APASL 2020| An in-depth interview with Prof. Beuer: Hot issues of related diseases of PBC, PSC and IGG4

During the 29th Asian Pacific Association for the Study of the Liver (APASL2020), Prof.Ulrich H. Beuers from university of Amsterdam in the Netherlands, who on behalf of The European Association for the Study of the Liver (EASL) attend the meeting, presided over the APASL - EASL joint BBS - liver disease complications management ", and published titled "cholestasis disease and the management of its complications" of the report, the introduction of Primary biliary cholangitis (PBC), Primary sclerosing cholangitis (PSC) and the latest progress of IGG4 related diseases.

 

Besides, Professor Beuers to have an in-depth interview with the journalist of Hepatology Digest on the topic of cholestasis, in which he Shared many academic connections with Chinese hepatology.

Hepatology Digest: 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.

 

Hepatology Digest: 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.

 

Hepatology Digest: 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.

 

Hepatology Digest: 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.

 

Hepatology Digest: 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.

 

Hepatology Digest: 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.