Key clinical information is often lacking in published reports of drug-induced liver injury, Dr. Vijay K. Agarwal and his colleagues reported in an article appearing in the May issue of Clinical Gastroenterology and Hepatology.

The finding is concerning, because accurate reporting of drug-induced liver injury – the single leading cause of acute liver failure in the United States – is essential for the development of reliable, interpretable data to help promote early detection and awareness of drug-induced hepatotoxicity, said Dr. Agarwal of Duke University, Durham, North Carolina, and his colleagues.

For the study, which was conducted on behalf of the U.S. Drug-Induced Liver Injury Network, the investigators developed a list of 42 elements necessary for evaluating causality of drug-induced liver injury, and they analyzed 97 published case reports or series of such injuries for the presence of these elements.

Basic disease, drug, and demographic information was present in the vast majority of reports, but numerous important elements for determining causality and eliminating alternate causes of liver injury were lacking. These elements included bilirubin level (missing in 12% of reports), initial alkaline phosphatase level (missing in 58% of reports), and competing viral etiologies (missing in more than 50% of reports).

None of the reports included all 42 elements, which the investigators considered to be minimally necessary for evaluating the causes of the adverse effects. A median of 48% of the elements were missing in the reports.

The reports evaluated included 23 single case reports, 7 brief communications, 46 small case series, and 21 letters to the editor, and they focused on six drugs from three drug classes: amoxicillin/clavulanic acid (35 reports), troglitazone (32), rosiglitazone (10), pioglitazone (8), zafirlukast (8), and montelukast (4). The first two drugs are known to cause clinically apparent drug-induced liver disease, while the other four rarely cause liver injury, but case reports have been important in documenting the medications’ potential for hepatotoxicity, the investigators noted.

Some studies included only vague descriptions of how certain diagnoses were excluded, and data on abnormal results from serial liver tests often were not included. Single case reports had significantly fewer missing elements than letters to the editor and small case series (a median of 33% vs. 50% and 48% of the elements were missing, respectively).

No significant differences were observed on the basis of journal type: The median percentage of missing elements was 50% for major internal medicine journals, 48% for gastroenterology and liver subspecialty journals, and 45% for other types of journals.

The authors noted that unless the essential details for interpreting the findings are included in such reports, it will be impossible to determine if episodes of hepatotoxicity can be causally assigned to a specific drug or combination of drugs. In addition, opportunities to identify rare events that might not be apparent in clinical trials, and to increase awareness of issues possibly associated with a drug early in its development and use, will be missed, the investigators said. They argued that a more standardized approach to the reporting of drug-induced liver injury is needed.

A checklist of minimal elements for diagnosing drug-related liver injury and for assessing causality should be developed, and a secondary list of elements that are helpful in many situations – such as results of assays for anti–hepatitis E virus antibodies to exclude hepatitis E, or magnetic resonance cholangiopancreatography to fully exclude biliary obstruction – would be useful, they said.

Such standards, which have been suggested in the past but not widely adopted, could be posted on a publicly funded Web site, with the goal that they would ultimately be adopted by journal editors, the authors suggested.

Funding for the Drug-Induced Liver Injury Network is provided by the U.S. National Institute of Diabetes and Digestive and Kidney Diseases; the study was conducted on behalf of this network. One author, Dr. John G. McHutchison, reported receiving research support from, and acting as a scientific adviser for, GlaxoSmithKline and Merck & Co.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

Vijay K. Agarwal博士及其同事发表在《临床胃肠病学和肝脏病学》5月刊上的一篇文章认为，那些已发表的有关药物诱导性肝损伤的报告常缺乏关键的临床信息。

 

Agarwal博士来自北卡罗来纳州达勒姆的杜克大学。他及其同事认为这一发现值得关注，因为在美国，药物诱导性肝损伤是造成患者急性肝功能衰竭的主要原因，准确的报告对于提供可靠的、有效的数据至关重要，这样才能有助于提高医生早期检测并认识药物诱导性肝中毒的能力。

 

研究者是代表药物诱导性肝脏损伤网络来进行的此项研究。他们列举了42项评估药物诱导性肝损伤病因的要素，并分析了97篇已发表的有关该疾病的病例报告或系列研究中描述上述要素的情况。

 

绝大多数报告中提供了基础疾病、药物以及人口统计学信息，但缺乏大量用以确定病因和排除其他致肝损伤病因的要素。这些要素包括胆红素水平(12%的报告中缺失该数据)、初始碱性磷酸酶水平(58%的报告中缺失该数据)和用以鉴别诊断的病毒病因学情况(超过50%的报告中缺失该数据)。

 

没有一项报告描述了所有42项要素。研究者认为这些要素是评估不良反应原因的最低要求。这些报告中缺失要素的比例(中位值)为48%。

 

该研究评估了23项单一病例报告、7篇简要通讯、46项小规模病例系列和21篇致编辑的信。这些文章涉及3大类的6种药物：阿莫西林/克拉维酸(35篇)，曲格列酮(32篇)，罗格列酮(10篇)，匹格列酮(8篇)，扎鲁司特(8篇)，孟鲁司特(4篇)。研究者指出，已知前2种药物可导致临床表现明显的药物诱导性肝脏疾病，而其他4种药物很少导致肝损伤，但病例报告对于证明药物潜在肝毒性非常重要。

 

有些研究仅粗略描述了如何除外某些诊断，而有关通过系列肝功能检测获得的异常结果的数据常未被包括在内。单一病例报告中所缺失的要素显著少于致编辑的信及小规模病例系列(所缺失要素比例的中位值分别为33%、50%和48%)。

 

未发现不同类型杂志间的显著差异：缺失要素比例的中位值在主要的内科杂志中为50%，在胃肠病学和肝脏病学专业杂志中为48%，而在其他类型的杂志中为45%。

 

研究者指出，除非这些报告中包含可解释其发现的重要细节，否则将无法把特定的药物或药物组合作为病因与肝中毒事件联系起来。另外，还将失去在临床研究中确定罕见不良事件的机会，并将失去在药物研发和使用早期对其可能造成肝损伤增强认识的机会。他们认为，需要一个报告药物诱导性肝损伤的更为标准的方法。

 

他们还指出，应建立一个诊断药物相关性肝损伤以及评估病因所需最少元素的清单。列举出用以鉴别诊断的次级要素也很有用，如检测抗戊型肝炎病毒抗体以除外戊型肝炎，又如行磁共振胰胆管造影术以完全除外胆管阻塞。

 

其实这些标准早已提出，但未被广泛采用。文章作者建议将这些标准置于政府资助的网站上，以助其最终为杂志编辑所采用。

 

药物诱导性肝脏损伤网络由美国国立糖尿病、消化病和肾病研究所提供资金支持。此研究由该网络组织实施。文章作者之一，John G. McHutchison博士，声明接受葛兰素史克公司和默沙东公司的研究资金支持，并担任上述公司的科学顾问。

 

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