Okay, so I'm going to go ahead and get started and introduce our speaker for today. I'm certain that people will continue joining, but I want to make sure that you have all the time in the world to get through your presentation and also that we have time for questions. Some of you may wonder why I'm doing the introductions and not Dr. Dara. My understanding is that Lily has been on, I don't know, six time zones or something like that in the last week or whatnot, and is currently away in DC at a meeting. So I am your host today. It is my pleasure to welcome Dr. Fernando Bessone, who is a professor of gastroenterology at the University of Rosario Medical School in Argentina, and Lily coordinated this one. We're so lucky to have you here, and I take no credit for the outstanding talk that will come next. I want to make sure Lily gets the full credit, but I do need to give you a little bit of background on Dr. Bessone's work. He obtained his PhD and MD from Argentina and is currently the head of the Department of Gastroenterology and Hepatology at the University Hospital of Rosario Medical School. Among his accolades, he's the past president of the Argentinian Association for the Study of Liver Disease. My impression from what is a short biosketch that can only be compiled into a page and a half is that he is an incredibly sought after consultant and expert in Dilley and has been a principal investigator or a co-investigator on upwards of 70 clinical trials. He's also an award-winning scientist and author of more than 100 published peer-reviewed papers, 30 book chapters, and 170 papers presented at meetings. Today he's going to talk to us about long-term experience of the Latin Dilley network focusing on NSAIDs, and I'll welcome him shortly. For those of you with questions, please put them in the chat. You'll see instructions from me there. It's perfectly fine to say you have a question. I will simply call on you at the end of the talk and try to coordinate that. Feel free to unmute, turn on your camera. If you'd prefer not to do that, just put your question in the chat and I will ask it for you. Welcome, Dr. Bassone. Looking forward to your talk. Okay. Thank you. Thank you so much, Jim and Lily, Dara, for inviting me to give this lecture. It's really a pleasure to develop my topic in this important SLD group. Having said that, as was proposed by Lily, I divided my lecture in two parts. The first one, I will tell you the long-term experience in the Latin Dilley network, and then I will focus on non-steroidal anti-inflammatory drugs. The growing and the amazing universe of hepatotoxicity is really growing and continues expanding its knowledge, including several topics and fields like genetics, genomic-wide association study, biomarkers, and in the last two decades, the creation of hepatotoxicity networks, they play an important role because they provide characterization on Dilley phenotypes, and it's important also to know that help to improve surveillance and facilitate collaboration between healthcare and professionals, and also helping and assist health authority providing data on drug safety and marking which drugs should be drawn from the market. Our Latin Dilley network began in 2012 because Latin America is a vast region, combining different ethnics, genetics, backgrounds, and demographic backgrounds. Our Dilley network began with the support of Raúl Andrade and Maribel Lucena from the Dilley network of Spain, many, many, many thanks to them, and all my gratitude for their support. Now, I actually have a registry with many, many countries, and Colombia just added recently to our Dilley. Our first paper was published in 2012, highlighting the most important project, how our cases will be collected. Five years later, we had 2,006 patients, and our results showed that we have the amoxicillin clavulanic acid at the top of the list, and in second place, anti-inflammatory drugs. As you can see here, different drugs are in second place in other registries. Seven years later, anti-TB drugs dropped in the fourth place, but amoxicillin clavulanic acid, nitrofurantoin, and diclofenac were in the same place. And, strikingly, 10 years later, as I will tell you further on, HDS moved to the second place on the list, and estanozolol moved into the fourth place, and green tea ranked in the top 10. It was a very, very interesting finding 10 years later, according to what happened with herbs around the world. Sorry. Then, our aims in this paper was perceptibly analyze phenotypes and clinical pattern of drug-induced liver injury in 460 patients to study demographic characteristics and the sample frequency of hospitalization, severity, and morbid mortality, and then to compare our results with other hepatotoxicity registries. Our results show that hepatocellular pattern was the most frequent, and age, as you can see there, was higher in the college study group, and female was important in the total our registry in 62% of cases. Interestingly, it was the fact that hypertension, arterial hypertension, was important in college study group. Maybe this kind of complication is more frequent in older patients. Jandice was important in our registry, 60%, and was lower in hepatocellular group, as corresponded that bilirubin is more elevated in college study group. Hospitalization was 42% lower in hepatocellular group, and the duration of therapy was in a median of 34 days, as you can see there, was more important in hepatocellular group. Interesting was the fact that 7% of cases had an elderly chronic liver disease, mainly histiopatosis, NASH, now MASH, and autoimmune hepatitis in 15% of cases. Regarding laboratory tests, as expected, hepatocellular parameters in laboratory were higher in hepatocellular against colostatic, and again, this result, colostatic parameters for alkaline phosphatase was higher in colostatic group. Important number of autoantibodies was found in almost 70% of cases in hepatocellular group, as you can see there, against colostatic group. We didn't see mild cases, as you can see there, were more frequent in hepatocellular group against colostatic and MASH group. And the other point important, we show 4% of fatal and liver transplantation in our group, it was higher and corresponded the major of cases in hepatocellular group. As expected, liver-related disease and liver transplantation were also higher in hepatocellular group. It's interesting that among cases with follow-up antiresolution, we had 28 cases, 12% of patients developed chronic DILI. Another important point was we made an exploratory multivariable model that showed that lower albumin-level rash increased, total bilirubin and ALT-level aldilurekinesium were found as bad prognosis, as a prognosis factor of worse outcome. This is our number. In total, we studied, we found 121 different drugs responsible of DILI. At the top of the list, similar to what happened in other registry, amoxiclavalinic acid was at the top of the list. Second, herbs and diuretic supplements, garcila, camellia sinensis, green tea, garcinia jamboya and herbalized product. In third place, combination, but in fourth place move, estanosolol and anabolic esteroid. It was, most of them were hepatocillular, had a hepatocillular pattern and only amoxiclavalinic and atorvartazine were a cholestatic pattern. It was interesting, we found that 31% of hepatocillular cases in amoxiclavalinic acid was observed in younger people, like other registry. According RUCAM scale, we found that close 70% were probable and only 6% were highly probable. Another interesting point was that 24, 5% of patients developed eosinophilia and systemic symptoms, as you can see there. And 9 cases were associated with autoimmune-like hepatitis. Regarding the predictive value of classic High's law, it was drug specific. I have two examples, for example, 20% of DILI associated with amoxiclavalinic acid and 35% a fulfilling criteria with nitrofurantoin, which fulfilled criteria of High's law. None of them evolved to fatal outcome. On the contrary, against the results, DILI associated with SDAs, anti-TB drugs, and nimesulids which fulfilled criteria of High's law, between 20 and 50% of cases died or needed a liver transplant. This is an important point because High's law was drug specific in our paper. Now, an analysis of calpidrug in presentation in autoimmune hepatitis, it corresponds to around 2% of cases. We found similar data that found by others because nitrofurantoin and minocycline were on the top of the list. Most of cases had a hepatocellular pattern and a very, very long latency in two cases, more than 1,000 and 2,000 days. All of them had any autoantibody. 60% were associated with elevated EGG, and most of them had filters comparable, similar to classic autoimmune hepatitis, like interface hepatitis, rosettes, and infiltrate, eosinophilic infiltrate. We didn't see severe cases of liver damage, only moderate and mild cases, and most of patients, except two patients, received corticosteroids, and three patients received corticosteroids and azathiophrine. Only one patient relapsed within this group. When we carried out a comparative analysis with other international registries, we found a not significant mean age, but you can see here, lower age was found in Latin Delhi, in Delhi, in American Delhi, and Indian registry. Female was significant in 62% in Latin Delhi compared with the other registry. Interesting was also the point that in Delhi, they have higher pre-existing liver disease. And another point, interesting, another point is that Indian registry had only 30% of hepatocellular pattern, if we have into account that anti-TB drugs are on the top of the list in India, no? And they had also the most important pattern in college study group. Hospitalization was lower also in Delhi group and in Latin Delhi group, and latency was longer also in Delhi group. As you can see here, amoxiclavulanic axis was the most frequent at the top drugs, while anti-TB and non-steroidal anti-inflammatory drugs were in Indian registry and Japan registry respectively. The second place was composed by different drugs, and in the third place also different drugs. It's important that HDS supplementary dietary supplements are important in most of the registry within the 10 first drugs. Herbal and dietary supplement analysis, we published the first publication in Latin America three years ago, where we found that an increase of consumption of herbs between 2011 and 2019, contrary what happened in the consumption of androgenics drugs. We found, we analyzed 377 patients, and we found 8% of Delhi attributed to herbals and dietary supplements. And on the top of the list, we found camellia sinensis, herbal products, argazinia cambogia. It's important to say that we didn't see any more cases maybe during the last 10 years. It was a group composed mainly by young women, no more in a mean age of 45 years, with a median time to onset of 31 days. Most of patients presented hepatocellular pattern of injury, and 66% were genders. It wasn't our concern that five patients, 70% developed acute liver failure. And in our recent paper, recently published no more than one, two months ago, with more than 400 patients, we analyzed herbs and dietary supplements in 42 patients and compared this group of patients with anabolic esteroids in 23 patients. This was very interesting data, because as expected, a mean age was higher in women using this kind of composed to lose weight, was higher than people that use bodybuilding drugs are very younger, obviously. And female was more frequent, obviously, in women trying to weight loss. And hepatocellular was more frequent in HDS compared with cholestatic group. On the other hand, cholestatic group, esteroids anabolic was more frequent, because this kind of patient developed frequently prolonged cholestasis with pruritus. When we analyzed Jandice, Jandice was more frequent in esteroids anabolics, as I said before, because they develop frequently cholestatic forms and prolonged form with pruritus. We didn't see significantly appearance of fever rash and hospitalization in this group, but duration of therapy was longer in patients who develop cholestasis regarding a steroid-anabolic patient. And when we analyzed the laboratory parameters, we saw, as expected, that the HDAs who develop frequently hepatocellular and liver damage had a higher level of transaminases against anabolic steroid. Regarding severity, we didn't see mild forms in anabolic steroids, but moderate cases were more frequent in anabolic steroids. Contrary to what happened when we analyzed fatal liver transplantation, as expected, because HDAs develop more frequently this kind of liver disease. Regarding modified steroids, we found it was drug-specific, too, in 40% and 50% respectively in HDAs and anabolic steroids. Time to resolution was longer in anabolic steroids because they develop a prolonged form, cholestatic prolonged form, sometimes associated with kidney damage and kidney disease. And, as expected, also severity or more severe forms of liver damage were seen in this kind of patient with HDAs liver damage against anabolic steroids. Okay, this is my first part of my talk. And now I would like to focus on non-steroidal liver damage. This is a very interesting talk. We published some papers and it specifically was always a very interesting field for me. You have to know that non-steroidal and inflammatory drugs are divided in three main cases. One-hand aspirin that acts irreversibly inhibits both COX-1 and COX-2 by covalent acetylation. These agents only induce liver damage when it's used in high dose. And COX-2 is a very interesting agent. These agents were designed and created to avoid gastrointestinal side effects induced by COX-1 and COX-2 inhibitors. And finally, non-selective COX inhibitors that inhibit COX-1 and COX-2 is composed by ibuprofen and naproxen. And it's important to know that we have another classification important published in liver talks that this kind of group is divided in propionic acid, acetic acid, phenamic acid, piercolone, and oxycans. And if we divide classes regarding COX-2, the only FDA-approved selective COX-2 inhibitor is selecoxib. And selecoxib is not FDA-approved, but this is approved in more than 60 countries around the world. You have to know that ibuprofen and diclofenac are the most frequent drugs sold in the United States over the country, and followed by ketoprofen, naproxen, intermedicine, and pyroxican. It's important to say that salindac has a restricted use only by 15 days because it is associated with a risk of severe liver damage, like happened with nimesolide that is approved in more than 50 countries around the world. But there was a warning by EMA in Europe restricting its treatment only for 15 days. I will comment you further on. This is really, we have amazing data regarding anti-inflammatory drugs because, if you can see here, 30 million people take non-steroidal anti-inflammatory drugs daily around the world. Consumption increased 40% from 2005 to 2010. And this is more important that 90% of individuals using, over the country, ibuprofen, 37% took another non-steroidal, and 11% exceeded recommended dose. This is really a concern and a problematic issue. Non-steroidal anti-inflammatory drugs account for 10% of total daily, and 25% of patients develop at least one adverse event, and 40.5% in 100,000 patients a year need hospitalization. 6% in a global group of non-steroidal anti-inflammatory drugs develop liver failure. And the last important point is that close to 20% of patients develop asymptomatic hypertransaminosemia. I think that's a very important number. And how to study the incidence of daily induced by non-steroidal anti-inflammatory drugs is really a conflictive issue, really a conflictive issue, because most of the past studies were retrospective in the science, and they lack the denominator by number of prescriptions. They do not take into account all population, inclusive people under 18 years, do not take into account hospitalization and death rates. It's a difficult group for analysis due to overlapping factors like alcohol, concomitant drug use, and insufficient number of pre- and post-marketing study. We need more than 100,000 individuals to have a real number of incidence. And there is another underreporting of asymptomatic hypertransaminosemia. More than one decade ago, we published a review and analysis trying to find which was the real incidence of these drugs. And we found dissimilar results ranging in one to nine cases by 100,000 patient year. Maybe that study carried out by Traversa was a very interesting study within the retrospective study, but the most important study was that published by LINE, which analyzed more 70,000 patients during five years, and we found a very low rate of toxicity induced by Diclofenax. Another very interesting results were published by a Thailand group. They analyzed more than 600 studies, and only 18 studies met the selection criteria. And within these only eight studies included three non-accessorized drugs, Selecoxib, Etoricoxib, and Diclofenax. And they found that Diclofenax had the highest proportion of delay and a low rate of liver hospitalization. It's my thought only. It was followed by Selecoxib in lower appearance, which ranged from 0.13 to 0.38, and Etoricoxib lower than Selecoxib. What do the different international dealing networks say? This is a very important point because when we analyze the impact on non-accessorized anti-inflammatory drugs in different networks, we found that Italy had 36% of patients consuming anti-inflammatory drugs with Nimesulide at the top of the list. And Diclofenax was the most important drug in dealing and the most important drugs in Ireland. And Nimesulide was the most important drug involved in dealing. And Ibuprofen was only in the top of the list in the Spanish registry. This is an example, a clear example, that Nimesulide is actually used in many, many, many countries. In summary, the three most common non-steroidal anti-inflammatory drugs in registry, Nimesulide, Diclofenax, and Ibuprofen are the most important drugs. Regarding Ibuprofen, we received an important number of patients during the last decades in the Spanish registry. And we plan to write a paper to analyze what happened with Ibuprofen in Spanish. We analyzed 31 Ibuprofen-induced daily in the Spanish registry and five cases in the Latin daily. And we compared this group with 76 idiosyncratic hepatotoxicity events and compared also with more than 800 patients suffering non-steroidal anti-inflammatory drug induced hepatitis in our database. And we didn't find differences regarding demographic data and clinical presentation. Only we find a lower age, a lower age in people major of 60 year old, maybe because Ibuprofen is used as an antipyretic also in young people. And treatment duration was lower in patients with Ibuprofen. Hepatocellular hypertension generally appears upon four weeks from treatment initiation. And we found 27% of autoantibodies in this sample. Interesting was that hypertension was lower in Ibuprofen group, but diabetes was higher. We don't have now robust data saying that diabetes represents more risk of hepatotoxicity, but we recommend Ibuprofen in diabetic patients at the lower dose, if possible. And fatal liver transplantation, despite of the fact it was really a very small sample, was higher when compared with other non-steroidal anti-inflammatory drugs and non-inflammatory anti-inflammatory drugs. Nimesulide had several papers reporting more risk of hepatotoxicity, like this study of Traversa and this study from Italy carried out by Donati, where the risk was increased when it was related with Nimesulide. And in addition to this concept, there was a warning issued from EMA in Europe restricting due to these several acute liver failure and Nimesulide had no more than 15 days. That presentation contained more than 30 doses in patients with chronic liver disease. When we took all this data, we thought that it was very interesting and important to analyze our cohort with 76 patients, 46 from Argentina and 11 patients from Spain, where Mines was 79 years. The median time to onset latency was 40 days and 80% of patients were Jandis. D-lipata was hepatocellular and MIGS only 21%. Transaminases were elevating, I mean, nearly 20-fold and total bilirubin, the mean elevation, was 13-fold upper limit unit. Liver histology in 14 patient cases, most of them showed a hepatocellular pattern. The median time, the recovery was 70 days and the interesting point was that 12 patients developed acute liver failure, 5 of them died and 3 patients were underwent liver transplantation and contrary to say EMA latency before 15 days, 12 patients developed liver disease induced by Nimesulide before 15 days and 1 patient developed acute liver failure before 1 week. In Greece, total bilirubin-ACST liver was independently associated with development of acute liver failure. This is only to show you the spectrum of histology. In slide A, you can see a pure cholestasis associating with the plaques, biliary plaques. In the second slide, B is a typical MIGS pattern with biliary plaque, moderate inflammation, pure hepatitis in C and acute liver failure with massive necrosis due to larmental pleasure as an attempt of liver regeneration. Diclofenac, again, this is the most interesting study because this prostrative line analyzed more than 70,000 patients during 18 months. He found only a 0.6% patient with ACLT more than 10 times and liver-related hospitalization was very, very lower. This drug is commonly associated with elevation generally in the first 4 and 6 months. I remember that a study published by Bank in 1995, he showed that around 10% were latency more than 6 months. Clinical liver events requiring hospitalization was rare, no more than 23 over 100,000 patients. Contrary to this result, a very, very interesting paper published by Dealing Group from the US showed 16 cases with a very important hepatocellular pattern, with a very important increase of transaminases, with a range of latency between 6 and 190 days. Six patients developed autoimmune hepatitis and four patients needed corticosteroids, but eight patients out of 16 cases developed coagulopathy, developed a severe, severe hepatitis. And like published by others, 12 out of 16 patients received at least 150 milligrams of the Glufenag. We know today that this is more probably developed, ideally associated with the Glufenag when the patient consumes more than 100 milligrams. And finalizing my talk, I present this oral paper two days ago in the Latin American meeting in hepatology. We compared different steroid anabolics in our database, and we analyzed 41 in Latin Delhi, and we analyzed 82 in the Spanish registry. Look at the interesting results. Ibuprofen in the top of the list in the Spanish registry, followed by the Glufenag and Nimesolide. And in the Spanish, the Glufenag is in the top of the list, followed by Nimesolide. But in the fourth place, with five cases, heteroicoxif against one only case in Spanish Delhi. When we analyzed the global group, females predominate 73 cases compared with 47 in Spanish. There was a tendency towards a higher hospitalization in the Spanish case against Latin Delhi, and Haislau showed again a drug-specific predictive value with ibuprofen, Nimesolide, and heteroicoxif. Look at this. Again, hospitalization, we compare ibuprofen and the Glufenag hospitalization had a tendency to be higher in the Spanish group. And Haislau was drug-specific, I just commented you before. Liver-related, this is a very small sample, but we saw one death and one liver transplantation in the Spanish group against zero in the Latin dealing group. No fatal outcome related to diclofenac was observed in both registries. Conclusion of this paper, differences in the incidence may be related with prescription difference, demographic difference, genetic difference, and healthcare access may be it is a difficult point. High slow showed to have drug specific predictive value with ibuprofen, nimesulid, and etoricoxib. And etoricoxib was associated to a several liver damage. Finalizing with Cox inhibitor, due to the lack of information 10 years ago, we were enthusiastic idea to analyze literature and we found that there was two generations of Cox inhibitor. The first generation with selecoxib is the only FDA approved in the U.S. And etoricoxib not approved in the U.S. but approved in more than 60 countries around the world. But most of them was withdrawn, was suspended, was removed from the pharmacological market because they are associated with cardiovascular event and except of lumarococci associated with severe liver damage. Things changed from that paper. We learned a lot of Cox inhibitors since that review. We wrote that scarce publications were associated with selecoxib and absence of prolonged cholestasis and etoricoxib only as symptomatic as my basic work described. But now we know that selecoxib is associated with hepatocellular and cholestatic form associated with intense pruritus, short period of latency, and this is a very interesting point because it's associated with allergic phenomena associated with the appearance and presentation of this drug. And many, many patients had a past of history of sulfonyl hypersensitivity. And prolonged cholestasis evolving to varnish in bile-like syndromes is a very, very interesting point and acute liver failure developed more frequently in females. And finally, you know that etoricoxib is rare. Asymptomatic hyperglycemia was only reported in 0.1%. My hepatitis was published only in one study. No cases to my knowledge were published associated with acute liver failure. But we analyzed our five cases in our registry, mainly in female, in the mean age, the 45-year hepatocellular pattern in all of patients, short period of latency, three over five shunties, and one of five hospitalizations. And one patient died regarding this agent, this drug. Final, this is my last point, take-home messages regarding 10 years of experience. Fetal auxilia in Latin America are comparable to other perceptive registry. Amoxiclavulanic is at the top of the list, but HDS moved to the second place. Nevertheless, there is a different pattern of drug response, increasing incidence of HDS. Fetal outcome was observed in 4% of patients and 12% of patients developed chronic deletion taken. The definition was elevated, laboratory tests more than one year. Finally, nimesolide and intrafluorantoline calling for a public health policy to raise awareness the potential risk nimesolide of acute liver failure and intrafluorantoline associated to autoimmune-like hepatitis. Regarding anti-inflammatory drugs, diclofenac, ibuprofen, nimesolide are the most common associated daily. Nimesolide can induce severe liver failure before 15 days against the opinion of the AMA in Europe. The risk of developing ibuprofen-induced liver injury is really low. Diclofenac is associated with a low rate of severe clinical rate at low rate of hospitalization. And we have to take into account that selicoxib and entericoxib can be associated with severe liver damage. Future liver direction, I have to talk different points, but only three points. Despite a good progress on the understanding of genetic just increasing daily, further studies are needed before we press implementation to prevent daily reaction, to identify the role of new molecular biomarkers in the mechanism of daily. And this biomarker should be combined with traditional biomarker and daily-related scoring system for helping in daily diagnosis. I would like to thank to my group, Maribel Lucena and Raul Andrade and Nelly Hernandez for helping me in all my talks in this registry and all Latin daily collaborators in Argentina and other Latin American countries. Thank you. Thank you really very much for inviting me. Thank you very much. That was fantastic. That's like a heroic, I mean, this is a downright heroic effort to put all of this together. So, and also thanks for summarizing that in the talk. That's great. We'll open it up for questions. Kind reminder, if you want to put your question in the chat or just let me know you have a question, I'll call on you in the order that those come out. And I believe we're starting with Jay. I saw a question that you had in the chat. Do you want to unmute and ask? Well, actually, my bigger question is ibuprofen, which we found very rarely in Dillon. And I wondered whether we were just missing it. We were assuming that it's a benign drug and missing it, but I have not been able to find it. So, I wonder whether there's some racial differences and, you know, as far as ancestry. I think it would be very helpful for the Dillon group to collaborate with you and with our friend Andrade, looking at these cases and looking at them in detail. You know, the specifics of them, not just, you know, when you say hepatocellular or cholestatic, that's not always a very clear-cut difference. You know, that depends on when you test the samples. For instance, anabolic steroids. Very frequently, the initial blood test looks hepatocellular because the alkaline phosphatase is normal, despite a bilirubin of 10. A normal alkaline phosphatase. And alkaline phosphatase goes up slowly, and the ALT and AST goes down very quickly. So, it looks hepatocellular, but actually, it's very cholestatic. As you know, they itch, and it's very prolonged. So, some of our definitions maybe are not so different, you know, these discrepancies. Furthermore, the definition of High's Law is very difficult as well. But anyways, I think, I don't understand why you see so much ibuprofen. What is the dose of ibuprofen used, typically? Is it higher that you're using than we use in the United States? This is a very interesting point, because doses is an open question, I think. Yes. Because ibuprofen in the United States, over the counter, is no more 200 milligrams. It's 400 milligrams in Spain, and it's 600 milligrams in Argentina. And now, it's a new dose, 800 milligrams in Argentina. We don't know, really, which is the dose triggering or impacting daily. I know that one patient took a suicide drug, many, many pills, and developed severe liver failure. Maybe around two grams is the risk dose. Right. Well, it's an over-the-counter drug in the United States, and so people will take it for a few days, then stop and take some. You know, it's very intermittent. I take it myself, you know, maybe once a week or something. So, it's a very different dosing, perhaps. It's different what happened with diclofenac, because we have studies showing that more than 100 milligrams of diclofenac is associated with more risk of dealing. Right. And in the United States, diclofenac is not over-the-counter. Is it over-the-counter in Latin America? Yeah, it's over-the-counter in Latin America, yeah. I see. No, it's prescribed here, so you see it in people with arthritis, you know, who need regular daily dosing. We have diclofenac with dose of 75 milligrams and 50 milligrams also. Oh, I see. And numesolide we don't have in the United States, and I don't think the Europeans should withdraw it from the market. It can cause a very nasty, very nasty effect. Yeah, yeah. In Argentina, it was suspended, it was withdrawn from the market. Due to our work in the beginning of 1990, we presented six cases, and one severe and laboratory here suspended suddenly, and our regulatory authority retired, removed from the market. That was intelligent. I think also methyl dopa should be withdrawn. Yeah. Spain also, Ireland, many, many countries in Europe take away numesolide. I could say that the HDS in the United States is number one. It's more common than amoxicillin, clavulanic acid. It's due to so many different things, though, you know. Yeah. It's not just one thing, it's many, many. Green tea is the most frequent, but there are other things, too. We were really very surprised with our numbers, where we saw that HDS. It's partly socioeconomic, you know. It's taken by people who have enough money to pay for that silliness. Yeah, yeah, yeah, yeah. I was in the United States, in Philadelphia, talking with Victor Navarro about this topic. I was very, very surprised. Yes, it's terrible. But I agree that these collaborations with the U.S. and your group would be very helpful. The herbs' consumption is really amazing in Latin America, really amazing, including turmeric compounds in pills, three pills a day, four pills a day. It's really amazing. They take several grams a day. Yeah. It's a different matter. I can't understand, really. So, I'll let someone else ask questions here. Yeah, let me jump in. Let me go to Dr. Avigan. Did you want to ask about—or, Avigan, do you want to ask about the HLAs, or just—? Yeah, I did, actually. Sweet. So, at the FDA, we get, from time to time, a drug development program, and lumericoxib rings bells. It was an important drug in development by Novartis, and it had a very clear HLA association for hepatotoxicity with the DRB11501 allele. In fact, the heterozygotes had a certain quantitative risk for liver test abnormalities, and actually, high as law. And then the homozygotes had a much higher risk, and that was nicely shown in clinical trials. So, it was actually a very seminal study. And the drug was not approved in the U.S. for that reason, and withdrawn elsewhere. So, the question is, what about the other NSAIDs? Have they been, for those that have this hierarchy of risk association, have they been actually interrogated for HLA associations? And then the second part of the same question, actually, is, you mentioned the different phenotypes. Some of the hepatotoxicity effects, like with bronfenac, for example, or benoxyprofen, were also associated with duration of use, so that very short-term use was not a problem, whereas other drugs, like ibuprofen, for example, there is this hypersensitivity effect, even with short-term use. So, have you thought about structure correlations with these different phenotypes? So, those are basically the two kinds of, two questions about the immunologic effects and HLA association across these different drugs and structures. You know, cellococcin has a sulfur molecule in it, so it makes sense that there's an association with sulfonamide injury. It's difficult to answer this question because we don't have data to respond or to replay this question. We know that diclofenac is a more studied drug within the anti-inflammatory drugs, and we know that the immune system is implicated in liver damage, it is clearly, but we don't know the behavior of ibuprofen because, on one hand, it induces hepatocellular damage, clearly associated with immunoallergic symptoms and signs, and on the other hand, it's typically idiosyncratic because it's associated with cholestasis, with ductal damage, ductopenia, vanishing bite-like syndrome. We don't know. I think that HLA studies will be very, very important in this field. Great, thanks. Yes, we need to get someone to provide that for us, don't we? The money to do it. Yeah. Dr. Zapata, did you want to unmute and ask your question? I think that the presence of, like, structural similarities was brought up. If you'd like to unmute for those, you can go to the chat, take a look. The question is basically, why haven't we seen more cases of cellucoxib hepatotoxicity given… Oh, there he is, excellent. I'm from Santiago, Chile. Thank you very much, Fernando. We saw each other a couple of days here in Santiago, so we had an excellent meeting. So, good to see you. I just wanted to ask, the coxselective medications are so used around the world, the trauma doctors use it, whatever do you have, sulfonamide, allergies, or no, they don't even ask. We are seeing in our clinics, I mean, hundreds of patients treated with coxibs, and we don't see so many hepatotoxicity cases. And the molecule, part of the molecule has a sulfonamide part. Any explanation? It's just time to have more hepatotoxicity due to cellucoxib. It's underreported. Any reason? I mean, in Chile, it's everywhere. We are using more coxibs than probably normal anti-inflammatory medications. Hi, Rodrigo, how are you? We met two days ago. Yes, yes. I think that the response, the answer is underreported. It's underreported because look at the more than 1,000 patients in Spain, only they have one case of hetero coxib. And in America, in Latin America, we have five cases in 400 patients. I don't know how to explain it. That is underreported because when we carried out a prospective study like LANE, they only found mild cases, mild hypertransaminasemia, no more than this, where dealing group in the U.S. analyzed 16 cases, reported to the network. They have eight patients with severe hepatitis. Look at the difference, no? What happened in prospective study and reporting cases to the billing network, no? I think that this is underreported. But you have to know that it's a very sure, safe drug, very safe drug. Coxib is a very, very safe, more tolerated than diclofenac, for example, in gastric and intestinal tolerance. Conduced liver injury is rare. You know, first of all, it's always rare. It's one in 2,000, one in 5,000, one in 10,000, one in 20,000. So, these prospective studies like LANE will just pick up one or two cases. That's the nature of the beast. And that's why we need these large networks that gather cases. We're talking about populations of billions of people. No more countries can evaluate this kind of prospective study like made my friend, Anna Jorson in Iceland, analyzing only a population of 3,000 patients, every hospital reporting. They're all northern Europeans. For instance, tuberculosis drugs is very rare in the United States because tuberculosis is rarer in the United States than it's ever been in history. You know, it's less than 1,000 deaths from TB in America a year. They could analyze the number of prescription. This is the key of the problem. Analyze the number of prescription drug. No? Right. Okay. I'm looking at the time, and I know that folks have got places to be, but the conversation should continue by email. I want to thank Dr. Bassone for the presentation. That was fantastic. Thank you very much. Yes, it was great. I appreciate the discussion from all of you. Thank you. Thank you so much for inviting me. Nice to meet you. I'm very happy. Thank you. All right. Thanks very much. Take care, everybody. Thanks for attending. Okay. Bye-bye. Take care. Thank you.

Dr. Fernando Bessone

drug-induced liver injury

Latin DILI Network

NSAIDs

Amoxicillin-clavulanic acid

herbal and dietary supplements

genetic studies

biomarkers

Hy's Law

international research