During this 20-25 minute pre-recorded lecture, Dr. Thomas D. Schiano discusses the topic of liver transplant 2. This in-depth review will provide an update on this topic for your clinical practice as well as supplement your learning for the ABIM Gastroenterology and Hepatology boards. CME pre-requiste of live Q & A webinar, 8th Annual Mount Sinai Intensive Board Review in Gastroenterology & Hepatology on Oct 13.
Hi everyone. Uh My name is Tom Schiano. I'm one of the uh of course directors. I welcome to our board review course. I hope that you find it um extremely uh educational. Uh and really uh uh an excellent update on what's going on in uh gi and liver. My charge is uh to talk to you about post liver transplant issues that I think may be pertinent to your uh practices and what's game on the uh gi boards? Approximately 30% if not more of G Board questions are hepatology related. So welcome. And let's begin. We'll start with a case. A 65 year old woman underwent an emergent transplant for a full minute liver failure due to a Tylenol overdose. At the time of the transplant she was very insightful, empathic in renal failure and intubated. The donor was a 75 year old diabetic who had been hospitalized for one month after suffering from a stroke. All of these keywords are important in deciding um what is going to before this patient. The cold ischemia time was 8.5 hours. Uh recipients suffered several episodes of hypertension during the case and arrhythmia. Uh Immediately after the transplant developed hypertension and rising einar and billy Rubin with a very high LDH the I. I. R. And billy Rubin continued to rise and post operative day one how is this patient best managed immediately listing for transplantation stabilization of BP and paddock arterial from back to me and I created dripping plasmapheresis or correction of cardiomyopathy and I. V. Antibiotics. The question is leading into that. This is primary non function. So the best answer is a immediately transplantation. Primary non function occurs in less than 3% of liver transplants. Uh More often than not, the ideology is unknown but can occur more frequently. And older donors with longer ischemia uh times. Um LDH and immuno translators are extremely elevated and in essence this is liver failure that needs to be re transplanted as soon as possible. Other uh complications seen post transplant or bleeding upwards of 15-20% of patients may need to go back to the operating room for some bleeding. There may be uh thrombosis of the hepatic artery, portal vein or paddock vein. Remember that the hepatic artery is a soul blood supply to the biliary plexus. So any interruption of blood for blood flow albeit even transient could lead to biliary ischemia and a sclerosing cholangitis type picture uh infections can occur especially in patients who have been hospitalized patients who have been hospitalized pre transplant. Um patient. Mhm. Upwards of 12-15% of patients may actually require another transplant within their uh their lifetime. And we're seeing this in our program which has been around for 30 years. We're starting to see patients who were transplanted in the early stages of the program require another transplant. The need for higher melt score often precludes re transplant suitability. Uh in most patients uh there's a higher weightless mortality because patients may not have very high mountains. And when they do then there uh prohibitively high risk candidates and no longer uh are suitable as you might expect, patients are at increased risk for infection. Um Being on immunosuppressive therapy and having a lot of adhesions from prior surgery. A lot of them have renal dysfunction and may uh require simultaneous liver kidney transplant. These cases are very technically challenging for our surgical colleagues and once portal hypertension develops uh it further complicates matters. This is intuitive as you can imagine someone who's on immuno suppression developed societies and spp it really becomes uh difficult for um difficult for a good outcome when there are abnormal liver chemistry tests. Post liver transplant is a broad differential diagnosis which we see in front of you uh things to take into account or uh whether someone's had a prior rejection episode or has non adherence both of which uh predisposed to recurrent episode of of rejection. A recent change in immuno suppression may also be a clue the timing. Post transplant recurrent hepatitis C. Or C. And B. Is not going to happen in the first couple of days after transplant. Um uh For instance. And then you can have other non padded trophic viral infections. Drug part of toxicity and um Preexisting or the oval malignancies. Uh We'll segue to another case. A 71 year old man underwent a liver transplant for hepatitis C. And H. C. C. And had an uncomplicated post operative course. His immune suppression was standard to columnist. Which is given in 95% of liver transplant programs that steroid taper and Michael Fennelly which is self set approximately four months later. Uh He presented with fatigue, loose bowel movements and low grade fevers. One month prior he had had normal liver chemistry test a hemoglobin 11.9 in a play on account of 100 and 27 1000. He discontinued infection prophylaxis at that time as per protocol was CCMP PcR. Even though I'm showing your liver biopsy you can obviate a biopsy by just getting A. C. M. V. P. C. Are not N. I G. G. Or N. I G. M. But um A PcR because the I. G. M. And the G. May be falsely elevated and CMB can cause abnormal liver chemistry tests. So biopsy can be obviated by getting the same VPc. Um The risk to the recipient is predicated on the donor recipient. CMB status of uh if a recipient has never been exposed to CMB they are at high risk for acquisition. CMB can cause retinitis, uh Pneumonitis, uh colitis and hepatitis Most programs prophylaxis. People with medications such as Val Ganciclovir for upwards of three months. But if they are a high risk recipient it can be upwards of six months. Some programs also use preemptive therapies where they just screen the patient without prophylaxis. Using the CMB. PcR is on a weekly basis and only start treatment. Uh If there is an elevation. uh when patients do develop, CMB I can be associated with the development of chronic rejection. And if Pepsi was present a more severe hepatitis C recurrence, the key here is Luca pini, a constitutional symptoms occurring 12 to 18 weeks. Post liver transplant infections per se are common in the immuno suppressed liver transplant patient. This is a very good breakdown. In a review article. You can see that uh gram negatives and those of corneal infections in the first month after transplant, especially in hospitalized patients, pre transplant and then you have your bacterial CMB and other nosocomial infections followed by late uh infections are PCP, fungi, michael bacteria and other bacterial infections related to complications of the liver transplant procedure. Uh rejection can be acute rejection or t cell mediated, which is a better term. This uh has the highest risk during the first three months. With the overall incidents decreasing because of the immunosuppressive agents that we use at our program. It's less than seven percent. It can occur anytime post transplant. So acute and chronic rejection did not the note the time frames which the rejection occurs. But really the histology, so acute rejection can occur uh two weeks or 20 years after transplanting chronic rejection can occur three months and uh three years after transplant, Chronic rejection is Dr. Pena, which is a progressive bile duct loss can occur anytime post transplant and it accounts for 3-5% of the causes of graft loss. You treat chronic rejection with pro graph acute rejection is treated with corticosteroids and otherwise optimizing the immuno suppression. Liver transplant programs are now seeing more cases of donor specific antibodies being involved with antibody, media rejection. This is something that I don't think you'll uh see on the boards. This is now however, being increasingly seen in liver transplant programs and has always been a major issue in renal and cardiac transplantation circles. Mhm. Which of the following is a side effect of the chromosomes, which is pro graph. The choices are oral ulcers. Her statism, hippo magnus anemia abnormal of a chemistry test and cataracts. The answer is see hypoglycemia, calcium and inhibitors are uh cyclosporin and pro graft. With the majority of centers using a great majority of senators using program if the side effects are similar between the castle and inhibitors, but they are more preponderant in one or the other. So for instance, hippo magnus anemia is much more of an issue with pro graph as is a diabetes, whereas her statism and Hyperloop anemia are more so in cyclosporin, nephew toxicity is a major problem for both, as is neuro toxicity and hypertension. Yeah, you all well know the side effects of corticosteroids. I'm not going to go into it. Suffice it to say that some programs you use steroid free regimens. While others uh taper off steroids anywhere between three and 12 months after the transplant. Some programs use em tour inhibitors such as a syrah Lemus orzo fortress, the important complications to know our pulmonary boop recurrent pneumonitis, or pleural effusions, peripheral oedema, harper, triglyceride, anemia, anemia and oral ulcer. So sometimes can be very difficult to tolerate these medicines. Uh Cellcept is similar to as a diaper in uh but I would say has more G. I symptoms and less um anemia and leukemia in general, all immunosuppressive medications lead to an increased risk of infection malignancy. So really make sure that patients adhere to american cancer society screening guidelines. PTSD, which is post transplant lymphoma, proliferated disease um is associated with long term immuno suppression. Use uh I N. H. Um a lot of medications can affect P 4 50 metabolism, which is the primary metabolic pathway for the counselor and inhibitor. So it's very important to let the patient know to inform you if another physician uh adds another medication. So the anti convulsants induce P 4 50 as does revamping, which means that program levels are driven lower. Uh Some of the HIV medications can have significant uh effects on uh program and cyclosporin metabolism. Doing these agents do the same. Richard mason and clarity. Myson uh inhibit as do these other uh medications. So it's very very important. Obviously if you started someone on uh Gloria console for a fungal infection and didn't adjust their program accordingly. The program level would rise significantly. The patient could develop renal failure. So very important to know what medications that the patient is using. Uh Thankfully recurrent hepatitis C is no longer the bane of the transplant pathologist existent. Um it used to be an upwards of 50% of patients would need another transplant within 10 years. The slide reviews the natural history of recurrent hepatitis C. Uh Interferon based therapies did not work very well and there were a lot of side effects associated with them. Almost every patient who has hepatitis C. Pcr pre transplant developed recurrent hepatitis C. And it really was an inexorable course to Allah graft failure because patients didn't tolerate hepatitis C treatment post transplant. We try to treat them pre transplant but ran into a lot of problems with interferon and ribavirin related side effects. A small group of patients develop fibrosis called static hepatitis. Similar to what happened in hepatitis B. Which we'll talk about uh later yeah. When patients develop hepatitis C. Recurrence, there were several factors associated with poor outcome. Uh these being older donor age, intuitively the earlier histological occurrence, more severe inflammation. On the first biopsy. These are intuitive treatment of acute cellular rejection with parental steroids, not with oral steroids. Oral steroids didn't seem to have a proper cause a problem. But parental steroids um did. And if patients at CMB or biliary obstruction if they had concurrent nash all of these factors were associated with the poorer outcome for recurrent hepatitis C. But again thankfully with the DEA agents. Um We do not have the same uh concerns. The first generation D. A. Um had poor tolerable Itty caused anemia. And and thus we were very hesitant to treat. There was an increased risk of rejection with interfere on based uh therapies. So um uh the first generation DHS helped us but we're far from ideal. Many patients still required re transplantation and had poor survival rates post re transplant in large part because they were very, very sick at the time. Mhm, Remarkably. The cure rates are now exceeding 90% of most patients using all of the agents, acute cellular rejection and graft dysfunction still occur but much less frequently as compared to interfere on based therapies. The need for re transplantation and the associated morbidity of recurrent disease are dramatically decreasing. We're hoping that this will allow more patients with chronic Allah graft failure to be evaluated as candidates for re transplantation. There's theoretical benefits of getting rid of hepatitis C to lower all cause mortality, including decreasing the incidence of diabetes and renal function. And if we don't have to worry about hepatitis C, post transplant hopefully will be a little will be able to be a little bit more aggressive with tapering immuno suppression and thus limiting the comorbidities associated with it. You can see remarkably, almost all of the data in curing post transplant Hepatitis C. Has come over the last five years. What has been the impact of these hepatitis C medicines. Well, transplant survival rates for a current pepsi much better. Uh overall survival for these patients. Post transplant is uh is improving. Um hopefully it will ultimately be similar to the hepatitis B paradigms that started in the early 1990s, where patients with hepatitis B not do better than any group of uh of individuals. Uh and this has also allowed us to consider the use of hepatitis C positive donors in hepatitis C negative recipients, which is really a change in standard of care. Um Because of the tragic opioid epidemic, there was an increase in young donors who were using drugs. And because of this, a lot of uh patients with hepatitis C younger patients um became organ donors. And this led significantly to the uptick in the overall liver transplant numbers over the last 3 to 4 years. Uh And as you can see here, the number of donors uh from 2010, 2000 and 17 significantly increased who were intravenous drug users and the incidence of hepatitis C positivity also increased with the donor age decreasing. So, or surgical colleagues are looking for ways to try to get more and more patients transplanted. So, with the data is available, we said, well, why don't we transplant these patients post transplant, give them a hepatitis C positive door, even if they don't have Hepatitis C. Using Hepatitis C positive donors. And Hepatitis C positive recipients has been standard of care for for two decades uh in that setting that the donor hepatitis C genotype took precedence and positive to positive cases. As I mentioned, this is rapidly become standard of care for all solid organ transplants. Using positive into negative recipients with close to 100% sustained biologic response rate using monotherapy without concurrent arrive of iron insurance hasn't been uh an issue. So that this has been a major uh treatment algorithm change in liver transplantation, uh lamiVUDine resistant mutation. Uh This is a picture of fibrosis call static hepatitis, which can also occur in hepatitis C, which I alluded to and has a rapidly progressive course in the late 19 eighties and early 19 nineties, Medicare actually withdrew approval to transplant patients with Hepatitis B because of the poor outcomes. But starting in 1993 center started using hepatitis B immune globulin as prophylaxis lifelong. And this really revolutionized transplantation in these uh individuals. So that recurrence was dramatically less of an issue. Um patients who had uh delta co infection um didn't have an increased risk of uh in of reinfection in large part because hepatitis B viral load was so low going into the transplant the same with fulminate liver failure patients. Um So since pre transplant therapy has changed and all patients are going into the transplant. Really viral load uh negative, we can get away with the oral nuclear side uh uh monologues, I call to your attention. If you have someone who does not have hepatitis B but they received a hepatitis B core antibody positive liver I may convey up to a 40% risk of hepatitis B transmission. So these individuals receive prophylaxis with a nuclear side uh analog patients with hepatitis B extremely uh well now and again because of the because of the nucleoside analog. Uh most people going into transplant are either sub form in patients who have a reactivation of the hepatitis B, possibly during chemotherapy for those patients who have HCC the complications. So most centers see very few patients who have decompensating liver disease related to hepatitis B alone. All of the autoimmune liver diseases recur but are rare causes of graft failure with PSC having the highest incidents. Uh They may all have a higher incidence of rejection and worse problems with preexisting osteopenia and osteoporosis. As many of them have required steroids for one reason or another activity of IBD is unrelated to the primary disease and may occur Dinovo because program and sell set primary immunosuppressive agents do not have any uh signatory effect on I. B. D. Um patients may develop plasma cell hepatitis post transplant which looks like autoimmune hepatitis but is a variant of rejection and occurs more commonly in autoimmune hepatitis autoimmune liver disease recurrence. More and more patients are being transplanted for uh nash thankfully graft loss is very infrequent infrequent. But unfortunately weight gain and diabetes are very frequent after transplant. Thus bariatric surgery is an appealing option. Both pre and post transplant, there's an increasing cardiovascular morbidity and mortality in patients post transplant. So we try to enlist the help of internists that can really deal with these issues on a very rigorous basis. Um insulin resistance is common post transplant. So uh we have to really uh speak to patients about weight gain and treatment of medical comorbidities and limit immuno suppression if possible. Some of the metabolic liver diseases, Wilson's disease doesn't recur, but pre existing neuropsychiatric symptoms may not regress after a transplant. So you transplant someone for Wilson's because of their liver and not because of neuropsychiatric symptoms. Human keratosis theoretically can re occur after transplant. Um because of ongoing absorption through the intestines of irons of patients may infrequently require for lobotomy, Post liver transplant. Uh patients who have our phone anti trips and efficiency. Usually the lung disease or the liver disease predominate not uh not both. Uh and you have to look for issues in patients who are heads. I go to typically can have worse disease from nash or other concurrent liver disease. This is the picture of Prometheus uh which was really the ancient Greeks knew a lot about liver regeneration. Uh post transplant complications. Uh you can see the incidences uh here you treat these uh complications the same as you would in a non transplant, a non transplanted individual. End stage renal disease major issue almost always related to. Uh the calcium or an inhibitor, there are many causes of renal dysfunction after transplant. But all really get funneled through the calcium, an inhibitor that causes interstitial fibrosis. You have to rigorously treat the hypertension and diabetes to prevent things from getting worse. Nonsteroidal anti inflammatory agents are strictly contraindicated post transplant as well as in psoriatic patients because of their propensity for causing renal failure. I mentioned the significant weight gain and patients, this is not only related to steroids as it occurs in steroid sparing regimens. Um uh significant weight gain leads to hernias, decrease uh self esteem and we need to do better at trying to treat this and prevent this. Uh uh statins are okay post liver transplant. Um The issue is that many physicians are scared to start the statin because of the perceived concern with regard abnormal liver tests. But we we started as often as possible and really try to stress to the patients the importance of management of the medical comorbidities. The incidents of skin cancers dramatically increased post transplant, especially basal cell carcinoma and squamous cell cancer. There's an increased incidence of certain solid organ. Neo plasma is I can't over emphasize enough the importance to follow american cancer society screening guidelines in these individuals. So a new day has dawned on the management of patients Post um liver transplant. I hope you have found this. Talk helpful uh and educational and I would say please feel free to contact uh myself or any of our colleagues for any questions related to your patients who have acute or chronic liver disease. Thank you very much.