Intestinal Rehabilitation, Episode 6: Cholestasis

Hello everyone. Welcome back to the Stay Current podcast. I'm Ellen and Cisco. I'm Cecilia Jigena. We're research fellows at Cincinnati Children's Hospital, and along with Stay Current, we're sharing knowledge to improve child health around the globe. And in this episode, we're going back to one of our prior series on intestinal rehabilitation. As a reminder, we're talking to two of the experts at Cincinnati Children's, Doctor Paul Wales and Doctor Michael Helmrath. I'm Paul Wales. I'm a pediatric surgeon here at Cincinnati Children's Hospital. I'm Michael Helmrath. I'm a pediatric surgeon also doing intestinal failure surgery and research here at Cincinnati Children's. So today we are talking about cholestasis and liver failure associated with intestinal failure. Exactly. So, to start out, we talked about the definition of cholestasis, and Doctor Wales as an expert, has actually been involved in the research going into how to define exactly what cholestasis means. Institutionally defined it as a conjugated bilirubin greater than 3 mg per deciliter or 50 micromoles per liter sustained for 2 weeks and not associated with a septic event. There was a recent publication in JPN back in 2021 of definitions related to pediatric intestinal failure and now. To be defined around 2 mg per deciliter or 34 micromoles per liter for 2 weeks, not associated with a septic event. So like he said, a direct or conjugated bilirubin level above 2 mg per deciliter for two weeks, not associated with a septic event is the definition of cholestasis. And advanced liver disease would be defined as conjugated bilirubin above 5 or 6 mg per deciliter. I believe though that as we've gotten better and we've learned how to use lipid emulgens differently and nutrition differently and our approaches. That the definition of cholestasis is not as much as a morbidity mortality as much as it is an indicator of underlying diseases that we need to address. Dr. Helmroth is saying that as we've gotten better at treating these patients with intestinal failure, liver disease has really been less. Of a mortality factor and more of just a factor that we need to pay attention to as we treat these patients. True, and they even mentioned that back in the days, 25 to 50% of the patients died because of associated liver disease, and now it's less than 2%. And Doctor Well points out that the type of liver disease that is seen in patients differs depending on their age. In the setting of young children, it's more of a cholestatic liver disease, whereas in older people, adolescents and adults, they tend to have Steatosis, there's a fatty deposition within the liver, and the term we use now is intestinal failure associated liver disease because that sort of indicates that it's a multifactorial process. And the risk factors are prematurity, lack of enteral feeding, sepsis, and the components of the TPN itself. Now, prematurity, we as clinicians, as a team, we don't have much control over that. But the other factors are modifiable, and we can have an impact on that. And so next, we need to talk about what to do about liver failure and how to prevent it in these patients. So when you talk about the kid that's cholestatic, it really starts at the very beginning. So the first question that I always ask is, has this child ever been enterally fed, and where did we start with our cholestasis and, and where are we at in gestational age and progress? The importance of introducing enteral feeding, getting that enteropathic circulation going, so being aggressive with introducing feeds, doing surgical procedures to optimize anatomy so that we can deliver those feeds. And then prevention of sepsis, we have to be responsible in the way we, we manage the TBN and the, and the sexy thing over the last, you know, decade at least has been the management of intravenous lipid emulsions. So to really address the treatment of these patients, we need to be aggressive with the internal feeding and optimize with surgical approaches the anatomy for that to happen. Avoid sepscess and take good care of lines. And manage the TPN components. And actually, Doctor Wales talked to us about line management and some of the locking solutions in a prior video we made, if you want to take a look at the video on vascular access in pediatric patients. Awesome. So, let's talk about TPN management. So you can do a couple of things to try to avoid. That one, to limit the amount of fat that we put in the TPN to 1 g per kilo per day. We know that there are new lipid emulsions that can reverse or prevent cholestasis, namely, it was omegavi first year in the US and then smallfoot was used in Europe and Canada, has become prevalent here over the last 3 or 4 years. So basically there are two ways of how to manage lipids. and a TPN. So you have the first part that is just limiting the amount of fat, and you can take it even like 1 g per kilo per day, and that can be done sometimes in some patients, but then you can also change the composition and include this new stuff that it's called smoth. So Smoth lipids, which I'm sure you've heard about SMOF, means that the lipids are composed of soybean oil, medium chain triglycerides, olive oil, and fish oil. One of the major advantages I think of the addition of SMP is the ability to provide more calories from fat, as much as 2 2.5 g per kilo. I think that people need to recognize that the management of These kids is healthy growth. We've always talked about that, and in many ways, the advantages of smart allows you to provide some of the calories more if there's fat, and then I think that that's a benefit. And Doctor Helmras points out that even if you have patients on these lipid emulsions trying to prevent cholestasis, it doesn't necessarily mean they can't become cholestatic. Like we talked about, there are other factors related to patient developing cholestasis. So what do we do when we develop cholestasis? When you think about the strategy for reversing cholestasis, you have two options. One is dose restriction. One is change of composition. And so our conventional lipid emulsion, which was intralipid made by soybeans, when they're metabolized, they lead to the production of frostaglandins and oisinoids that are pro-inflammatory. So the addition of newer 3rd generation lipid emulsions like small. Lipid, it promotes bile flow, so it's hepatoprotective, can deliver it at conventional dose and still get the somatic growth, but hopefully the neurologic nutrients that you need, but also protect the liver. So smo lipids stimulates bioflow, is hepatprotective, and helps the growth and neurodevelopment of our patients. But it doesn't have enough arachidonic acid in it, so the risk with moth lipid, like Dr. Hellras said. You still can develop essential fatty acid deficiency if you dose restrict small lipids. When delivered at conventional dosing, nobody has essential fatty acid deficiency. So what's the recommended amount of fatty acids that we should be giving to patients? By convention, people are kind of settling on 2.5 g, but I think for preterms and babies, it's important to realize that the actual nutrition guidelines state 3 4 g per kilo per day. And another thing Doctor Wales points out is that the 2 mg per deciliter threshold to say patient is called static is really low. So probably when patients reach that threshold, they don't need to change to smuff immediately. Because probably even 90% of them will get better just by observation. People will use SWP. The billy hits 2, and then they come off Swamp and they put them on a Megavin or they dose restrict them because they think this patient has dangerous polystatic liver disease. My opinion is that a billy of 2 is not by any stretch advanced liver disease, and it's not dangerous, and it's usually transient. So I personally would not change the lipid emulsion out of Billy to. So a problem that might come up is rising bilirubin that isn't necessarily cholestasis, and the example Doctor Helmrath gave is a patient with a proximal adrenostomy who undergoes a takedown, the one that has a high output proximal jejunostomy, who's cholestatic, but you're going to do a takedown on, and so you take them down. One of the first things that you'll get your neonatologist telling you about when you start feeding is they'll get worried because the direct bilirubin goes up. That's normal. So when you start refeeding a cholestatic liver, especially if there's ileum, you're reintroducing the bile acid pool back to the liver, and you're stimulating the liver now to become more active in the production of bile salts. You'll notice that the GDT will go up, AST, ALT will go up the first week or Two after surgery, as will the direct billy, and then you'll start to slowly see them come down. It may take several weeks for the levels to come back down, so we might just have to be patient. Other than ruling out urinary tract infection, a gram-negative infection, which can also show up at a direct belly, you don't need to do a whole lot of imaging, ultrasounds and stuff. So we talked a lot about the medical management of cholestasis and cholestasis prevention, but how does what we do in the operating room have an effect? So I think it's really important to try to provide proximal drainage of the duodenum. The ultimate goal when Paul and I operate initially on these high-risk kids is to control whatever the damage is proximally and be able to decompress that duodenum, which oftentimes for me is placing a delay drain that I like. It's Doctor Hamrath explained here, as he explained in previous episodes. So that he likes to leave a lake drain to decompress the duodenum. So if you see ongoing cholestasis and there's a proximal blockage that unfortunately puts the pressure in the biliary system at a much higher level and it really, really speeds up the cholestatic process. And by keying them precise enough, G tubes do not decompress the duodenum. So Doctor Helmer says that this lake drain can also help identify the proximal bowel. And helps leave the bowel with the appropriate size to make the future anastomosis easier, so you don't have a big size mismatch. Another surgical consideration, not only in making sure to decompress the biliary tree with, you know, by decompressing the duodenum, but making sure to look at the gallbladder because, you know, that's definitely, there could be an anatomic explanation for cholestasis that could be easy to miss if you forget to actually see what the gallbladder looks like. Very commonly when we operate, do secondary surgical or autologous reconstruction. Procedures in this population, we'll take a liver biopsy at the time to give us kind of an up to-date snapshot under the microscope. And one intervention that was considered in the field was a prophylactic cholecystectomy, but they do not recommend it because the gallbladder helps with the enterohepatic circulation, and many of these patients won't even need it. So we've talked about kind of prevention, some of the treatment strategy to prevent cholestasis. How do we monitor these patients long term and what do we do with them long term? We follow liver function and biochemistry, or, you know, with it as an inpatient quite routinely as an outpatient with clinic visits. But there's other tools available as well, such as elastography or fiber scan. Problem with it is that it seems to be pretty good for mild or no fibrosis or very, very advanced fibrosis. It's, it's the patients in the middle that it's not as sensitive. Ongoing monitoring is obviously, you know, really important. Finding the best way to do that is still in, in evolution. So how often do we actually see these kids Follow up once they're out of the acute illness phase and out of the hospital. Depends on the patient. I'd say the range of visits for a kid on TBN at home would be anywhere from every 1 to 3 months, 34 months. It really depends on the patient, how stable they are. Actually, sometimes when a kid is actually really actively adapting, you know, you see them more frequently because you're making rapid changes, but it does vary a little bit depending on the status of the child at home. Awesome. So to summarize, we talked about cholestasis in intestinal failure patients. We talked about the definitions of cholestasis and of liver disease in these populations. We talked about the medical management and prevention of cholestasis, including using different types of lipid emulsions, as well as what to do when we have cholestastasis and how to manage it. Then we talk about The surgical considerations to help prevent cholestasis, including making sure that the duodenum is decompressed and to not forget to look at the gallbladder to make sure there is not an anatomic cause for cholestasis. And finally, we talked about the long term surveillance of these patients and how it's changed over the years and things to consider. As always, we would emphasize, that all this takes a multidisciplinary team with the surgical experts, the dietitians, APPs, and a lot of other people involved to make sure these patients get the best care. If you liked this episode, make sure to leave us a rating and a review wherever you're listening. Check out the videos on YouTube. Check out the Stay Current and pediatric surgery app where we have more podcasts, videos and everything. I'm Ellen and Cisco and I'm Cecilia Gena. We're research fellows at Cincinnati Children's Hospital and along with Stay Current, we're sharing knowledge to improve child health around the globe.