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

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

江姿宜

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

中國醫藥大學藥學系博士班學位論文

2013年

碩士

鮑柏穎

繁體中文

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。

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.

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