编者按：2020年美国肝病研究学会（AASLD）年会期间，《国际肝病》编辑有幸采访了《欧洲肝病学会临床实践指南：药物性肝损伤》制订者之一冰岛国立大学Einar Bj?rnsson教授，就药物性肝损伤（DILI）诊治中的热点问题进行评述，包括DILI分型、诊断标志物进展，及如何权衡新药临床试验中的肝损伤风险。Bj?rnsson教授在本届会议上应邀于“Hyman J. Zimmerman Hepatotoxicity State-of-the-Art Lecture?”专题，介绍检查点抑制剂、生物制剂、小分子药物导致的肝脏毒性。

 

《国际肝病》：药物性肝损伤（drug-induced liver injury）的发生率约每10万人中14～19例，药物性肝损有三种类型，分别为直接型、特异质型和间接型，这三种类型的特征和区别是什么？

 

: Drug-induced liver injury is estimated to be 14 to 19 cases per 100,000 persons. There are 3 types of drug-induced liver injury: direct hepatoxicity, idiosyncratic hepatotoxicity and indirect hepatotoxicity. What are the characteristics and differences among the 3 types of drug-induced liver injury?

 

Einar Bj?rnsson教授：以往药物性肝损伤（DILI）仅分两型：直接型和特异质型，2019年《新英格兰医学杂志》发表的一篇论文中，引入了第三种类型，即非直接型DILI。

 

直接型DILI的特征为药物剂量相关，剂量越高，肝损风险越高，以急性肝坏死为表型。布洛芬为常见引起直接型DILI的药物，其他常见的有传统化疗药物例如甲氨蝶呤，以及抗心律失常药物可达龙。

 

特异质型DILI少见，同样剂量疗程的药物在多数患者中可耐受，仅在少数患者中出现罕见的特异质型DILI。通常情况下特异质型DILI和剂量无关，但近期也有报道显示其和剂量的相关性，一些药物随着治疗范围内的剂量增加，可发生与代谢或免疫反应相关的特异质型DILI，例如阿莫西林克拉维酸钾、抗结核药物异烟肼。常见的生化和组织形态学特征为淤胆型肝炎，也可表现为谷丙转氨酶、谷草转氨酶升高的肝细胞型，或单纯淤胆型，例如合成类固醇可引起单纯淤胆。

 

非直接型DILI多与药物本身特性相关，由药物对肝脏或免疫系统的非直接作用导致。在特异质型DILI中，药物代谢引发的免疫反应可导致易感人群发生DILI，与非直接型DILI有所不同。例如英夫利昔单抗不从肝脏代谢，但可影响免疫系统，导致肝炎，免疫检查点抑制剂也是愈发常见的影响免疫，进而导致非直接型DILI的药物。

 

Prof. Einar Bj?rnsson: Before last year, drug-induced liver injury was divided into only two types, direct hepatotoxicity and idiosyncratic hepatotoxicity. But in a paper in the new England journal of medicine that was published in 2019, this 3rd type indirect hepatotoxicity was introduced. 

 

The characteristics of the direct hepatotoxicity is that it's dose-related. The higher the dose of the agent, the higher risk of liver injury. The phenotype is cluttered by acute hepatic necrosis in several cases, this is usually related to high exposure and high doses of the drug. Most people are familiar with acetaminophen, as is called in the US but paracetamol mostly in Europe. But other type of drugs leading to direct hepatotoxicity is cancer chemotherapy of the old type and methotrexate, which is used in some type of cancer therapy, for example, in children and in other conditions. And this can also be related to amiodarone, which is an anti-arrhythmic drug given intravenously. All these drugs can cause direct hepatotoxicity which is dose-related as I mentioned earlier. 

 

However, the idiosyncratic type is rare. It's a rare adverse effect of a drug that leads to liver injury when most people tolerate the drug in the same dose or the same duration. This is usually not related to the dose, although recently there's been shown that this is not without dose relationship. For some drugs, the higher the dose, the more likely, although within the therapeutic range, that they can develop idiosyncratic injury, which is thought to be related to the metabolic or immunological reaction probably in many cases. for example, antibiotics such as amoxicillin and clavulanic acid, and isoniazid used for tuberculosis are typical drugs that can lead to idiosyncratic drug-induced liver injury. Many other drugs are of this type. One of the most common biochemical and histological phenotype is cholestatic hepatitis. Idiosyncratic type of reaction can also be hepatocellular with dominant AST and ALT elevation, or a cholestatic, or pure cholestatic reaction. A good example is a bland cholestasis related to the use of anabolic steroids. 

 

The 3rd type indirect hepatotoxicity is mostly caused by the action of the drug rather than its toxicity. In the idiosyncratic type, the hypothesis is that metabolic reaction can trigger the immune system in a certain amount, which leads to either direct toxicity in the susceptible individual, or immunological activation that can lead to injury. But this indirect hepatotoxicity is related mostly to what the drug does rather than what it is in the case of idiosyncratic reaction that is leading to direct toxicity. A good example is infliximab-induced hepatitis. It's not thought to be related to the toxicity of infliximab, which is not even metabolized within the liver, but is related to the imbalance in the immune system. This can also be seen with the increasingly used checkpoint inhibitors which lead to imbalance in the immune system. When the drug is interfering with the immune system, this can lead to all auto-immune phenomenon in different parts of the body and also within in the liver. To summarize the 3rd part, it's an indirect action of the agent on the liver or the immune system that leads to this reaction. 

 

《国际肝病》：目前DILI无特异诊断标志物，传统血清学标志物包括ALT/AST、ALP、GGT、白蛋白和TGF-β1，新型血清学标志物包括PON-1、miRNA (miR-122, miR-129) 、GLDH、GSTs等。您认为哪项指标最有价值？诊断标志物方面的最新进展有哪些？

 

: With few exceptions, there are no specific diagnostic markers for drug-induced liver injury. The traditional serologic markers are ALT/AST, ALP, GGT, albumin and TGF-β1. New serum markers include PON-1, miRNA (miR-122, miR-129), GLDH, GSTs and so on. In your opinion, which one is the most promising marker in terms of sensitivity, specificity and predictivity? What is the development prospect of diagnostic markers?

 

Einar Bj?rnsson教授：目前临床缺乏DILI的诊断标志物。当患者怀疑为丙肝时，可通过丙肝抗体等检测方法明确，但DILI目前缺乏特异性标志物，通常经排除其他病因来确诊。SAFE-T研究（Safer and Faster Evidence-based Translation）是目前欧洲正在进行的一项探索DILI标志物的创新医学研究，研究多种不同药物的各类副作用，包括肝损伤、肾损伤、血管损伤及中枢神经系统损伤等。在疑似DILI的患者中探索标志物与肝损严重程度及早期诊断的相关性，通过标志物检测以区分DILI和其他病因引起的急性肝损伤。

 

这项TransBioLine研究中，通过欧洲Pro-Euro DILI 注册网前瞻性地纳入患者，将疑似DILI但最终确诊为病毒性肝炎或其他病因的患者作为对照人群。一些DILI患者可有黄疸或急性肝衰，甚至肝衰致死或需要进行肝移植。

 

希望通过这项研究能明确早期诊断DILI、预测严重程度及预后的标志物。就目前来说，没有证据显示哪些标志物更优，一些新型标志物例如microRNA的价值正在探索中，有待进一步的研究证实。

 

Prof. Einar Bj?rnsson: This is a very good but also a very difficult question. Unfortunately, I cannot state that I'm an expert in biomarkers but this is obviously a very important question. There is a big medical need to find the biological marker for DILI. As we know, we don't have a biological marker. When patients are suspected of having hepatitis C we can measure antibodies against hepatitis C, and also the virus itself in the blood with appropriate molecular diagnostic methods. But we lack up specific marker for DILI. We rarely have a complete proof of the role of the drug and relies on many other things and exclusion of other etiologies. This issue has been intensively studied in recent years. One of the studies that have tried to validate the biomarkers with DILI is so-called SAFE-T which was an innovative medicine initiative, Safer and Faster Evidence-based Translation consortium in Europe. There were several markers that mentioned here, for example, the miRNA. The SAFE-T study was ongoing and dealing with many different drugs, different adverse effects, also analyzing kidney injury, vascular injury and central nervous system injury. In terms of the DILI, the collection of cases is ongoing to evaluate these new biomarkers. These biomarkers are measured in patients with suspected DILI as both a mechanistic assessment for the severity of reaction and also for early diagnosis. Obviously it's a big medical need and would be very appropriate if we could have a market. In some way it can distinguish DILI from other causes of acute liver injury. In this TransBioLine study, cases are recruited in the PRO prospective European DILI registry, Pro-Euro DILI within Europe. Some of those patients who are suspected of DILI turn out to have other diagnoses such as virus hepatitis and cases who have an alternative diagnosis were used as a control group. This is valuable because one hypothesis is that some of these biomarkers can be used for early diagnosis. Hopefully they can be used to distinguish between DILI itself and other diagnoses. These biomarkers are for mechanistic assessment, early diagnosis, and also for predicting the course of reaction and prognosis. Some patients who develop DILI, will also particularly develop jaundice or acute liver failure, either die from liver failure or need a liver transplantation. But so far, I don't think we have very good evidence that these biomarkers are better than the others. Other biomarkers for example microRNA are tested. I cannot say which is the most promising biomarkers. I think we have to wait for the results of this TransBioLine effort.

 

《国际肝病》：新药有致肝损伤的可能性，如果采用探索性新药（Investigational New Drug, IND）来治疗DILI，如何平衡获益和风险？您认为如何减少这类新药临床试验中肝损伤恶化的风险？

 

: If there is a drug-induced liver injury treatment IND (Investigational New Drug) approved for clinical trials, the population are all liver injury patient. We know that the all the new drugs have the probability of liver injury. So how to balance the benefits and risks in the trials? How to reduce the risk of liver function deterioration in the trials?

 

Einar Bj?rnsson教授：多数DILI患者仅有轻中度肝损，当停药后可自行恢复。这类临床试验的目的之一是改变DILI的自然病程，仅针对部分特殊患者，例如抗结核药物引起的DILI可严重至肝衰，因此有必要对DILI进行治疗以挽救生命。

 

我并不完全同意所有新药都存在肝损风险这一说法。在美国注册的新药中，仅约50%存在DILI风险，一项研究对乙酰氨基酚引起DILI的RCT研究结果显示，DILI是可治愈的。当然在进行治疗DILI的临床研究中，有必要设立对照组。

 

研究DILI治疗的临床研究相对复杂，可尝试RCT研究来探索严重DILI的治疗，但在尝试新药治疗前应持谨慎的态度，以确保对DILI没有加重恶化的影响。目前对严重DILI的治疗手段有限，而并非所有患者都能进行肝移植治疗，因此，非常有必要进一步探索DILI的治疗策略。

 

Prof. Einar Bj?rnsson：Thank you for this important question. One of the goals of the clinical therapeutic trials is to alter the natural history of patients with DILI. This will be only for a specific part of those with DILI because most patients who have mild and moderate DILI don't require any treatment at all because they will recover when the implicated agents are discontinued. But a certain group of DILI, for example patients with anti-tuberculosis regiments can die of liver failure. There is a medical need to try to develop a therapeutic strategy that can save these patients with severe DILI. 

 

I think this is a very good and important question because we don't want to further worsen this liver injury by giving them another potentially hepatotoxic drug. But I'm I don't really completely agree with this question that all new drugs have the probability of liver injury. When you look at drugs on the market, for example, drugs that are registered in the United States, only approximately 50% of these drugs have a potential of DILI when scrutinized. For example, a drug that was given in a US RCT study to treat acetaminophen-induced liver injury, showed that DILI can be therapeutic. Therapeutic advances have been shown in early phases. 

 

I'm quite sure that not all drugs on the market have the probability of liver injury. In clinical trials, other therapeutic agents that have been used for prevention and treatment of DILI have not shown convincingly to have effect on DILI. So if people would like to do a therapeutic trial on DILI, I think placebo would be comparative to our intervention. It is complicated to design a therapeutic trial on DILI and it's conceivable that at least in some patients an RCT system could be tried to as a treatment for advanced DILI. This design and endpoints need to be really analyzed before we can decide on a treatment for DILI. But obviously, I agree completely with that the people should be very cautious when starting a treatment. The treatment should not have a worsen effect. 

 

I think we need to come up with a therapeutic strategy in patients with very advanced DILI within the scientific community and the medical field because at this moment, we don't have any means other than a liver transplantation which unfortunately cannot be achieved by all patients.