抗菌药是药物诱导性肝损伤的主要药物类型

费城——美国国立卫生研究院（NIH）开展的一项旨在追踪特发性药物诱发性肝损伤（DILI）的注册研究，在很大程度上证明了既往小型研究结果和教科书概要提示的显著风险。

印第安纳大学医学院胃肠与肝病科的Naga P. Chalasani医生报告称，根据这项注册研究，DILI最常由抗菌药物所致，相当一部分DILI患者死于这种并发症或需要接受肝移植，而且本身患有肝炎或其他肝病的患者因DILI而发生不良结局的风险大大增加。

Naga P. Chalasani医生

2004年NIH建立了药物诱发性肝损伤网络，自那以后，已有1257例患者被招募入组，通过对因果关系的判断，裁定委员会判断其中899例患者为很可能或明确DILI。总死亡率为6.2%，另有4%的患者接受了肝移植。

引起DILI的最常见药物类型为抗菌药物（45.4%），其后依次为草药和膳食补充剂（16.1%）、心血管药物（9.7%）和中枢神经系统药物（9.1%），此外还有多个类型的药物可引起DILI。在最常引起DILI的10种药物中，有9种是抗菌药物（阿莫西林-克拉维酸排名首位）。唯一的例外是排在第10名的双氯芬酸。

“临床医生可能感兴趣的是，DILI平均需要多长时间才能康复？”Chalasani医生观察发现，大约70%的患者表现为黄疸，平均在70天左右康复。

将DILI区分为肝细胞型、胆汁淤积型和混合型，可能有助于评估风险。Chalasani医生指出，胆汁淤积型的DILI相关性死亡发生率高于肝细胞型，但前者的肝移植风险更低。在混合型中，肝脏相关性死亡并不常见，尽管此类患者更常发生慢性DILI，但没有患者需要接受肝移植。

从暴露于药物至发生DILI的平均间隔时间较短的药物为36天。潜伏期较长的（定义为超过1年）药物包括呋喃妥因、他汀类、胺碘酮和巯嘌呤。“这种长潜伏期的特征非常有趣。患者常常在一段时间内使用固定剂量的某种药物，并且病情控制良好，但此后逐渐增加剂量，然后突然有一天发生了DILI。”尽管研究者猜测长潜伏期与短潜伏期的特征和结局存在差异，但并未观察到这种现象。

在本项注册研究中，大约1%的DILI患者发生了Stevens-Johnson综合征（SJS）。抗菌药物与SJS的发生有关，不过最常引起SJS的药物还包括拉莫三嗪和卡马西平。

原本已患有肝病（例如肝炎或非酒精性脂肪性肝病）的患者在这一队列中占10%。在有肝病的患者中引起DILI的药物与无肝病的患者相似，但这些药物在有肝病的患者中更易引起DILI。“尽管已被写进了教科书，但这是首次有数据集显示，与原本无肝病的患者相比，有肝病者发生DILI后死亡风险增加2倍。”

DILI是一种罕见疾病，发生率仅为20例/10万。因此，这项NIH注册研究被认为是收集这种并发症的数据以评估其病因和预后的一件必要工具。

Chalasani医生报告称，自己与合著者有多项利益冲突，但均与本项研究无关。

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By: THEODORE BOSWORTH, Internal Medicine News Digital Network

PHILADELPHIA – A registry created by the National Institutes of Health (NIH) to track idiosyncratic drug-induced liver injury (DILI) largely confirms the significant risks suggested by small studies and textbook summaries,

according to newly summarized data presented at the American College of Gastroenterology (ACG).

According to the registry, antimicrobials dominate cases of DILI, a substantial minority of DILI patients die of this complication or require liver transplant, and the risks of adverse outcomes from DILI are far greater in the presence of hepatitis or another preexisting liver disease, reported Dr. Naga P. Chalasani, chief of the division of gastroenterology and hepatology, Indiana University school of medicine, Indianapolis.

Since 2004, when the Drug Induced Liver Injury Network was established by the NIH, 1,257 patients have been enrolled of which 899 were found to have probable, highly likely, or definite DILI by an adjudication committee charged with determining causality. The mortality rate overall was 6.2% with an additional 4% undergoing liver transplant.

The most commonly implicated causal agents by class were antimicrobials (45.4%), herbal and dietary supplements (16.1%), cardiovascular agents (9.7%), and CNS agents (9.1%) with a wide variety of other classes falling in at much lower representation. Nine of the top 10 individual agents implicated in DILI (amoxicillin-clavulanate led the list) were antimicrobials. The exception — and in the 10^th spot — was diclofenac.

 “What may be of interest to the clinician is how long it takes on average to recover,” Dr. Chalasani observed. For those who present with jaundice, which represented about 70% of patients in the registry, the average was about 70 days. This information may be useful “if a patient asks you how long I am going to be yellow.”

Characterizing DILI as hepatocellular, cholestatic, or mixed may have value in assessing risk. According to Dr. Chalasani, the rates of DILI-related death were higher in cholestatic than hepatocellular presentations, but the risk of liver transplant was lower. In the mixed group, liver-related death was uncommon, and there were no liver transplants even though these patients more often developed chronic DILI.

The average time from exposure to DILI in drugs with a short latency was 36 days. Drugs with a long latency, defined as more than 1 year, included nitrofurantoin, statins, amiodarone, and mercaptopurine.

“The pattern of long latency is very interesting. Patients are often on a stable dose of a given drug for a length of time and doing well and then the dose is escalated and, boom, they present with DILI,” Dr. Chalasani reported.

Despite the hypothesis that there might be differences in characteristics and outcomes from long versus short latencies, none were seen.

Stevens-Johnson Syndrome (SJS) was observed in about 1% of the DILI patients in the registry. Antimicrobials were again implicated in patients who developed SJS, but the list of most common drugs in this subset also included lamotrigine and carbamazepine.

Patients with preexisting liver disease, such as a form of hepatitis or nonalcoholic fatty liver disease, represented 10% of the registry population. The causative agents were similar with the exception of azathioprine, which appeared to impose an even greater risk in those with liver disease than in those without.

“Although it has been written in the textbooks, this is the first set of data to show DILI in patients with preexisting liver disease imposes a three times higher likelihood of death than in those without liver disease,” Dr. Chalasani reported.

DILI is a rare disease, occurring in only about 20/100,000 patients. As a result, the NIH registry is considered an essential tool for gathering data on this complication in order to assess its causes and prognosis.

Dr. Chalasani reports that he and his coauthors have multiple financial relationships with industry but none that are relevant to this study.