1 00:00:00,000 --> 00:00:09,360 Hello everyone, welcome back to another episode of the Stay Current podcast. 2 00:00:09,360 --> 00:00:14,720 I'm Cecilia Gigena, a research fellow at Cincinnati Children's Hospital, and along with Stay Current, 3 00:00:14,720 --> 00:00:19,920 we are sharing knowledge to improve child health around the globe. 4 00:00:19,920 --> 00:00:25,400 So today we are going to talk about updates in liver transplant with Dr. Jonathan Meralda, 5 00:00:25,400 --> 00:00:28,920 a transplant surgeon from Cincinnati Children's Hospital. 6 00:00:28,920 --> 00:00:31,000 Let's start with some background. 7 00:00:31,000 --> 00:00:37,220 Up until the 1980s, the vast majority of children on the transplant waitlist passed away due 8 00:00:37,220 --> 00:00:39,840 to the lack of available organs. 9 00:00:39,840 --> 00:00:45,800 And really in the 1990s, a technique that took advantage of the liver's segmental anatomy 10 00:00:45,800 --> 00:00:50,000 and ability to regenerate greatly increased organ availability. 11 00:00:50,000 --> 00:00:54,680 These segmental transplants are called barium grafts or segmental grafts. 12 00:00:54,680 --> 00:01:01,000 And thanks to them, the mortality of the waitlist decreased from 80% to just 10%. 13 00:01:01,000 --> 00:01:07,680 But still, for children that are under one year of age, mortality remains at about 30%. 14 00:01:07,680 --> 00:01:14,720 Unfortunately, due to size, kids under one year of age still have higher mortality rates. 15 00:01:14,720 --> 00:01:18,480 And what are the indications for liver transplant? 16 00:01:18,480 --> 00:01:24,840 Images for liver transplant in kids include biliary atresia, metabolic liver disease, 17 00:01:24,840 --> 00:01:26,960 liver tumors, and acute liver failure. 18 00:01:26,960 --> 00:01:32,480 But by far and away, the most common is biliary atresia. 19 00:01:32,480 --> 00:01:36,960 Biliary atresia is a rare congenital condition in which the bile ducts inside and outside 20 00:01:36,960 --> 00:01:42,560 the liver are abnormally narrow, blocked, or absent, leading to bile buildup in the 21 00:01:42,560 --> 00:01:43,560 liver. 22 00:01:43,560 --> 00:01:47,880 This obstruction causes liver damage and cirrhosis if left untreated. 23 00:01:47,880 --> 00:01:54,320 The first treatment for biliary atresia is a Casay procedure, or a portoenterostomy. 24 00:01:54,320 --> 00:02:00,920 So the old dogma of a third gets better, third stays the same, and a third gets worse is 25 00:02:00,920 --> 00:02:02,480 really out the window. 26 00:02:02,480 --> 00:02:07,520 In previous years, the usual prognosis for patients with biliary atresia was that after 27 00:02:07,520 --> 00:02:13,800 a Casay procedure, a third often will improve, a third will remain the same, and a third 28 00:02:13,800 --> 00:02:14,800 will get worse. 29 00:02:14,800 --> 00:02:20,440 But now, the native liver survival after a Casay can be as high as 80%. 30 00:02:20,440 --> 00:02:28,480 The keys to this were early diagnosis and selective use of antibiotics and steroids. 31 00:02:28,480 --> 00:02:31,760 So how does this influence the transplant? 32 00:02:31,760 --> 00:02:36,560 Well, most with biliary atresia may end up requiring a transplant. 33 00:02:36,560 --> 00:02:42,660 Facilitating that native liver survival earlier in life delays the overall immunosuppressive 34 00:02:42,660 --> 00:02:49,320 exposure and decreases competition for the scarce size match graft, and is ultimately 35 00:02:49,320 --> 00:02:53,440 associated with much lower healthcare costs. 36 00:02:53,440 --> 00:02:56,160 Great. 37 00:02:56,160 --> 00:03:01,320 Let's change gears a little and talk about how do you decide who gets the liver. 38 00:03:01,320 --> 00:03:06,520 Organ allocation in the US is based on the principle that the sickest patients should 39 00:03:06,520 --> 00:03:11,320 be given the highest priority, and adults is based on the MELD score. 40 00:03:11,320 --> 00:03:16,280 MELD score is a score that estimates a patient's chances of surviving their disease in the 41 00:03:16,280 --> 00:03:18,080 next three months. 42 00:03:18,080 --> 00:03:24,680 It goes from 6 to 40, being worst when higher, and it is based on creatinine, bilirubin, 43 00:03:24,680 --> 00:03:35,760 serum sodium, and internal normalize ratio, or INR. 44 00:03:35,760 --> 00:03:41,600 MELD score is used for children under 12 years of age, and it is calculated using ovumine, 45 00:03:41,600 --> 00:03:47,480 bilirubin, INR, and degree of growth failure without creatinine. 46 00:03:47,480 --> 00:03:57,120 And it also has a special designation of 1A for acute liver failure and 1B for hepatoblastoma. 47 00:03:57,120 --> 00:04:00,800 So now let's dive into acute liver failure. 48 00:04:00,800 --> 00:04:07,640 Acute liver failure manifests with diffuse hepatocyte necrosis and release of these damage 49 00:04:07,640 --> 00:04:12,200 associated peptides and then cause a SERS response. 50 00:04:12,200 --> 00:04:18,560 SERS is a systemic inflammatory response syndrome, and it is characterized by an exaggerated 51 00:04:18,560 --> 00:04:23,800 defense response from the body and that can lead to multi-organ failure. 52 00:04:23,800 --> 00:04:30,480 Together, only about 25% of kids with acute liver failure survive their condition without 53 00:04:30,480 --> 00:04:32,840 a transplant or death. 54 00:04:32,840 --> 00:04:38,200 And so a score has been recently where you can predict which patients should go on to 55 00:04:38,200 --> 00:04:39,920 be listed for a liver transplant. 56 00:04:39,920 --> 00:04:43,720 Great, but is there any treatment for these kids? 57 00:04:43,720 --> 00:04:50,000 The study from a major liver center in Denmark where they had 16 children and criteria for 58 00:04:50,000 --> 00:04:57,040 plasma exchange was bilirubin over 20, or if they had toxic ingestion as a cause. 59 00:04:57,040 --> 00:05:02,700 And so if they met those criteria, then they got high volume plasmapheresis. 60 00:05:02,700 --> 00:05:07,920 So high volume plasmapheresis is bilirubin reaches 20. 61 00:05:07,920 --> 00:05:09,040 Any other option? 62 00:05:09,040 --> 00:05:14,600 A clever surgical solution to acute liver failure that's been described takes advantage 63 00:05:14,600 --> 00:05:17,700 of the liver's regenerative capacity. 64 00:05:17,700 --> 00:05:24,640 And it turns out that a native liver with over 90% necrosis will eventually recover. 65 00:05:24,640 --> 00:05:27,120 And what does the procedure consist of? 66 00:05:27,120 --> 00:05:33,360 To take advantage of this, a native left liver can be resected, leaving the right lobe behind, 67 00:05:33,360 --> 00:05:38,800 and then transplanted with a new left lobe and with immunosuppression that transplanted 68 00:05:38,800 --> 00:05:44,480 left lobe graft can be maintained for a period of 6 months, at which time the native liver 69 00:05:44,480 --> 00:05:45,920 is able to recover. 70 00:05:45,920 --> 00:05:46,920 Perfect. 71 00:05:46,920 --> 00:05:51,440 So tracheal liver transplant, though very complicated, can be performed in cases of 72 00:05:51,440 --> 00:05:56,520 acute liver failure to give time to the native liver to recover. 73 00:05:56,520 --> 00:06:00,480 Now let's have some details on hepatoblastoma. 74 00:06:00,480 --> 00:06:04,720 This is really the most common liver tumor for kids that are under 5. 75 00:06:04,720 --> 00:06:09,520 For tumors that are too extensive to be resected, transplants are really the only treatment 76 00:06:09,520 --> 00:06:10,520 of choice. 77 00:06:10,520 --> 00:06:14,680 How many kids with hepatoblastoma were required transplant? 78 00:06:14,680 --> 00:06:20,280 About 60% of hepatoblastomas are unresectable at the time of diagnosis. 79 00:06:20,280 --> 00:06:27,400 Therefore chemotherapy is given upfront and about 20% of patients remain unresectable 80 00:06:27,400 --> 00:06:29,520 after chemotherapy. 81 00:06:29,520 --> 00:06:36,080 Okay, so we talk about the main indications being biliary atresia. 82 00:06:36,080 --> 00:06:41,120 But what is the second most common indication for pediatric liver transplant? 83 00:06:41,120 --> 00:06:47,620 The second most common indication for pediatric liver transplant is venous liver disease. 84 00:06:47,620 --> 00:06:53,300 And most of these are caused by single gene mutations, which affect enzymes that are principally 85 00:06:53,300 --> 00:06:54,840 harbored in the liver. 86 00:06:54,840 --> 00:07:00,300 There are multiple metabolic diseases from the liver, such as Wilson's disease or Kregel 87 00:07:00,300 --> 00:07:05,280 Neja, which are characterized for having an enzyme deficiency. 88 00:07:05,280 --> 00:07:11,800 And so since the vast majority of this enzyme is harbored in the liver, the cure for is 89 00:07:11,800 --> 00:07:13,680 a liver transplant. 90 00:07:13,680 --> 00:07:18,360 But even though we still don't have a better treatment outcome, Dr. Merola explained what 91 00:07:18,360 --> 00:07:21,840 the future may hold for these patients. 92 00:07:21,840 --> 00:07:28,320 Now we can isolate fluripotent stem cells, correct the deficient gene, and expand lipid 93 00:07:28,320 --> 00:07:34,360 organoids that can then be infused back into the patient as a cellular therapy. 94 00:07:34,360 --> 00:07:39,560 And so I think, and I'm hopeful that in the future, many of these metabolic liver diseases 95 00:07:39,560 --> 00:07:43,920 can be cured with these cellular therapies. 96 00:07:43,920 --> 00:07:46,520 Awesome. 97 00:07:46,520 --> 00:07:51,360 Now that we know the indications, let's talk about how the procedure is done here at Cincinnati 98 00:07:51,360 --> 00:07:53,560 Children's Hospital. 99 00:07:53,560 --> 00:07:59,160 Here we offer a living donor liver transplant, which like with the kidney offers the advantage 100 00:07:59,160 --> 00:08:05,120 of hastening organ access and a vaster recipient recovery. 101 00:08:05,120 --> 00:08:10,400 For planning these operations, they use CT and MRI to determine which portion is optimal 102 00:08:10,400 --> 00:08:15,080 and can be safely resected from the donor and be adequate for their recipient. 103 00:08:15,080 --> 00:08:20,720 Well, most of these living donor recipients have a much shorter length to stay and require 104 00:08:20,720 --> 00:08:25,720 fewer transphagians because we don't have to wait till they're extremely sick for 105 00:08:25,720 --> 00:08:28,640 them to have access to an organ. 106 00:08:28,640 --> 00:08:33,800 Use of segmental grafts, however, comes with a new challenge, and that's greater size 107 00:08:33,800 --> 00:08:35,680 mismatches. 108 00:08:35,680 --> 00:08:40,320 Mismatches in size not only occur from the organ itself, but with segmental grafts, it 109 00:08:40,320 --> 00:08:42,160 happens with blood vessels. 110 00:08:42,160 --> 00:08:46,920 Fortunately, there are techniques that can be used to avoid or alleviate this. 111 00:08:46,920 --> 00:08:51,400 The small native hepatic artery is often inadequate. 112 00:08:51,400 --> 00:08:57,560 And so we make pretty liberal use here of infernal aortic conduits where a piece of 113 00:08:57,560 --> 00:09:02,520 the donor iliac artery is placed enticide on the aorta. 114 00:09:02,520 --> 00:09:06,880 And then the other end is an estomosed end-to-end to the recipient. 115 00:09:06,880 --> 00:09:12,120 And that really gives excellent arterial flow to the transplanted liver. 116 00:09:12,120 --> 00:09:13,600 Great. 117 00:09:13,600 --> 00:09:17,600 Now, let's move on to outcomes. 118 00:09:17,600 --> 00:09:22,320 Overall, however, outcomes after pediatric liver transplant are excellent. 119 00:09:22,320 --> 00:09:26,740 And graft survival routinely exceeds 30 to 40 years. 120 00:09:26,740 --> 00:09:31,840 And this is especially the case for living and partial donor grafts. 121 00:09:31,840 --> 00:09:34,160 And what about complications? 122 00:09:34,160 --> 00:09:40,360 One of the most feared complications is primary non-function, which results due to a severe 123 00:09:40,360 --> 00:09:44,640 ischemic injury and possibly due to preformed antibodies. 124 00:09:44,640 --> 00:09:51,840 But fortunately, this terrible complication happens in less than 1% of the transplants. 125 00:09:51,840 --> 00:09:56,400 Vascular complications are much more common in pediatric transplant. 126 00:09:56,400 --> 00:10:00,120 And usually occurs within the first 30 days. 127 00:10:00,120 --> 00:10:03,280 Urgent revascularization isn't possible. 128 00:10:03,280 --> 00:10:05,240 Urgent retransplant is the only option. 129 00:10:05,240 --> 00:10:10,840 And so there's a special priority designation that's made in those cases. 130 00:10:10,840 --> 00:10:15,960 So hepatic artery thrombosis is the most common vascular complication. 131 00:10:15,960 --> 00:10:20,960 And when it happens within the first week of the transplant and revascularization is 132 00:10:20,960 --> 00:10:29,040 not possible, it receives a special designation since urgent retransplant is the only treatment. 133 00:10:29,040 --> 00:10:34,840 And probably the most common transplant complication, you know, the Achilles heel has always been 134 00:10:34,840 --> 00:10:36,240 miliary strictures. 135 00:10:36,240 --> 00:10:41,200 But thankfully, most of these can be managed with endoscopic dilation. 136 00:10:41,200 --> 00:10:47,520 Also, acute rejection in children is about 20% in the first year, but does not affect 137 00:10:47,520 --> 00:10:52,560 survival of the liver transplant if treated early with steroids. 138 00:10:52,560 --> 00:10:57,400 And treated rejection can lead to chronic injury, which is the most common cause for 139 00:10:57,400 --> 00:10:59,640 late graft loss. 140 00:10:59,640 --> 00:11:06,000 Late post-transplant complications include infections, particularly viral infections. 141 00:11:06,000 --> 00:11:11,440 And as occur in other transplant patients treated with T-cell decleidin agents, they 142 00:11:11,440 --> 00:11:14,920 are in higher risk for B-cell malignancies. 143 00:11:14,920 --> 00:11:18,040 And finally, autoimmune diseases can recur. 144 00:11:18,040 --> 00:11:23,680 And so close monitoring for patients with those diagnoses is important. 145 00:11:23,680 --> 00:11:29,080 In addition, in adolescents who stopped in wound suppressors, chronic ductopenic rejection 146 00:11:29,080 --> 00:11:32,120 with severe cholestasis can be seen. 147 00:11:32,120 --> 00:11:33,120 Awesome. 148 00:11:33,120 --> 00:11:40,920 So now that we covered pretty much all the standards in pediatric liver transplant, let's 149 00:11:40,920 --> 00:11:47,960 talk about these new concepts about organ perfusion, or as some commonly refer, liver 150 00:11:47,960 --> 00:11:49,080 pumps. 151 00:11:49,080 --> 00:11:54,120 So the liver pump, there's kind of two types of platforms that are available now. 152 00:11:54,120 --> 00:11:59,400 There's the normal thermic platform and the cold perfusion pulsatile platform. 153 00:11:59,400 --> 00:12:05,240 Both have been shown to help livers recover when they're high risk grafts. 154 00:12:05,240 --> 00:12:10,600 The so-called liver pumps are machines that perfuse the liver while outside of the body 155 00:12:10,600 --> 00:12:16,520 to keep it oxygenated and metabolically functional in an ex-pivotal setting. 156 00:12:16,520 --> 00:12:22,920 Many transplant centers, particularly in the adult population, are using the pump daily, 157 00:12:22,920 --> 00:12:25,120 putting high risk livers on pump. 158 00:12:25,120 --> 00:12:30,520 And if they perform moving forward and if they don't, then they have that treadmill 159 00:12:30,520 --> 00:12:31,880 to be able to decide. 160 00:12:31,880 --> 00:12:32,880 Great. 161 00:12:32,880 --> 00:12:37,120 So ex-pivotal organ perfusion can help not only to maintain the liver in the best way 162 00:12:37,120 --> 00:12:42,920 possible but also to assess high risk graft performance before being transplanted. 163 00:12:42,920 --> 00:12:46,720 I think is really the next step is treatment of livers. 164 00:12:46,720 --> 00:12:50,520 Can we make fatty livers less fatty? 165 00:12:50,520 --> 00:12:53,200 Can we enhance the immune compatibility? 166 00:12:53,200 --> 00:12:55,540 Can we change blood group antigens? 167 00:12:55,540 --> 00:13:02,200 So I think we're, you know, the auto-technology's head. 168 00:13:02,200 --> 00:13:04,320 So now it's time to summarize. 169 00:13:04,320 --> 00:13:08,840 Liver transplant has evolved in the last years going from a mortality rate in the waiting 170 00:13:08,840 --> 00:13:19,080 list of 80% to 10% and a mortality rate after the transplant of 50% also to less than 10%. 171 00:13:19,080 --> 00:13:24,520 The main causes for requiring a pediatric liver transplant are bilirotrichia followed 172 00:13:24,520 --> 00:13:27,440 by metabolic diseases. 173 00:13:27,440 --> 00:13:33,400 To address who will receive the liver, we use the Pelt score and it has specific considerations 174 00:13:33,400 --> 00:13:39,960 for patients with acute liver failure and hepatoblastoma. 175 00:13:39,960 --> 00:13:45,000 Some common complications after liver transplant can be a failure in the graft or an acute 176 00:13:45,000 --> 00:13:49,760 rejection, as well as hepatic artery thrombosis. 177 00:13:49,760 --> 00:13:54,700 Rejection can be treated with steroids and it has fortunately a good outcome without 178 00:13:54,700 --> 00:13:58,440 affecting the overall graft survival if treated correctly. 179 00:13:58,440 --> 00:14:04,960 Finally, we talk about the future of the liver transplant that includes ex vivo organ perfusion 180 00:14:04,960 --> 00:14:10,680 that can not only sustain a liver oxygenated and metabolically functional, but also may 181 00:14:10,680 --> 00:14:17,800 be useful to have some directed therapy to the graft. 182 00:14:17,800 --> 00:14:19,920 And that was everything for today. 183 00:14:19,920 --> 00:14:23,200 Don't forget to subscribe to the Stay Current MD YouTube channel. 184 00:14:23,200 --> 00:14:27,840 Follow our social media channels and download the Stay Current MD app for tons of content 185 00:14:27,840 --> 00:14:30,880 in pediatric surgery. 186 00:14:30,880 --> 00:14:36,520 Global Cast MD, along with Cincinnati Children's Hospital, sharing knowledge to improve child 187 00:14:36,520 --> 00:15:00,440 health around the globe.