藥物引起的急性肝衰竭很罕見但會致命

作者：Laurie Barclay, MD  
出處：WebMD醫學新聞

　　July 15, 2009 — 根據7月份肝臟移植期刊的回溯世代研究結果，雖然藥物引起的急性肝衰竭(drug-induced acute liver failure，DIALF)很罕見，但是會致命。
　　
　　馬里蘭大學醫學院的Ayse L. Mindikoglu等人寫道，急性肝衰竭(Acute liver failure，ALF)是一種不常見但可能致命的藥物相關副作用，通常會需要肝臟移植(liver transplantation，LT)，甚至致死。它也是美國在過去50年間管理當局採取行動的主要原因，包括將藥物下市、限定適應症、對健康照護者和病患提出警訊。
　　
　　使用器官分享標準移植分析與研究聯合網路的檔案，研究者辨識與分析於1987年10月1日至2006年12月31日間，因為DIALF而接受肝臟移植之661名病患(567名成人與94名18歲以下小孩)的資料。其中20名受贈者與6名捐贈者的人口統計學與臨床變項資料進行分析。
　　
　　最常與DIALF有關的四類藥物為acetaminophen (n = 265人；40%)、抗結核病藥物(n = 50人；8%)、抗癲癇藥物(n = 46人；7%)以及抗生素(n = 39人；6%)。估計一年存活率，acetaminophen組為76%、抗結核病藥物組為82%、抗癲癇藥物組為52%、抗生素組為82%，其他藥物引起的DIALF者為79%。
　　
　　對於抗癲癇藥物引起的ALF，存活率降低主要是因為孩童的死亡率，因為抗癲癇藥物引起ALF的22名18歲以下病患中，第一年內的死亡率為73%。這些病患也最不可能被列為狀態1，在等候名單上的時間最久，溫缺血和冷缺血的時間最長。不過，在多變項分析中控制這些變項之後，並未改變這組病患相對較低的存活可能性。
　　
　　雖然整體的存活率在acetaminophen相關與非acetaminophen相關ALF之間相似，但前者在肝臟移植前需要透析的比率顯著高於其他藥物組(27% vs 3% - 10%；P < .0001)。
　　
　　18歲以下因抗癲癇藥物引起的DIALF ，根據Cox比例風險回歸分析，需要生命支持以及血清肌酸酐升高，都是肝臟移植後死亡的移植前獨立預測因子。研究者演算出一種數學預測模式，顯示整個研究族群有強力預測能力。
　　
　　研究作者寫道，在美國，因為DIALF而需要LT的主要藥物為acetaminophen、抗結核病藥物、抗癲癇藥物與抗生素。因為抗癲癇藥物而發生ALF的小孩，相較於其他藥物，在LT之後的死亡風險較高。因為acetaminophen相關ALF而移植的病患，需要透析的比率顯著較高。
　　
　　研究限制包括，無法確認因果關係且小兒樣本較小。
　　
　　在編輯評論中，北卡羅萊納大學的Paul H. Hayashi以及Hamner健康科學研究中心藥物安全研究中心的Paul B. Watkins認為，需要更多聚焦於藥物引起肝臟損傷的小兒研究。他們也指出，這個臨床模式在確認後的臨床用途也有限。
　　
　　編輯結論表示，大型登記資料如器官分享聯合網絡(UNOS [United Network for Organ Sharing])提供建構假設的、更有價值的族群基礎資料，但是它們缺乏病患的表現型資訊。多中心研究如Acute Liver Failure Study Group與Drug Induced Liver Injury Network可以提供更詳細的病患資料、血清、與基因組DNA，可用於研究這些新的假設。這些努力都可望進一步釐清預防因素，包括基因易感性，以及讓我們不再只有案例報告和系列案例。
　　
　　健康資源與服務局支持本研究。內容並非反應健康與人類服務部的觀點或政策，美國政府也未對文中的商品名或機構背書。研究者之一受雇於Eli Lilly。  

Drug-Induced Acute Liver Failure Very Rare, But Can Be Fatal

By Laurie Barclay, MD
Medscape Medical News

July 15, 2009 — Although drug-induced acute liver failure (DIALF) is very rare, it can be fatal, according to the results of a retrospective cohort study reported in the July issue of Liver Transplantation.

"Acute liver failure (ALF) is an uncommon but potentially lethal drug-related adverse effect that often leads to liver transplantation (LT) or death," write Ayse L. Mindikoglu, from the University of Maryland School of Medicine in Baltimore, and colleagues. "It is also the leading cause of regulatory action, including withdrawal of drugs from the market, restrictions in indications, and warnings to healthcare providers and patients, in the United States over the past 5 decades."

Using the United Network for Organ Sharing Standard Transplant Analysis and Research files, the investigators identified and analyzed data from 661 patients (567 adults and 94 children < age 18 years) who underwent liver transplantation for DIALF from October 1, 1987, through December 31, 2006. Data were analyzed for 20 recipient and 6 donor demographic and clinical variables.

The 4 drug groups most often responsible for DIALF were acetaminophen (n = 265; 40%), antituberculosis drugs (n = 50; 8%), antiepileptics (n = 46; 7%), and antibiotics (n = 39; 6%). Estimated 1-year survival rates were 76% for acetaminophen, 82% for antituberculosis drugs, 52% for antiepileptics, 82% for antibiotics, and 79% for DIALF caused by other drugs.

For antiepileptic-induced ALF, the lower survival rate was attributed mostly to deaths in children, with a mortality rate of 73% within the first year among the 22 patients younger than 18 years who had ALF caused by antiepileptics, These patients were also least likely to be listed as status 1, spent the most time waiting on the transplant list, and had the longest warm and cold ischemia times. However, controlling for these variables in multivariate analysis did not change the relatively low survival probability in this patient subgroup.

Although overall survival rate was statistically similar for acetaminophen-related and non–acetaminophen-related ALF, the former group required dialysis before liver transplantation at a significantly higher rate than all other drug groups (27% vs 3% - 10%; P < .0001).

The need for life support, DIALF caused by antiepileptic drugs at age younger than 18 years, and elevated serum creatinine levels were independent pretransplant predictors of death after liver transplantation, based on Cox proportional hazards regression analysis. The investigators derived a mathematical prognostic model that showed strong predictive ability in the entire study population.

"The leading drug groups causing LT due to DIALF in the United States were acetaminophen, antituberculosis drugs, antiepileptics, and antibiotics," the study authors write. "Children who had ALF due to antiepileptics had a substantially higher risk of death after LT in comparison with other drugs. Patients transplanted for acetaminophen-related ALF required dialysis at a significantly higher rate."

Limitations of this study include inability to determine causality and small pediatric sample.

In an accompanying editorial, Paul H. Hayashi, from the University of North Carolina at Chapel Hill, and Paul B. Watkins, from the Institute for Drug Safety at the Hamner Institutes of Health Sciences, Research Triangle Park, North Carolina, recommend more focused research on drug- induced liver injury in pediatric populations. They also note that the clinical usefulness of the predictive model, if validated, may be limited.

"Large registries such as the UNOS [United Network for Organ Sharing] database provide valuable population-based data to form hypotheses, but they lack all desired phenotypic information about the patients," the editorialists conclude. "Multicenter studies such as the Acute Liver Failure Study Group and Drug Induced Liver Injury Network can provide detailed individual patient data, sera, and genomic DNA, which can be used to investigate these new hypotheses. The combined efforts will hopefully shed better light on preventive factors, including genetic predisposition, and move us beyond simply reporting cases and case series."

The Health Resources and Services Administration supported this study. The content does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. One of the study authors is employed by Eli Lilly.

Liver Transpl. 2009;15:675-676, 719-729.