草药及补充剂伴随肝毒性风险

伦敦——在由欧洲肝脏研究协会（EASL）主办的国际肝脏大会（ILC）上，专家们警告称，草药及其他偏方或补充剂是导致肝毒性的一个显著原因。这与世界顺势疗法推广周（World Homeopathy Awareness Week ，WHAW）上的专家观点不谋而合。

尽管被誉为结核病最后治疗手段的草药并不是导致药物性肝损伤（DILI）的最常见原因，但以顺势疗法为基础的治疗在西方国家的应用可能正在逐渐增加，而且患者常常并未向临床医生报告其使用这些药物。

Dominique Larrey博士

法国蒙彼利埃中央大学医院的Dominique Larrey博士在会上指出：“草药是导致肝损伤的一个重要原因。草药可以引起几乎所有类型的肝胆病变，其中尤以急性肝炎最为常见。”

Larrey医生认为，在西方国家中，草药的使用很可能正在增加。其原因是多方面的，例如很多移民来自大量使用传统药物的国家，部分人认为“天然的东西有益而无害”、“草药与经典药物相比完全无毒”，等等。此外，一些严重疾病（例如癌症、多发性硬化症、艾滋病和丙型肝炎）仍缺乏满意的治疗手段，这就意味着人们常常愿意尝试补充或替代药物（CAM）。

据估计，2010年美国的草药总销售额为52亿美元，并且在过去10年间以每年3%的速度增长。问题在于，患者常未告知医生其对CAM的使用情况。令人吃惊的是，一项研究显示，服用抗凝药物华法林（因治疗窗极窄且需要谨慎监测而闻名）的患者90%正在服用草药。

草药的崛起

Larrey博士指出，草药在世界上很多地区的传统医学中都占据着非常重要的地位，尤其是在亚洲、非洲和拉丁美洲。草药的使用既有传统的因素，也有文化的因素。与管制药物相比，草药更容易获得且费用更低廉。

关于西方国家草药使用情况的前瞻性研究非常缺乏，但已有针对肝病患者的此类研究，结果提示多达1/5（Hepatology 2008;47:605-12）~1/3（Gastroenterology 2001;120[Suppl 1]:A228）的肝病患者可能在其医生不知情的情况下服用了草药。

评估方面的问题

关于草药导致肝损伤的频繁程度的数据较为有限，但是根据估计，发生率介于2%~16%。Larrey博士补充道，报告的病例恐怕只是冰山一角。

“草药肝毒性显然由于诸多原因而被低估了。首先，难以分析草药的摄入量；其次，肝损伤的机制常常不明确；第三，难以证实草药与肝损伤的因果关系。事实上，并非所有草药都像处方药那样接受了严格的检查或监管，而且网上销售的方式使得所有人都很容易获得草药。”

不仅如此，草药中的真实成分有哪些？是否使用了植物中应该使用的部分？储存的方式是否正确？是否曾被其他肝损伤性药物或微生物污染？这些问题都存在不确定性。

给临床医生的建议

Robert Fontana博士

Fontana博士参加了美国国立卫生研究院资助的药物性肝损伤网络（DILIN）项目，这是一项着眼于美国药物性肝损伤（DILI）病因、危险因素和转归的多中心、前瞻性注册研究（Drug Saf. 2009;32:55-68）。来自这项注册研究的数据显示，在确诊DILI病例中，大约9%使用了草药和膳食补充剂。他的建议是：“患者们应当告诉医生自己正在服用哪些药物。而作为临床医生，我们都应当有这方面的意识，或许应当询问患者更多的相关问题。”“在美国，甚至我认为在全世界，草药的使用率正在增加。当我们开始审视注册数据时，我想我们将看到更多的肝毒性病例。”

由国立糖尿病、消化病与肾病研究所和国立医学图书馆推出的LiverTox 网站，是一个免费的在线资源，可帮助用户了解某种药物、草药或其他补充剂是否已被证实可导致肝脏问题。据Fontana博士介绍，该网站将开设一个针对草药的新版块，推荐在日常临床实践中使用这一网站，以便更好地与患者探讨其可能正在服用的处方药或CAM。

Larrey博士和Fontana博士无相关利益冲突披露。

新的中药可抑制丙型肝炎病毒活性

根据在本次会议上发布的一篇壁报，一种名为SBEL1的化合物被发现对丙型肝炎病毒（HCV）生命周期具有多重效应。台湾大学上皮细胞系统生物学实验室的研究者筛选了6种草药，发现其中一种（SBEL1）可抑制受感染细胞中HCV活性的90%。

Cheng-Wei Lin和Ming-Jiun Yu采用草药提取物对肝细胞进行了预处理，然后用HCV感染这些细胞。结果显示，与对照细胞相比，采用SBEL1预处理的细胞所含的病毒蛋白质减少了23%。这一结果提示，SBEL1可阻止HCV进入经过了预处理的细胞。

上述结果还提示，SBEL1可减少内部核糖体进入位点介导的转录，后者是病毒蛋白质生成所必需的。SBEL1还可能干扰RNA复制过程。

EASL秘书长、奥地利维也纳大学的Markus Peck-Radosavljevic博士在由该协会举办的新闻发布会上指出：“SBEL1显示出了对处于生命周期不同阶段的HCV的显著抑制作用。”

Peck-Radosavljevic博士未参加这项研究。他认为这项研究的结果令人兴奋，因为它使我们得以更深入了解病毒及其与其他化合物的相互作用，并引导我们找出更好的治疗选择。

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By: SARA FREEMAN, Frontline Medical Communications

LONDON – Herbal medicines and other home remedies or supplements are a significant cause of hepatotoxicity experts warned recently during a symposium at the International Liver Congress, which unintentionally coincided with World Homeopathy Awareness Week.

Although they are not at the very top of the list when it comes to drug-induced liver injury (DILI) – that accolade being reserved for antimicrobial agents used to treat tuberculosis – the use of homeopathy-based approaches are potentially on the increase in the western world and the use of such substances are often not reported to physicians.

"Herbal medicines represent a significant cause of liver injury," Dr. Dominique Larrey (Central University Hospital, Montpellier, France), said at the meeting that was sponsored by the European Association for the Study of the Liver. "Herbs can cause almost the whole spectrum of hepatic and biliary lesions, acute hepatitis being the most frequent one," he added.

The rise of herbal medicine

Dr. Larrey, who works in the liver and transplantation department of Saint Eloi Hospital, also in Montpellier, noted that the use of herbs in traditional medicine was very important in many parts of the world, notably in Asia, Africa, and Central and South America. They are used for both traditional and cultural reasons, he added, are often easy to access and are low cost in comparison to regulated medicines.

Their use is probably on the increase in western countries for a variety of reasons, Dr. Larrey suggested, such as the migration of people from cultures in which the use of traditional medicines is high, to the thinking that "what is natural can only be good" and "herbal medicines are considered completely innocuous in contrast to classical drugs." Furthermore, the lack of satisfactory treatments for some severe diseases – cancer, multiple sclerosis, AIDS, and hepatitis C virus infection to name a few – mean that people often are willing to try out complementary or alternative medicines (CAM).

In the United States, the total sale of herbal remedies in 2010 was an estimated $5.2 billion per year, having increased around 3% a year over the past decade, Dr. Larrey pointed out.

The problem is that patients do not often tell their doctors about their use of CAM. A staggering 90% of patients taking the anticoagulant drug warfarin – which is renowned for having a very narrow therapeutic window and careful monitoring is required – were taking herbal medicines in one study, he said.

Prospective studies on the use of herbal medicines in western countries are scarce but those that have been conducted specifically in patients with liver disease suggest that as many as one-fifth (Hepatology 2008;47:605-12) to one-third (Gastroenterology 2001;120[Suppl 1]:A228) might be taking herbal remedies unbeknownst to their doctor.

The problem of assessment

There are limited data on how frequently herbal medicines cause liver damage, but estimates range from 2% to 16%, Dr. Larrey observed, adding that reported cases could be just the tip of the iceberg.

"Herbal medicine hepatoxicity is clearly underestimated for many reasons," he suggested. First, their intake is hard to analyze. Second, the mechanism of liver damage is often uncertain, and third, it is hard to confirm causality. Indeed, herbal medicines do not have to undergo the rigorous testing or regulation in the same way that prescribed medicines do, and sales via the Internet make them easily available to all.

There is then the uncertainty of what is really in the preparations, if they contain the right plant at all or the wrong part of it, and then whether or not they have been stored correctly, or if they have been contaminated with other liver-damaging agents or microorganisms.

Advice for physicians

DILI from prescription and nonprescription medicines is an important but rare event in the westernized world, Dr. Robert Fontana of the University of Michigan in Ann Arbor said in an interview. However, because it can bring about very bad and unpredictable liver injury, it is of great importance for hepatologists and general family physicians alike.

"In the United States and I think worldwide, the frequency in use of [herbal treatments] is increasing and as we start to see registry data I think we will start to see more and more cases [of hepatoxicity]," Dr. Fontana said.

Dr. Fontana is part of the National Institutes of Health–funded Drug-Induced Liver Injury Network (DILIN), a multicenter, prospective registry looking at the etiologies, risk factors, and outcomes of DILI in the United States (Drug Saf. 2009;32:55-68). Data from the registry show the prevalence of herbal and dietary supplements is around 9% (n = 300) in confirmed DILI cases.

"Patients need to tell their doctors what they are taking," he advised, adding that, as physicians, "we all need to be aware and maybe ask more questions of our patients."

The LiverTox website – produced by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Library of Medicine – is a valuable online and freely available resource for determining if a medication, herbal, or other supplement is known to cause liver problems. This is going to have a new chapter on herbal medicines, Dr. Fontana said, and is worth using in daily practice to help advise patients on the prescription or CAM they might be talking.

Dr. Larrey and Dr. Fontana had no disclosures relevant to their comments.

New Chinese herbal medicine inhibits HCV activity

A compound named SBEL1 after the laboratory in which it was discovered has multiple effects on the hepatitis C virus (HCV) life cycle, according to data from a late-breaking poster presented at the meeting.

Researchers from the Systems Biology of Epithelia Laboratory at the National Taiwan University, Taipei, screened six herbal medicines and found that one of these – SBEL1 – inhibited HCV activity by about 90% in infected cells.

Cheng-Wei Lin and Ming-Jiun Yu pretreated liver cells with the herbal extract and then infected these cells with HCV. Compared with control cells, SBEL1-treated cells contained 23% less viral protein. This suggested that SBEL1 prevented HCV from entering the pretreated cells.

Their findings also suggested that SBEL1 reduced internal-ribosome entry site–mediated translation, a process vital for viral protein production, and might also have interfered with the RNA replication process.

"SBEL1 has demonstrated significant inhibition of HCV at multiple stages of the viral life cycle," Dr. Markus Peck-Radosavljevic, the secretary-general of the European Association for the Study of the Liver, said in a press release issued by the Society.

Dr. Peck-Radosavljevic (University of Vienna, Austria), who was not involved in the research, added that this "is an exciting discovery because it allows us to gain a deeper understanding of the virus and its interactions with other compounds. Ultimately, this adds to our library of knowledge that may bring us closer to improving future treatment options."