第29届亚太肝病学会年会（APASL2020）期间，荷兰阿姆斯特丹大学Ulrich H. Beuers教授代表欧洲肝病学会（EASL）出席会议、主持“APASL-EASL联合论坛-肝病并发症管理中”，并发表题为“胆汁淤积性疾病及其并发症的管理”的报告，介绍原发性胆汁性胆管炎（PBC）、原发性硬化性胆管炎（PSC）和IgG4相关性疾病的最新进展。
此外，非常难得的是，Beuers教授接受了《国际肝病》记者采访，就胆汁淤积性疾病问题进行了深度访谈，其中还分享了与中国肝病学同道的多次学术结缘。访谈内容详见下文，文末可查看英文实录。
《国际肝病》：在2020 APASL年会上，您讨论了自己与中国的交往，20年前，您在中国演讲时，被告知中国没有原发性胆汁性胆管炎（PBC），目前情况已经变化。您能谈谈这一点吗?
Beuers教授：我认为，对一种新的疾病作出诊断时，总是存在一个问题，就是仅仅去寻找这种疾病的认知问题。中国的发展给我留下深刻印象，自从我第一次到访中国，至今已经来中国讲学12次。在演讲中，我所报告的内容是胆汁淤积性肝病的诊断和治疗，一开始，并没有引起参会人员的太多兴趣，他们说有大量乙肝患者，但是，并未见到自身免疫性或免疫介导性疾病。
上海同行在这方面做了出色的研究工作，从他们那里得知，以PBC为例，中国和欧洲的PBC患病率非常相似（30～35例/10万居民），这意味着在1000位年龄为50岁的女性中，就有1例PBC患者，这一点非常重要，因为我们目前有很好的治疗方法，所以，这一点特别重要。
PBC是一种典型、并且最常见的慢性胆汁淤积性疾病，2/3的PBC患者可以享有正常的预期寿命。之前，通常情况下，如果患者不进行肝移植，会在10年后死于肝功能衰竭。
其他胆汁淤积性疾病也相似，诸如原发性硬化性胆管炎（PSC），中国比西方少见，我们一定不要忽视这种疾病。在过去十年内，我们也得知关于PSC的很多新知识。我们知道，看起来像PSC的疾病可能不是PSC，最好的例子就是IgG4相关性胆管炎。
在15年前，没有人知道这种疾病的存在。目前，我们知道，所谓的PSC患者，有10%～15%为IgG4相关性疾病，对这些患者应用糖皮质激素治疗特别成功，与PSC完全不同，PSC对糖皮质激素治疗无应答。因此，我们必须更好地认识这些不同的疾病，以作出诊断。我们仍然认为PSC是一种非常疑难的疾病。
与之前20年的认识不同，目前，我们不再认为PBC是一种自身免疫性疾病。我的观点为：PBC是一种胆道系统产生碳酸氢盐的分泌缺陷，我正在与越来越多的同行分享这一观点。我们知道，碳酸氢盐是胆管的关键保护因素，当胆管上皮细胞不能产生碳酸氢盐时，患者的胆管就会出现问题。胆管内的胆汁酸具有很强的侵袭性，如果没有碳酸氢盐作为胆管的保护伞，周围的胆管细胞就会暴露于胆汁酸。
我们认为，对于可能是继发于胆汁酸所致胆管上皮细胞损伤的所有免疫机制，这是理解的关键，这一点已被实验证明。因此，数据表明，首先是碳酸氢盐的分泌缺陷；第二步，具有疾病发生倾向的患者存在免疫反应；此外，对于某一个体会发生疾病，而另一个体不会发生疾病，还存在遗传因素的影响。
与PBC截然不同，PSC患者发生胆管癌的风险较高（病程随访期间，高达13%～15%的患者发生胆管癌），这些胆管癌患者通常很年轻。我们每年对患者进行超声检查，还要观察胆囊，两项大型队列发现3%的PSC患者会发生胆囊癌，因此，我们每年应用超声，对胆囊以及胆管和肝脏进行检查。
未来，如果核磁共振成像（MRI）和磁共振胰胆管成像（MRCP）变得更加便宜，甚至可以每年进行MRI和MRCP检查。但是，目前，每年进行超声检查即可。我们可以考虑每年进行CA19-9检测，但是，数据并不是很有说服力，因为炎症可以导致CA 19-9生化指标的升高。
有2/3的PSC患者合并炎症性肠病（IBD）。对于这些患者，我们每年常做的第二项检查是结肠镜检查，以观察异型增生和结肠癌的情况。因为与单独IBD患者相比，IBD合并PSC患者的结肠癌发生率高出5倍。因此，这些患者发生结肠癌的风险较高。
《国际肝病》：您还谈到IgG4相关性疾病和HISORt标准，能给我们解释一下吗？
Beuers教授：现今，IgG4相关性疾病是一个重要问题，在我个人的诊所里，有大约100例IgG4相关性疾病患者，他们最初都被误诊了。1/3的患者因为怀疑胆管癌或胰腺癌，而接受了半肝切除术或Whipple手术，但是，发现只是炎症，本来可以应用糖皮质激素治疗，就能够得到成功；另外2/3患者被误诊为PSC。
IgG4相关性疾病与PSC有相同的体征，但是，IgG4相关性疾病对泼尼松龙治疗的应答非常好，而PSC则对泼尼松龙治疗无应答。目前，我们知道，PSC队列的10%～15%并非PSC，而是IgG4相关性疾病。未来，我们可能会发现类似于PSC、但并非PSC的其他疾病。
HISORt标准是西方国家和地区用于诊断IgG4相关性疾病的标准。
“H”是指组织学（histology）—IgG4阳性浆细胞、席纹状纤维化和闭塞性静脉炎，这是三条标准，在对患者的组织进行检查时，需要符合两条或以上；“I”是指影像学（imaging）—器官肿胀，1型自身免疫性胰腺炎是IgG4相关性疾病的器官表现；“S”是指血清标志物（serum marker），但是，血清IgG4升高只见于75%左右的患者，所以，很可惜，IgG4并不是灵敏的标志物；“O”是累积其他器官（other organ involvement），可以是胰腺、胆管、前列腺、睾丸、肺、淋巴结、甲状腺和腮腺，这些都是分泌器官，在我看来，IgG4相关性疾病的病理生理学与许多这样的腺器官有关；HISORt的“Rt”是对糖皮质激素治疗的应答，这些患者对类固醇治疗的应答非常好。
《国际肝病》：在您谈到IgG4相关性疾病时，给出两个例子，一个是关于养蜂人的，另一个涉及与职业有关的过敏原的作用，您能详细说明一下吗?
Beuers教授：我们对IgG4相关性疾病的研究，始于1997年的一篇论文。该论文对加那利群岛的养蜂人进行了血清IgG4的研究，发现人们饲养蜜蜂的时间越长，就会产生越多的IgG4。同样明显的是，IgG4水平最高的那些养蜂人对严重过敏反应有更好的保护作用。
基于该项观察以及我们和他人的研究数据，IgG4是一种对免疫系统有抑制作用的免疫球蛋白，并非具有侵略性的免疫球蛋白，当它遇到抗原时，会温和地抑制免疫系统的强烈反应，我们认为这是一种保护机制。
我们的想法是利用新一代测序技术，寻找IgG4 B细胞受体克隆，与健康人群或其他患者相比。我们发现IgG4相关性疾病患者的IgG4克隆增加，这与健康人群以及诸如血清IgG4水平升高的PSC或胆管癌患者等其他对照明显不同。
应用这一复杂、耗时且昂贵的技术，诊断IgG4相关性疾病的敏感性和特异性均达到100%，因此，能够对IgG4相关性疾病与PSC或胆管癌进行鉴别，而PSC和胆管癌是IgG4相关性胆管炎患者的主要鉴别诊断。
《国际肝病》：那么，这个故事的寓意是什么？被蜜蜂蛰伤有好处吗？
Beuers教授：这是个好问题！但是，答案是被蜜蜂蜇伤并没有好处，对抗蜜蜂蜇伤毒素的IgG4，并不是我们保护器官所需要的IgG4相关性疾病的IgG4。
《国际肝病》：另外一个故事是许多蓝领工人都表现出这种情况……Beuers教授：这是我们的观察结果，在我们的研究队列中，多数患者为男性（85%），并且多数为高龄（>60岁），让我们非常困惑。我的同事去患者的家里，非常仔细地记录了他们的病史，我们发现很大一部分患者是蓝领工人（大约75%）——卡车司机、船长、油漆工和使用大量溶剂/柴油/石油产品的其他职业。实质上，这些物质是环境毒素，他们并没有出现传统意义上的过敏反应。
第一步，是确定这些物质被吸收的机制，我们仍然在进行研究，确定哪种分子是引发这种疾病的罪魁祸首。我认为，很多患者吸入了这些环境毒素，进入敏感器官，而胰腺似乎是敏感的中心，多数患者有自身免疫性胰腺炎，然后，其他器官受累，可能表现为无症状的自身免疫性胰腺炎。
自身抗原被免疫系统检测到，然后受到攻击，疾病就会进展。暴露发生于很长一段时间，并且可能是很久以前，所以，看上去是一个非常缓慢的过程。但是，目前还不能说更多，我们还在继续调查研究。
《国际肝病》：在报告总结中，您说解决这些问题的关键是反复再三地回顾病史，可以解释一下吗？
Beuers教授：我举了一个具体的例子，一位黄疸患者在另一家医院接受了大量检查，没有得出诊断。我并不是应用之前已经做过的各种昂贵的检查结果，而是通过反复再三地询问患者，可能是什么原因导致这种疾病，从而作出了诊断。
最后，我发现她在几周前曾经接受抗生素治疗，而她和她的女儿都忘记了这一点，但是，这一点被记录下来，所以，这是一例药物性肝损伤。这种情况经常发生，但是，实际上，我们经常忽略。这是我几十年来一直采用的方法，那位患者因此得以诊断。
《国际肝病》：EASL和APASL之间有很多合作，您能谈谈这两个学会之间的友谊吗？
Beuers教授：这是一种长期关系，我们一直致力于相互交流，并且联合制定诊断和治疗肝脏疾病的指南及策略。我们代表不同的患者群体，但是，在许多情况下，原则和问题是相同的。我们只有互相学习，才能够找到诊断和治疗患者最有效的方法。成功的秘诀是合作，实现共赢。
原文呈现：（可上下滑动查看）
: At APASL2020, you discussed your association with China. When you spoke in China twenty years ago, you were told China saw no primary biliary cholangitis (PBC). Now that has changed. Can you discuss that?
Dr Beuer: I think it is always a problem when you make a diagnosis of a new disease, that there is a problem of awareness to simply look for the disease. I was impressed with development on my first visit to China, and I have returned twelve times since to give talks. I was talking about the diagnosis and management of cholestatic liver disease in my lectures, and initially there was not much interest. People said they had a lot of hepatitis B, but were not seeing the autoimmune/immune-mediated diseases. We know from our colleagues in Shanghai who did excellent investigation in this field, that the prevalence rates of PBC, as an example, were very similar to those seen in Europe (30-35/100000 residents). This comes down to 1 in 1000 women fifty years of age. That becomes relevant, and particularly relevant because we now have good treatment for this condition. It is a typical example of a chronic cholestatic disease, and the most frequently seen, with two-thirds of patients living a normal life expectancy. Formally, patients would die after ten years due to liver failure without a liver transplantation. It is comparable to other cholestatic diseases, like primary sclerosing cholangitis (PSC), which is less common in China compared to the West, and we need to be sure not to overlook it. We have also learned a lot about PSC over the last ten years, and we know that what looks like PSC may not be PSC. The best example of that now is IgG-related cholangitis. Fifteen years ago, no one knew that this existed. Now we know that 10-15% of our patients who we called PSC have IgG-related disease, for which there is a completely different (and successful) treatment using corticosteroids. PSC does not respond to corticosteroids. So we have to better at our awareness of these different diseases to make diagnoses. We still consider PSC a very difficult disease. PBC is now not considered an autoimmune disease, as we thought for the previous twenty years. My view (and I am sharing this view with increasingly more colleagues) is that PBC is a secretory defect in the production of bicarbonate in the biliary tree. We know that bicarbonate is a key protective factor in the bile ducts, and when bicarbonate is not produced by the biliary epithelial cells, patients develop problems with their bile ducts. Bile acids in the bile ducts are very aggressive, and without the protective biliary bicarbonate umbrella, the cholangiocytes surrounding the bile ducts are exposed. We think this is a key to understanding that all the immune mechanisms are probably secondary to the damage done to the bile duct epithelial cells by bile acids. This has been experimentally shown already, so we have data to show that firstly there is a secretory defect of bicarbonate, and secondly, there are immune reactions in those patients who tend to develop this disease. Additionally, there are genetic factors that have an impact on whether one individual will have this condition, while another individual will not. We know PSC, as opposed to PBC, has a high risk of developing cholangiocarcinoma (up to 13-15% of patients during the course of their disease). These cholangiocarcinoma patients are usually young. We do annual ultrasound to look at the gall bladder as well. In 3% of two large cohorts, they found gall bladder carcinoma, so we check that annually, along with the bile ducts and liver using ultrasound. Maybe in the future should it become more affordable, we will even do annual MRI and MRCP, but at this moment, annual ultrasound is fine. We could consider CA 19-9 determinations annually, but the data are not that convincing, as inflammation can induce increases in CA 19-9 as a biochemical marker. The second annual test we always do is colonoscopy in patients who have the combination of PSC with inflammatory bowl disease (IBD), seen in two-thirds of patients. The annual colonoscopy looks for dysplasia and colon carcinoma, because colon carcinoma frequency is five times higher in patients with PSC and IBD, compared to patients with IBD alone. So there is a higher risk for the development of carcinoma.
: You also talked about the IgG4-related disease and the HISORt criteria. Could you define that for us?
Dr Beuer: IgG4-related disease is a problem today. In my personal clinic, I have around 100 patients with this condition, who were all initially incorrectly diagnosed. One third of them underwent hemihepatectomy or a Whipple procedure for suspicion of cholangiocarcinoma or pancreatic carcinoma, but there was found to only be inflammation that could have been successfully treated with corticosteroids. The other two-thirds of patients had been misclassified as PSC (primary sclerosing cholangitis), for example, because they show the same signs, but respond very well to prednisolone, which PSC does not do. We know today that 10-15% of our PSC cohorts are not PSC but IgG4-related disease. In the future, we will probably be able to detect other diseases that mimic PSC, but are not PSC. The HISORt criteria are the diagnostic criteria we use in the Western world for making the diagnosis of IgG4-related disease. The “H” is for histology - IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. Those are the three criteria, and two need to be fulfilled in the histology workup of a patient’s tissue. “I” stands for imaging - swelling of organs. Autoimmune pancreatitis type 1 is one organ manifestation of IgG4-related disease. “S” is for serum marker, but serum IgG4 is only elevated in around 75% of patients, so this is a non-sensitive marker unfortunately. “O” is other organ involvement, and that can be the pancreas, bile ducts, prostate, testes, lungs, lymph nodes, thyroid and salivary glands. These are all secretory organs, and this pathophysiology is linked to many of these glandular organs in my opinion. “Rt” of HISORt is the response to corticosteroid treatment. These patients respond very well to steroid therapy: During your talk on IgG4-related disease, you gave two illustrations, one related to beekeepers, and the other concerned the role of occupational allergens. Can you elaborate on that?
Dr Beuer: Our research started in IgG4-related disease based on a paper from 1997 where beekeepers from the Canary Islands were investigated for serum IgG4. They found that the longer people keep bees, the more immunoglobulin G4 (IgG4) they develop. It was also obvious that those beekeepers with the highest levels of IgG4 had better protection against severe allergic reactions. Based on that observation and our own consequent data and from others, IgG4 is an immune system damping immunoglobulin. It is not an aggressive immunoglobulin, but gently turns down intense reactions of the immune system when it meets an antigen. We think it is a protective mechanism. It was our idea to look for IgG4 B-cell receptor clones using a novel next-generation sequencing technique, and we saw that our IgG4 patients had increased IgG4 clones compared to otherwise healthy patients. This was strikingly different from healthy patients and other controls, such as patients with elevated serum IgG4 PSC/cholangiocarcinoma patients. We showed 100% sensitivity, 100% specificity using this complicated, time-consuming and costly technique and thus able to distinguish the difference between IgG4-related disease and PSC and cholangiocarcinoma, which are the major differential diagnoses in patients with IgG4-related cholangitis.
: So is the moral of the story, that there are benefits to being stung by bees?
Dr Beuer: That is a good question. But the answer is no in this case. The IgG4 against the bee sting toxin is not the IgG4 we need for IgG4-related disease to protect our organs.
: The other story was that a lot of blue-collar workers were exhibiting this condition.
Dr Beuer: That was our observation. In our cohorts, most of the patients were male (85%) and most were elderly (>60 years), and that puzzled us. My colleague went to patients’ homes and took very careful histories, and we found a large proportion of our patients were blue-collar workers (around 75%) – truck drivers, ship captains, painters and occupations where a lot of solvent/diesel/oil products are used, essentially environmental toxins. They are not experiencing an allergic reaction as such, as we traditionally see allergic reactions. The first step is determining the mechanism whereby these substances are absorbed and we are still busy identifying the culprit molecules for initiating this disease. But I think many patients inhale them, and they get to sensitive organs, and the pancreas seems to be a center of sensitivity. Most of the patients have autoimmune pancreatitis, and then other organ involvement. This can be a silent autoimmune pancreatitis. Autoantigens are detected by the immune system and then attacked, so the disease progresses. Exposure occurs over a long time, and could have been a long time ago, so this appears to be a very slow process. But I can’t say much more at this time as our investigations continue.
: In your summary, you stated that the key to these conditions is to take a thorough history again and again and again. Can you explain that?
Dr Beuer: I used a specific case as an example of a jaundiced patient who was worked up extensively in another hospital and they couldn’t arrive at a diagnosis. How I reached a diagnosis was not with fancy expensive investigations that had already been performed, but by asking the patient again and again and again what the cause of the disease could be. Finally, I found out that she had been treated with an antibiotic a few weeks previously, and she and her daughter had both forgotten about it. It was documented however, and we were able to access that. So it was a drug-induced liver injury, as occurs very often, and indeed, we overlook very often. That has been my approach for decades though, so it paid off for that patient.
: There is a lot of collaboration between EASL and APASL. Can you talk about that friendship?
Dr Beuer: This is a long-term relationship. We always try to have interactions and take a joint approach to developing guidelines and strategies in the diagnosis and treatment of liver diseases. We represent different patient groups, but in many cases, the principles and problems are the same. We can only learn from each other in discovering the most effective approaches to diagnosis and treatment for our patients. The secret to success is collaboration, and it is to everyone’s benefit.