Liver transplant with Dr. Jonathan Merola

Hello everyone, welcome back to another episode of the Stay Current podcast. I'm Cecilia Gigena, a research fellow at Cincinnati Children's Hospital, and along with Stay Current, we are sharing knowledge to improve child health around the globe. So today we are going to talk about updates in liver transplant with Dr. Jonathan Meralda, a transplant surgeon from Cincinnati Children's Hospital. Let's start with some background.

Up until the 1980s, the vast majority of children on the transplant waitlist passed away due to the lack of available organs. And really in the 1990s, a technique that took advantage of the liver's segmental anatomy and ability to regenerate greatly increased organ availability. These segmental transplants are called barium grafts or segmental grafts. And thanks to them, the mortality of the waitlist decreased from 80% to just 10%.

But still, for children that are under one year of age, mortality remains at about 30%. Unfortunately, due to size, kids under one year of age still have higher mortality rates.

And what are the indications for liver transplant? Images for liver transplant in kids include biliary atresia, metabolic liver disease, liver tumors, and acute liver failure. But by far and away, the most common is biliary atresia. Biliary atresia is a rare congenital condition in which the bile ducts inside and outside the liver are abnormally narrow, blocked, or absent, leading to bile buildup in the liver. This obstruction causes liver damage and cirrhosis if left untreated.

The first treatment for biliary atresia is a Casay procedure, or a portoenterostomy. So the old dogma of a third gets better, third stays the same, and a third gets worse is really out the window. In previous years, the usual prognosis for patients with biliary atresia was that after a Casay procedure, a third often will improve, a third will remain the same, and a third will get worse. But now, the native liver survival after a Casay can be as high as 80%.

The keys to this were early diagnosis and selective use of antibiotics and steroids. So how does this influence the transplant? Well, most with biliary atresia may end up requiring a transplant. Facilitating that native liver survival earlier in life delays the overall immunosuppressive exposure and decreases competition for the scarce size match graft, and is ultimately associated with much lower healthcare costs. Great.

Let's change gears a little and talk about how do you decide who gets the liver. Organ allocation in the US is based on the principle that the sickest patients should be given the highest priority, and adults is based on the MELD score. MELD score is a score that estimates a patient's chances of surviving their disease in the next three months. It goes from 6 to 40, being worst when higher, and it is based on creatinine, bilirubin, serum sodium, and internal normalize ratio, or INR.

MELD score is used for children under 12 years of age, and it is calculated using ovumine, bilirubin, INR, and degree of growth failure without creatinine. And it also has a special designation of 1A for acute liver failure and 1B for hepatoblastoma.

So now let's dive into acute liver failure. Acute liver failure manifests with diffuse hepatocyte necrosis and release of these damage associated peptides and then cause a SERS response. SERS is a systemic inflammatory response syndrome, and it is characterized by an exaggerated defense response from the body and that can lead to multi-organ failure. Together, only about 25% of kids with acute liver failure survive their condition without a transplant or death.

And so a score has been recently where you can predict which patients should go on to be listed for a liver transplant. Great, but is there any treatment for these kids? The study from a major liver center in Denmark where they had 16 children and criteria for plasma exchange was bilirubin over 20, or if they had toxic ingestion as a cause. And so if they met those criteria, then they got high volume plasmapheresis. So high volume plasmapheresis is bilirubin reaches 20. Any other option?

A clever surgical solution to acute liver failure that's been described takes advantage of the liver's regenerative capacity. And it turns out that a native liver with over 90% necrosis will eventually recover. And what does the procedure consist of?

To take advantage of this, a native left liver can be resected, leaving the right lobe behind, and then transplanted with a new left lobe and with immunosuppression that transplanted left lobe graft can be maintained for a period of 6 months, at which time the native liver is able to recover. Perfect. So tracheal liver transplant, though very complicated, can be performed in cases of acute liver failure to give time to the native liver to recover. Now let's have some details on hepatoblastoma.

This is really the most common liver tumor for kids that are under 5. For tumors that are too extensive to be resected, transplants are really the only treatment of choice. How many kids with hepatoblastoma were required transplant? About 60% of hepatoblastomas are unresectable at the time of diagnosis. Therefore chemotherapy is given upfront and about 20% of patients remain unresectable after chemotherapy. Okay, so we talk about the main indications being biliary atresia.

But what is the second most common indication for pediatric liver transplant? The second most common indication for pediatric liver transplant is venous liver disease. And most of these are caused by single gene mutations, which affect enzymes that are principally harbored in the liver. There are multiple metabolic diseases from the liver, such as Wilson's disease or Kregel Neja, which are characterized for having an enzyme deficiency.

And so since the vast majority of this enzyme is harbored in the liver, the cure for is a liver transplant. But even though we still don't have a better treatment outcome, Dr. Merola explained what the future may hold for these patients. Now we can isolate fluripotent stem cells, correct the deficient gene, and expand lipid organoids that can then be infused back into the patient as a cellular therapy.

And so I think, and I'm hopeful that in the future, many of these metabolic liver diseases can be cured with these cellular therapies. Awesome.

Now that we know the indications, let's talk about how the procedure is done here at Cincinnati Children's Hospital. Here we offer a living donor liver transplant, which like with the kidney offers the advantage of hastening organ access and a vaster recipient recovery. For planning these operations, they use CT and MRI to determine which portion is optimal and can be safely resected from the donor and be adequate for their recipient.

Well, most of these living donor recipients have a much shorter length to stay and require fewer transphagians because we don't have to wait till they're extremely sick for them to have access to an organ. Use of segmental grafts, however, comes with a new challenge, and that's greater size mismatches. Mismatches in size not only occur from the organ itself, but with segmental grafts, it happens with blood vessels. Fortunately, there are techniques that can be used to avoid or alleviate this.

The small native hepatic artery is often inadequate. And so we make pretty liberal use here of infernal aortic conduits where a piece of the donor iliac artery is placed enticide on the aorta. And then the other end is an estomosed end-to-end to the recipient. And that really gives excellent arterial flow to the transplanted liver. Great. Now, let's move on to outcomes.

Overall, however, outcomes after pediatric liver transplant are excellent. And graft survival routinely exceeds 30 to 40 years. And this is especially the case for living and partial donor grafts. And what about complications? One of the most feared complications is primary non-function, which results due to a severe ischemic injury and possibly due to preformed antibodies. But fortunately, this terrible complication happens in less than 1% of the transplants.

Vascular complications are much more common in pediatric transplant. And usually occurs within the first 30 days. Urgent revascularization isn't possible. Urgent retransplant is the only option. And so there's a special priority designation that's made in those cases. So hepatic artery thrombosis is the most common vascular complication.

And when it happens within the first week of the transplant and revascularization is not possible, it receives a special designation since urgent retransplant is the only treatment. And probably the most common transplant complication, you know, the Achilles heel has always been miliary strictures. But thankfully, most of these can be managed with endoscopic dilation.

Also, acute rejection in children is about 20% in the first year, but does not affect survival of the liver transplant if treated early with steroids. And treated rejection can lead to chronic injury, which is the most common cause for late graft loss. Late post-transplant complications include infections, particularly viral infections. And as occur in other transplant patients treated with T-cell decleidin agents, they are in higher risk for B-cell malignancies.

And finally, autoimmune diseases can recur. And so close monitoring for patients with those diagnoses is important. In addition, in adolescents who stopped in wound suppressors, chronic ductopenic rejection with severe cholestasis can be seen. Awesome. So now that we covered pretty much all the standards in pediatric liver transplant, let's

talk about these new concepts about organ perfusion, or as some commonly refer, liver pumps. So the liver pump, there's kind of two types of platforms that are available now. There's the normal thermic platform and the cold perfusion pulsatile platform. Both have been shown to help livers recover when they're high risk grafts. The so-called liver pumps are machines that perfuse the liver while outside of the body to keep it oxygenated and metabolically functional in an ex-pivotal setting.

Many transplant centers, particularly in the adult population, are using the pump daily, putting high risk livers on pump. And if they perform moving forward and if they don't, then they have that treadmill to be able to decide. Great. So ex-pivotal organ perfusion can help not only to maintain the liver in the best way possible but also to assess high risk graft performance before being transplanted. I think is really the next step is treatment of livers. Can we make fatty livers less fatty?

Can we enhance the immune compatibility? Can we change blood group antigens? So I think we're, you know, the auto-technology's head.

So now it's time to summarize. Liver transplant has evolved in the last years going from a mortality rate in the waiting list of 80% to 10% and a mortality rate after the transplant of 50% also to less than 10%. The main causes for requiring a pediatric liver transplant are bilirotrichia followed by metabolic diseases. To address who will receive the liver, we use the Pelt score and it has specific considerations for patients with acute liver failure and hepatoblastoma.

Some common complications after liver transplant can be a failure in the graft or an acute rejection, as well as hepatic artery thrombosis. Rejection can be treated with steroids and it has fortunately a good outcome without affecting the overall graft survival if treated correctly.

Finally, we talk about the future of the liver transplant that includes ex vivo organ perfusion that can not only sustain a liver oxygenated and metabolically functional, but also may be useful to have some directed therapy to the graft. And that was everything for today. Don't forget to subscribe to the Stay Current MD YouTube channel. Follow our social media channels and download the Stay Current MD app for tons of content in pediatric surgery.

Global Cast MD, along with Cincinnati Children's Hospital, sharing knowledge to improve child health around the globe.