:
  188. cholestasis associated with benazepril therapy. Am J
    連結:
  189. Gastroenterol 2009; 104:245-6.
    連結:
  190. Epidemiol 2012; 65:560-7.
    連結:
  191. safety research: a critical review. Qual Saf Health Care
    連結:
  192. studied epidemiologically? Epidemiology 1993; 4:487-9.
    連結:
  193. Fluoroquinolone therapy and idiosyncratic acute liver
    連結:
  194. related diagnosis and procedure codes. CMAJ 2012;
    連結:
  195. 184:1565-70. 2013年2月24日索檢自
    連結:
  196. assessment in hepatotoxicity by drugs and dietary
    連結:
  197. supplements. Br J Clin Pharmacol 2008; 66:758-66.
    連結:
  198. population survey. Aliment Pharmacol Ther 2007;25:1401-9.
    連結:
  199. Fluoroquinolone therapy and idiosyncratic acute liver
    連結:
  200. the Roussel Uclaf Causality Assessment Method for
    連結:
  201. assessing causality in drug-induced liver injury.
    連結:
  202. Hepatology 2008; 48:1175-83.
    連結:
  203. 1.Tisdale JE, Miller DA. Drug-Induced Diseases: Prevention,
  204. Detection, and Management: Amer Soc of Health System,
  205. 2010.
  206. 2.黃靖雅, 謝右文. 全國藥物不良反應通報系統「藥物引起之肝毒
  207. 性」通報資料分析. 藥物安全簡訊 2011;36:22-28.
  208. 3.101年底人口結構分析. 內政統計通報(102年 第四週). 內政部統
  209. 計處. 2013年2月檢索自
  210. http://sowf.moi.gov.tw/stat/week/list.htm.
  211. 4.台灣流行病學學會. 2007年台灣地區高血壓、高血糖、高血脂之追
  212. http://www.bhp.doh.gov.tw/BHPNet/Web/HealthTopic
  213. /TopicArticle.aspx?id=201102140001&parentid=200712250011.
  214. 5.全聯會記者李彩蓮.去年明星用藥排行榜 誰領風騷.藥師週刊電
  215. 子報2012年 第1767期. 2013年1月檢索自
  216. http://ys34485257.imgshelf.com/1767/1767-2-1.htm.
  217. 6.聯合晚報╱記者陳麗婷、李樹人/台北報導. B肝20年後將從「國
  218. 病」除名.2013年3月18日索檢自
  219. http://udn.com/NEWS/HEALTH/HEA1/7765565.shtml.
  220. 7.Chen CH, Yang PM, Huang GT, et al. Estimation of
  221. in Taiwan from a large-scale survey of free hepatitis
  222. 55.
  223. 8.Hagley MT, Hulisz DT, Burns CM. Hepatotoxicity associated
  224. 9.Guo JJ, Wigle PR, Lammers K, Vu O. Comparison of
  225. liver injury: an analysis of 461 incidences submitted to
  226. the Spanish registry over a 10-year period.
  227. 11.Andrade RJ, Lucena MI, Kaplowitz N, et al. Outcome of
  228. follow-up in a hepatotoxicity registry.Hepatology 2006;
  229. 44:1581-8.
  230. Modified: July 12,2011. Retrieved July 04, 2012,from
  231. https://sslvpn.cmu.edu.tw/micromedex2/librarian/ND_T
  232. /evidencexpert/ND_PR/evidencexpert/CS/63B3F7/ND_App
  233. Produt/evidencexpert/DUPLICATIONSHIELDSYNC/A1BD21/ND_PG
  234. /evidencexpert/ND_B/evidencexpert/ND_P/evidencexpert/PFAc
  235. tionId/,DanaInfo=www.micromedexsolutions.com+evidencexpert
  236. .IntermediateToDocumentLink?docId=9374&contentSetId
  237. =50&title=ACE+INHIBITOR-INDUCED+HEPATOTOXICITY
  238. &servicesTitle=ACE+INHIBITOR-INDUCED+HEPATOTOXICITY.
  239. 13.藥物不良反應通報資料庫資料申請須知.行政院衛生署全國藥物
  240. 不良反應通報中心(2007).2013年2月12日檢索自
  241. http://medwatch.fda.gov.tw/db/download/29.pdf.
  242. 14.全民健康保險研究資料庫-資料庫內容. 2013年2月12日檢索自
  243. http://nhird.nhri.org.tw/date_01.htm.
  244. 15.Davern TJ, Chalasani N. Drug-induced liver injury in
  245. biomarkers of drug-induced liver injury. Clin Lab Med
  246. 17.Petronijevic M, Ilic K, Suzuki A. Drug induced
  247. database. Pharmacoepidemiol Drug Saf 2011; 20:416-23.
  248. 18.Miljkovic MM, Dobric S, Dragojevic-Simic V. Consistency
  249. between causality assessments obtained with two scales
  250. 19.Garcia-Cortes M, Stephens C, Lucena MI, et al. Causality
  251. 20.Aithal GP, Watkins PB, Andrade RJ, et al. Case
  252. 21.Pugh AJ, Barve AJ, Falkner K, et al. Drug-induced
  253. Dis 2009; 13:277-94.
  254. 23.Lammert C, Einarsson S, Saha C, et al. Relationship
  255. between daily dose of oral medications and idiosyncratic
  256. drug-induced liver injury: search for signals.
  257. 24.Russmann S, Kullak-Ublick GA, Grattagliano I. Current
  258. 25.Watkins PB, Desai M, Berkowitz SD, et al. Evaluation of
  259. drug-induced serious hepatotoxicity (eDISH): application
  260. trials of rivaroxaban after total hip or knee
  261. replacement surgery. Drug Saf 2011; 34:243-52.
  262. 349:474-85.
  263. Retrieved August 06, 2012, from http://www.fda.gov
  264. /downloads/Drugs/.../Guidances/UCM174090.pdf.
  265. multicenter, prospective study. Hepatology 2010; 52:2065-
  266. 76.
  267. 29.Andrade RJ, Robles M, Ulzurrun E, Lucena MI. Drug-
  268. 30.Fontana RJ, Seeff LB, Andrade RJ, et al. Standardization
  269. 58:1555-64.
  270. 32.Garcia-Cortes M, Lucena MI, Pachkoria K, et al.
  271. analysis of 1100 cases reported to the Danish Committee
  272. 34.Padda MS, Sanchez M, Akhtar AJ, Boyer JL. Drug-induced
  273. Zealand: 21 years experience. N Z Med J 1996; 109:315-9.
  274. 36.Conforti A, Leone R, Ghiotto E, et al. Spontaneous
  275. reporting of drug-related hepatic reactions from two
  276. Italian regions (Lombardy and Veneto). Dig Liver Dis
  277. 2000; 32:716-23.
  278. reactions to drugs--I. A novel method based on the
  279. application to drug-induced liver injuries. J Clin
  280. adverse reactions to drugs--II. An original model for
  281. validation of drug causality assessment methods: case
  282. reports with positive rechallenge. J Clin Epidemiol
  283. 40.Chalasani N, Fontana RJ, Bonkovsky HL, et al. Causes,
  284. 41.Fontana RJ, Watkins PB, Bonkovsky HL, et al. Drug-
  285. 42.Narci C. Teoh SC, and Geoffrey C. Farrell. CHAPTER 86
  286. 2010.
  287. 43.Buratti S, Lavine JE. Drugs and the liver: advances in
  288. metabolism, toxicity, and therapeutics. Curr Opin
  289. Pediatr 2002; 14:601-7.
  290. 45.Lammert C, Bjornsson E, Niklasson A, Chalasani N. Oral
  291. medications with significant hepatic metabolism at
  292. higher risk for hepatic adverse events. Hepatology 2010;
  293. 51:615-20.
  294. 46.Lucena MI, Kaplowitz N, Hallal H, et al. Recurrent drug-
  295. 47.Bjornsson E, Talwalkar J, Treeprasertsuk S, et al. Drug-
  296. Feldman: Sleisenger and Fordtran's Gastrointestinal and
  297. 52.Pincus MR, Tierno PM, Fenelus M, et al. Evaluation of
  298. Liver Function. McPherson: Henry's Clinical Diagnosis
  299. and Management by Laboratory Methods,22nd ed.2011:296-
  300. 311.
  301. Disease. Goldman: Goldman's Cecil Medicine, 24th ed
  302. 2011:979-984.
  303. 29:393-9.
  304. patient with jaundice. Prim Care 2011; 38:469-82; viii.
  305. severe drug-induced liver disease. Hepatology 2005;
  306. 42:481-9.
  307. 58.Russmann S, Jetter A, Kullak-Ublick GA. Pharmacogenetics
  308. 59.Chalasani N, Bjornsson E. Risk factors for idiosyncratic
  309. 138:2246-59.
  310. 61.Ferrajolo C, Capuano A, Verhamme KM, et al. Drug-induced
  311. hepatic injury in children: a case/non-case study of
  312. 62.Molleston JP, Fontana RJ, Lopez MJ, et al.
  313. injury in children: results from the DILIN prospective
  314. 63.Lacaille F. Liver tumours, toxic hepatitis, intestinal
  315. 65.Lucena MI, Andrade RJ, Kaplowitz N, et al. Phenotypic
  316. injury: the influence of age and sex. Hepatology 2009;
  317. 49:2001-9.
  318. hepatotoxicity: a prospective series from Spain.
  319. 67.Devarbhavi H, Dierkhising R, Kremers WK, et al. Single-
  320. center experience with drug-induced liver injury from
  321. India: causes, outcome, prognosis, and predictors of
  322. 68.Snijdewind IJ, Smit C, Godfried MH, et al. Hcv
  323. in pregnant women starting antiretroviral therapy. J
  324. Infect 2012; 64:409-16.
  325. CYP3A Activity) during pregnancy. Am J Obstet Gynecol
  326. 70.Seitz CS, Pfeuffer P, Raith P, et al. Anticonvulsant
  327. tricyclic antidepressant agents. Ann Allergy Asthma
  328. Immunol 2006; 97:698-702.
  329. 71.Hagley MT, Benak RL, Hulisz DT. Suspected cross-
  330. 72.Miquel M, Soler A, Vaque A, et al. Suspected cross-
  331. 73.Nakad A, Bataille L, Hamoir V, et al. Atorvastatin-
  332. 74.Hunt CM. Mitochondrial and immunoallergic injury
  333. increase risk of positive drug rechallenge after drug-
  334. induced liver injury: a systematic review. Hepatology
  335. 75.Lucena MI, Garcia-Martin E, Andrade RJ, et al.
  336. Mitochondrial superoxide dismutase and glutathione
  337. 76.Andrade RJ, Lucena MI, Alonso A, et al. HLA class II
  338. genotype influences the type of liver injury in drug-
  339. induced idiosyncratic liver disease. Hepatology 2004;
  340. 39:1603-12.
  341. 77.Andrade RJ, Robles M, Fernandez-Castaner A, et al.
  342. Assessment of drug-induced hepatotoxicity in clinical
  343. 78.Agarwal VK, McHutchison JG, Hoofnagle JH, Drug-Induced
  344. Liver Injury N. Important elements for the diagnosis of
  345. comparison with two previous scales. Hepatol Res 2004;
  346. 30:148-154.
  347. 80.Lucena MI, Camargo R, Andrade RJ, et al. Comparison of
  348. 81.Rockey DC, Seeff LB, Rochon J, et al. Causality
  349. Roussel-Uclaf causality assessment method. Hepatology
  350. 82.Aithal GP, Rawlins MD, Day CP. Clinical diagnostic
  351. scale: a useful tool in the evaluation of suspected
  352. 33:949-52.
  353. 83.Miljkovic MM, Dobric S, Dragojevic-Simic V. Consistency
  354. between causality assessments obtained with two scales
  355. hepatotoxicity. Pharmacoepidemiol Drug Saf 2011;20:272-
  356. 85.
  357. 9th ed. 2012:955-974.
  358. 87.CAPOTEN® (Captopril Tablets, USP) -Labeling Revision.
  359. Reference ID: 3174695. Drugs @ FDA. Action Date: August
  360. 27, 2012. Retrieved December 06, 2012, from
  361. http://www.accessdata.fda.gov/drugsatfda_docs/
  362. label/2012/018343s084lbl.pdf
  363. 88.藥物許可證暨相關資料查詢作業. 行政院衛生署食品藥物管理
  364. 局.2013年6月2日索檢自http://www.fda.gov.tw/MLMS/(S
  365. (dm5arxnwigxt3a242dnovo55))/HList.aspx.
  366. prospective, randomized, open-label, comparative study.
  367. 90.Medicines -Enzymes as Medicines. Salters Chemistry.
  368. Retrieved July 04, 2012, from
  369. www.4college.co.uk/a/Md/medicine.php.
  370. Gisvold's Textbook of Organic Medicinal and
  371. Pharmaceutical Chemistry: Wolters Kluwer
  372. 92.Chitturi S, George J. Hepatotoxicity of commonly used
  373. Dis 2002; 22:169-83.
  374. 94.Hourmand-Ollivier I, Dargere S, Cohen D, et al. [Fatal
  375. benazepril-hydrochlorothiazide (Briazide)].
  376. 95.Dizaye K, Rashid BZ. Effects of Ramipril on glycosylated
  377. patients. MIDDLE EAST JOURNAL OF INTERNAL MEDICINE 2009.
  378. 96.da Silva GH, Alves AV, Duques P, et al. Acute
  379. 97.Chou JW, Yu CJ, Chuang PH, et al. Successful treatment
  380. 98.Yeung E, Wong FS, Wanless IR, et al. Ramipril-associated
  381. 99.Zalawadiya SK, Sethi S, Loe S, et al. Unique case of
  382. 100.Jeserich M, Ihling C, Allgaier HP, et al. Acute liver
  383. 101.Lubel JS, Herath CB, Burrell LM, Angus PW. Liver
  384. disease and the renin-angiotensin system: recent
  385. discoveries and clinical implications. J Gastroenterol
  386. 102.Vandenburg M, Parfrey P, Wright P, Lazda E. Hepatitis
  387. treatment. Br Med J (Clin Res Ed) 1983; 287:1676.
  388. 104.Rahmat J, Gelfand RL, Gelfand MC, et al. Captopril-
  389. 106.Deira JL, Corbacho L, Bondia A, et al. Captopril
  390. 107.Schattner A, Kozak N, Friedman J. Captopril-induced
  391. jaundice: report of 2 cases and a review of 13
  392. 322:236-40.
  393. 108.Macias FM, Campos FR, Salguero TP, et al. Ductopenic
  394. 109.Todd P, Levison D, Farthing MJ. Enalapril-related
  395. 110.Bas V, Erkan T, Caliskan S, et al. Toxic hepatitis due
  396. to enalapril in childhood. Pediatr Int 2003; 45:755-7.
  397. 111.Nunes AC, Amaro P, Mac as F, et al. Fosinopril-induced
  398. 112.Romero-Gomez M, Miralles EJ, Garcia Diaz E, et al.
  399. 35:309-10.
  400. 113.Palta R, Thobani S, Donovan JA, et al. Prolonged
  401. 114.Lee CH, Wang JD, Chen PC, Health Data Analysis in
  402. Taiwan Research G. Case-crossover design: an alternative
  403. strategy for detecting drug-induced liver injury. J Clin
  404. 115.Zhan C, Miller MR. Administrative data based patient
  405. 2003; 12 Suppl 2:ii58-63.
  406. 116.Guess HA. How should acute hepatic drug effects be
  407. 117.Paterson JM, Mamdani MM, Manno M, Juurlink DN.
  408. injury: a population-based study. Appendix 1: Liver-
  409. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3470619
  410. /bin/supp_184_14_1565__index.html.
  411. 118.Teschke R, Schwarzenboeck A, Hennermann KH. Causality
  412. 119.Sabate M, Ibanez L, Perez E, et al. Risk of acute liver
  413. injury associated with the use of drugs: a multicentre
  414. 120.Paterson JM, Mamdani MM, Manno M, Juurlink DN.
  415. injury: a population-based study. CMAJ 2012; 184:1565-70.
  416. 121.中國醫藥大學附設醫院檢驗醫學部-檢驗項目介紹. 2013年2月16
  417. 日檢索自http://61.66.117.10/HTML/dept/1t24/index.htm.
  418. 122.全民健康保險B型肝炎帶原者及C型肝炎感染者醫療給付改善方案
  419. (102.01.01 修訂第三版). 2013 年 5月9日索檢自
  420. http://www.nhi.gov.tw/resource/bulletin/4482_1020021262-
  421. 7.pdf.
  422. 123.梁文敏, 葉懿諄. SPSS教戰手冊<第十六章 列聯表(一) - 卡方
  423. 檢定> e報37期,2009. 2013年5月24日索檢自
  424. http://biostatistics.cmu.edu.tw/.
  425. 124.梁文敏, 葉懿諄. SPSS教戰手冊<第十六章 列聯表(二) -費雪精
  426. 確性檢定> e報38期,2009. 2013年5月24日索檢自
  427. http://biostatistics.cmu.edu.tw/.
  428. 125.梁文敏, 葉懿諄. SPSS教戰手冊<第十七章 邏輯斯迴歸分析
  429. (一) - 單變數邏輯斯迴歸分析>e報43期,2010. 2013年5月24日索
  430. 檢自http://biostatistics.cmu.edu.tw/.
  431. 126.梁文敏, 葉懿諄. SPSS教戰手冊<第十七章 邏輯斯迴歸分析
  432. (二) - 多變數邏輯斯迴歸分析> e報44期 ,2010. 2013年5月24日
  433. 索檢自http://biostatistics.cmu.edu.tw/.
  434. 127.AMTREL TABLETS
  435. BESYLATE > 藥品仿單. 2013年索檢自
  436. http://www.fda.gov.tw/licnquery/DO81E0T1.asp?
  437. LicId=01046742.
  438. 128.TANATRIL TABLETS 5MG (Imidapril)藥品仿單. 2013年4月1日索
  439. 檢自 http://www.fda.gov.tw/licnquery/DO81E0T1.asp?
  440. LicId=01043950.
  441. 129.MONOPRIL® (fosinopril sodium tablets). -Patient
  442. Population Altered . Drugs @ FDA. Action Date: May 27 ,
  443. 2003. Retrieved December 06, 2012, from
  444. http://www.accessdata.fda.gov/drugsatfda_docs/
  445. label/2003/19915se5-037_monopril_lbl.pdf.
  446. 130.Rochon J, Protiva P, Seeff LB, et al. Reliability of