Dr. Terrault details the elements of transplant complications such as infection, malignancy, metabolic syndrome, and recurrent liver disease.
It's now my pleasure to introduce Nora tomorrow she is kindly joining us from her vacation in europe. Were very jealous. Um She is a very well known hepatology gist who is a visiting professor of medicine and chief of division of GI and liver at the keck School of Medicine at USC. She is obviously a well known woman in the area of Hepatology and we're so very thankful for her to have joined us. We are inviting her today to present on what the G. I. Needs to know for a liver transplant patient. It's a pleasure to be here. And I want to thank the organizers, Doctor fernet and Dr Park Rose for their very kind invitation. Um it was terrific to be part of the scripts annual meeting. I'll be addressing what the gastroenterologist needs to know in terms of post transplant management, focusing on some key complications. These are my disclosures shown here is post transplant mortality. Uh looking over at the changes over the past decade. You can see that overall the proportion that are dying, post transplant is decreasing over time. Um and that overall um we have excellent survival. You can see it one year shown in green that more than 90% of patients survive. So the mortality less than 10%. At the five year mark, the mortality rate is approximately 20%. And um at the 10 year mark it's about a 640% mortality. So 60% survival. And in terms of the causes of death beyond a year. They're depicted here. So again, looking first on the left, this again, is showing over time how the cause of death have shifted or changed. Um the first set of bars on the far left are from 1987 to 1990. Um and then on the right. Most recent Data from 2011 to 2016. And you can see that graft failure as a cause for death has decreased over time as has deaths related to infection. Um And what you see is there's a an increase in the proportion dying of cancer. Um And I'm going to speak a little bit more about that in subsequent slides going a little bit deeper into potential into the cause of death shown on the right are now data from the N. I. D. D. K. Liver transplant database with about a 13 year follow up and in this large cohort where they had much more detailed information about cause of death, Approximately one quarter where he Paddick causes. Um But the majority, as you can see, we're non hepatic and of the nana paddock, we have almost equal representation from infection complications, cardiovascular disease, malignancy and um and other and I'll lump Ritalin with cardiovascular. So um as we discuss the post transplant management of patients, you'll see that um it's management of these um complications that are non paddock that are very much a focus as much so as the management of recurrent uh Paddick diseases. So my outline for my talk is going to be looking at infections with a focus on SARS Kobe too, metabolic complications, malignancy risk and it's mitigation and then finally recurrent diseases with a focus on primarily nah field and alcohol. Um to remind you that really what sets transplant patients apart is the fact that there are long term immunosuppressive therapy shown in this table are the common drugs that are used. We have the calcium, urine inhibitors to problemas and cyclosporin. The anti metabolite drugs microphone like mafia till and is a tire print and then the entire inhibitors, cyril Amos and several Hamas. predniSONE of course is still used with typically it used in higher doses early and then often weaned off and as you know, there are a predominance of metabolic complications that accompany almost all of the drugs that we use as well as some small telegenic risk in the case of michael Fennell it um offer to um and an overall um excessive immuno suppression of course raises the risk for liberal proliferated disease um as well as some other malignancies. So it's a balancing act. We obviously want to protect, protect the graft from being rejected but we're always trying to minimize immuno suppression with the goal of minimizing these side effects. Um So let's talk first about post transplant infections um and I want to just very briefly touch on the risk periods and the standard preventive measures that we use much of this is often done by the transplant team because the primary period of intense risk is in the early post transplant. So shown in this figure here is on the left months after liver transplant and the infections for which the patient is at highest risk. And you'll see that early on HSV CMB are major concerns as well as fungal infections as well as the usual risks for hospitalized patients that include bacterial infections. Uh for the concerns for HSV N. C. M. V. We prophylaxis patients with acyclovir in val ganciclovir, that's shown in the table on the right and for the anti fungal infections and the unusual Pneumocystis infections which are risks in the early post transplant period. We uh typically prophylaxis, P. J. P. With uh cetra and fungal. Any fungal to using fluconazole typically anywhere from 1 to 6 months after transplant. Most of the patients will be off their prophylactic antivirals and anti fungal and then are moving into just a monitoring that is typical of of any patient in terms of being risk for um infectious complications. Now of course, Covid has been a very interesting sort of time in many ways and I just wanted to spend a little bit of time on its impact from the point of view of liver transplant recipients. So, first of all, what was the influence of the outcome of patients that it influenced their survival? And these are data that were published very recently in gastroenterology showing on the left is a figure looking at survival probability among individuals That had received a liver transplant and then were infected with COVID-19. And you can see that if they were at home they had a very high survival probability. But as they were admitted to hospital or and or I see you you can see their outcomes were significantly reduced. And when they looked at what are the factors that are associated with a higher rate of death. Among those liver transplant recipients who were infected with COVID-19, you can see that older patients, those that had chronic kidney disease were the groups at highest risk. And in this analysis those were the independent predictors and not their immunosuppressive therapy has shown here where the problem is therapy if anything was shown to be protective. So indeed, it seems like liver transplant recipients per se are probably not at higher risk, but it's like a non transplant patient, those that had metabolic risk, those that were older with the groups at higher risk of dying related to their infection. Shown here is an algorithm for managing patients with who had a liver transplant who develop Infection with COVID 19. And you can see that the algorithm um is influenced by whether they're early post transplant versus um uh far beyond transplant. Um And I'm not going to go through the algorithm in detail. It's it's an excellent review in a s put out by the A. S. L. D. Task force and published in Hepatology in 2020. But the main takeaway messages are that if individuals are diagnosed with COVID-19 recommendation is to minimize the use of high dose steroids uh to minimize or reduce even discontinue anti metabolite drugs such as a the Sky Prim and mmF. Um But in terms of the cns it's recommended that they not be stopped. And in fact the study I just showed you suggested that that should not be done. Um And the idea is to keep them on sufficient immuno suppression to minimize any chance for rejection. And then sort of the final aspect related to um uh covid 19 and transplantation. Is there effective vaccination? So there's been a very recent publication highlighting that transplant recipients are are less likely to respond in terms of an antibody response to the SARS cov two vaccinations. So shown here is a study in which 80 liver transplant recipients received the vaccine. This is the fighter um M. RNA vaccine versus 25 healthy controls. And you can see that a positive anti body response was only seen it about half of the patients and that among those that developed an antibody that the tighter was in fact lower. What we don't know yet is whether a third dose, for example would make a difference or other strategies. But just to keep in mind that while we should advocate for the vaccine and our patients that indeed there's a lower likelihood of them responding. And indeed in this study where they looked at what were the factors associated with lower chances of responding to the vaccine? It was older age, those that had chronic renal insufficiency, those on high dose steroids during the 1st 12 months, triple immuno suppression or mmf. So again, you know, those more heavily immuno suppressed were less likely to respond. So stay, stay aware that this may be an area in which we see change and different recommendations going forward. But at the moment is still recommended we have our liver transplant patients vaccinated. There's no um adverse events in in in this patient population in doing so, but recognize that they may not enjoy the full protection that we see in non transplant patients. Okay, so I'm gonna shift to malignancy now among transplant recipients in this table highlights the key malignancies to be aware of in our transplant recipients and the relative risk. So you can see that the most common malignancy is actually skin cancers. Um And those include both squamous basil as well as melanoma Relative risk 20-70% over the lifetime of a patient whose post transplant. Um The next is melanoma with post transplant. Little proliferated disease. Still an important variable. Very much related both the amount of immune suppression that a patient receives as well as their E. B. V. Status and then the others that I want you to be aware of is or forensic cancer including um as well as the esophageal cancer, lung cancer and colorectal cancer. And I'm going to focus a little bit on the non skin malignancies. Um And what's recommended in terms of surveillance and um practice shown here are the incidents rates um For de novo non skin malignancies among liver transplant recipients are really showing the similar to data to what I showed you before but now more specific to the organs. So shown on the left is that G. I. Malignancies are the most common followed by long guo and or affair and deal. Um And that the incidence rates at 10 years approaches 15%. Um When we look on the right by the pre transplant liver disease, you can see that the highest rate of malignancy is among patients who have PSC. And alcohol associated liver disease as their underlying ideologies of disease. Those were the only diseases which were independently predictive of post transplant malignancy. Other factors included older age and smoking history. So what's recommended in terms of surveillance? Well for skin it's recommended that they should have an annual skin exam and if they fall into the high risk group or where they've been diagnosed with a skin malignancy then um I used to have them seen by dermatology every three months for colorectal. Um It should be of course per age and family history as as per usual guidelines. But in PSC patients with IBD it's recommended that they have annual colonoscopy. You recognize that that PS group was one of the groups that have the higher rate of malignancy post transplant and it's related to the development of colorectal cancer. Um in terms of long um annual chest C. T. is indicated if patients are recent or within the last 10 years. Um recent meeting within the last 10 years or current smoker high rates for lung but also or oral fair and deal cancers as well. Um And although there's less definitive information about how to monitor for head and neck cancers. Um I think a good oral exam either by the dental by a dentist or anti person on an annual basis is important for those that have a history of smoking or the alcohol associated liver disease group. Um For renal and your analysis annually is recommended. And for PTL Day there's no P. T. L. D. Air post transplant, little proliferated disease. No specific, you know surveillance just I think we have to have a high index of suspicion when we see patients presenting with unusual symptoms. Okay. P. T. L. D. I think it's very interesting in that it can present in many sites lymph nodes, the liver graft itself. G. I tracts cns spleen. So that's why there has to be a high end suspicion for this condition. Um In most cases it appears to be triggered by E. B. V. Although not all are BBV associated. The highest risk group for the development of P. T. L. D. Is the patient in whom the donor is positive, that the recipient is negative. Other factors that have been linked with PTSD is of course sort of aggressive or sort of heavy immuno suppression with monoclonal antibodies. Um or other and some other viral co infections are thought to be important. When we make the diagnosis of P. T. L. D. The first line treatment is usually to reduce immuno suppression and sometimes that actually can result in significant improvement. Uh But now these days, second line therapy is very quickly brought on board and that is in the form of riTUXimab shifting now to the metabolic complications of liver disease. Um The major ones are listed here and shown in the table on the right is that these metabolic complications culminate in Heightened risk for cardiovascular disease and for chronic kidney disease. And you can see the frequency of the metabolic complications are up to 60% in some instances. For example, for diabetes and obesity and to slip anemia up to 85 with systemic hypertension. I'm going to focus on two specific issues the obesity and chronic kidney disease. First kidney disease. Um as mentioned, up to 80% of liver transplant patients will develop chronic kidney disease over their lifetime. The cumulative risk of end stage renal disease at 10 years Is estimated to be at a minimum 5-8% in some studies, showing up to 25%,, especially in individuals who have underlying risks. And what are those risks? Uh calcium and inhibitor use hypertension. Uh this lymphedema and diabetes hepatitis C as a factor post liver transplant, acute kidney injury and of course, the presence of preexisting kidney disease of which with the current um uh frequency of nash as a co morbidity and indication for liver transplantation, we have seen an increasing proportion that also have kidney disease. So in terms of thinking about ways to modify the metabolic risks, it's important to remember that the immunosuppressive drugs are at the core of of risks and that we can make changes to potentially modify those risks. And I'm showing here just um potential ways to minimize the risk of renal injury. Um, calcium inhibitors, as I mentioned, are well recognized to be a culprit for uh leading to chronic kidney injury. And we often use either a calcium and inhibitor sparing approach which would mean that we might use low dose C. N. I. With a microphone like Moffett Eel or alternatively use enter inhibitors which are much less likely to cause renal disease. So these are just to highlight that we need to continually be reassessing the immunosuppressive therapies to see what needs to be changed to modify these metabolic risks. Also shown on this table is that there's a propensity for many of these medications to cause weight gain. Um And so um the weight gain is recognized as being very common after transplant With the one in three year wait gains being five and 10 kg, respectively, um most pronounced in the first six months after transplant. So very important to intervene early and um their obesity is now sort of arising as an important cause of morbidity and mortality in our post transplant patients. There's been increasing interest in the use of bariatric surgery in the context of liver transplant. And I just wanted to highlight that has been a very nice review. They're very small case reports. But if you add up 190 patient papers that have been written, It's a total of 144 patients. And you can see that the timing of when bariatric surgery is being considered in the context of managing obesity and metabolic complications is that it's primarily being considered post transplant. But there is an increasing experience of both doing a concurrent with liver transplant as well as even a modest experience of doing it on the waiting list. Sleeve gastrectomy is the preferred bariatric surgery in all of these settings with ruined mine being a distant second. And I'm going to just share with you data that we recently published looking at the role of bariatric surgery when it's used pre transplant Here, we compared uh patients, 14 of whom underwent sleeve gastrectomy, pre transplant while on the waiting list. And compare them to 56 patients who used wait. Um used medical weight loss management. Um The sleeve gastrectomy group has shown in the dark um solid line and you can see that they not only enjoyed uh an improvement in their body mass index while on the waiting list, but that this was more likely to be sustained post transplant shown on the right. Is that also if we look at the post transplant um factors such as diabetes and post transplant, nash, that sleeve gastrectomy pre transplant was an independent factor protective of those complications post transplant. So I think you're going to see more related to considerations such as bariatric surgery in this patient population, given the very high frequency of metabolic comorbidities. And then finally I'm going to shift to talking about recurrent disease. And um listed on this slide are common indications for liver transplantation on the left. Um And it's to make the point that essentially all of the diseases are largely uh can be recurrent post transplant. The viral hepatitis uh diagnoses used to be among our more common diagnoses for transplantation and management of recurrent disease in the past has been a big challenge. But you can see that while recurrent disease is certainly a high risk, we now have very effective therapies to both treat and prevent um these viral infections so they're no longer an issue for us. Um alcohol. Now number one, in terms of an indication for transplantation in terms of the number of patients being transplanted for this uh indication. Um I'll show you data that suggests that of course there is a risk for relapse. Um and so that managing recurrence of that disease is important. The effective therapy here being abstinence PSC PBC. Autoimmune hepatitis can recur. The five year risks are listed in this table for PSC. It's 11% PBC 20%. And for autoimmune hepatitis 25%. And then finally for nah field and nash again, this is also now a very common indication for transplantation number two in the country. And you can see there certainly is a risk for recurrence. I'm going to try to focus on preventing recurrence and I'm going to focus on alcohol and natural ganache. And then also just one slide on PBC since there's some new data about preventing recurrence. So first for snaffled, these are the, you know, the key drivers of post transplant complications of the obesity. Uh the cardiovascular risk. And then I'm going to speak about really naff aled recurrence which is a risk for graft loss. Driving much of this is the metabolic risk, including the weight gain and shown here is that nash patients when they undergo transplantation are more likely to gain their weight earlier and to a greater extent than non nash patients. Although everybody is at risk. You can see that if you look at the nash patients at three years here, Uh that over 60% of them are obese at this point in time. Um and that's a much greater proportion than what you see in the non national group. So um if we look at the natural history of the national post transplant, actually, we have not great data, but it's pretty clear that if you had nash before as your indication for transplant, you're much more likely to get recurrence after transplant than patients who did not have that diagnosis. Although de novo novel does also occur. The risk factors for it appeared to be similar to those in non transplant patients have shown on the right are the most common risks associated with recurrent nash post transplant. You can see it's B. M. I. It's alcohol use, its hyper livadia mia as being kind of dominant ones as well as diabetes. And in a meta analysis that has been recently performed. Um it was shown that about there's a 60% incidence of her current baffled if you look 123 years out in patients who are undergoing uh surveillance for recurrence. But interestingly thus far, at least with the follow up, we have out to say 3-5 years, we're not seeing any impact in terms of graft survival, but that just may be a matter of time. And similar to kind of early days with Pepsi when we didn't think that was also going to be a problem that was longer follow up that. Well, we we will see recurrence of novelty being a cause for graft loss. So how do we approach the management of nash post transplant? It's it's very similar to the pre transplant. We focus on lifestyle management um and risk reduction, but recognize that part of this is also immunization, immuno uh immuno suppression optimization. So being thoughtful about the drugs that might be contributing to worsening of diabetes or weight gain, I did suggest to you that a bariatric surgery is probably going to have an increasing role in this arena, both as a consideration pre concurrent with or post transplant. And while there is a lot of pharmacologic therapies that are being evaluated for Nash currently, uh to my knowledge, none of them are being studied in transplant recipients as yet. So this is clearly an area where future work is needed. I'm going to shift to alcohol and acknowledge that in the transplanted patients for alcohol associated liver disease, their causes for morbidity, mortality. Long term are somewhat different than ask patients early on. It's infections that are a big concern than they have a greater risk for certain malignancies as we highlighted earlier and then of course the issue of alcohol relapse and we have two sets of data to share here. This is a data from a prospective study where they were looking at patients with alcohol associated cirrhosis and then followed them post transplant with a timeline follow back uh as a means to quantify alcohol use. And they interviewed them at um at frequent intervals, views as inter bulls and also used family members and blood levels of alcoholic clinical clinical visit to enforce to um to capture um alcohol use. And so they saw that there were four patterns um You can see at the bottom are there's definitely a group that's abstinent and a group that's got low level fluctuating alcohol use. But they did identify both an early onset rapid to moderate use and a late onset moderate use a pattern. And what they showed is that these early onset groups, as shown here in the green and the yellow had a greater risk of having graft failure um and also of rejection. So highlighting that early use uh heavy use in particular were very problematic. Recently. We also published a data using among patients who are transplanted for severe alcohol associated hepatitis. And interestingly, we found very similar patterns in that we had two groups that had early onset of harmful drinking, either frequent or binge. And um and um noteworthy, a noteworthy, we also had a group that were abstinent, 70% indeed were abstinent um in our cohort uh that was followed. But similarly, we showed in our analysis that the group that had this early onset of harmful alcohol use also had a worse um survival. And that's shown in the figure on the right. Um And you can see that in those that did not have relapse or had very low level or late relapse, we did not see any impact on graft survival, but return to moderate heavy use early on definitely was associated with worse survival. So the message, of course, is that we have to think about interventions and to do so early. So what can we do? Well, pre transplant? I think we have to be thoughtful about patient selection. Um there's some new approaches to how we think about selection what the risk groups are. We want to treat and manage anxiety and depression as those can sometimes trigger alcohol use. And we want to try to have patients engage in absolute programs and think about using medications to help. And then of course post transplant we want to really facilitate ongoing support for abstinence through an integrated post transplant care. Think about using medications to reduce cravings such as a compress eight or naltrexone. And in our program and others we recommend monitoring for alcohol use primarily as a means of identifying the need for early intervention And then finally I'll just close with one slide on PBC because I think our thinking about peace BC has also been changed by this recent meta analysis of 15 studies um in which they showed that prophylactic use of ursa deoxyribonucleic acid improved liver test and reduce the risk of recurrent PBC. So shown on the graphic on the left is in this meta analysis. The group that had you D. C. A. Used prophylactically is shown at the bottom in the solid line and you can see that their risk for h. For PBC recurrence was much lower than in the studies in which it was not used prophylactically and similarly shown on the right is a similar data. Again showing that the proportion with PBC recurrence in the group that received prophylactic you D. C. A. Was 17%. Whereas in the group that did not have prophylactic you D. C. A. Uh the risk for recurrence was 23%. Um They also showed that there was a lower incidence of recurrent PBC if the patients were on cyclosporin versus two christmas. Um I think this needs to be confirmed further. But certainly this suggests that we can do something now to try to minimize our patients risk for PBC by using prophylactic or so deoxyribonucleic acid. And so then just to close overall our outcomes with our transplant patients is Up to 50% of our patients are surviving more than 20 years. And certainly um up to five years, 80% of patients are surviving survival depends on minimizing the effects of early on infection and later the effects of malignancy, metabolic syndrome and recurrent diseases. And I've highlighted that in terms of malignancy, there is important role for doing uh surveillance for certain types of malignancy and in particular groups of patients such as those with PSC or those with alcohol associated liver disease. The very major role that metabolic syndrome plays in terms of post transplant complications. Um uh the role of obesity and how we can manage that, but also managing cardiovascular risk and minimizing the risk for chronic renal disease. And then finally recurrent disease. Certainly now, with alcohol and non alcoholic fatty liver disease being our number one and two diagnoses, these need particular attention because we don't have medications to specifically treat those diseases. So much of this is focused on our ability to manage them through lifestyle modification and support of programs of abstinence and attention to healthy lifestyle. And with that all close. Thank you very much for your attention.