Chapters Transcript Video Neonatal Cholestasis Good morning everyone. Welcome to Grand Rounds. It's my pleasure to introduce uh Doctor Preetha Mohanty, um, who is an associate professor in the Department of Pediatrics, uh, division of Pediatric Gastroenterology, pathology and nutrition at UCSF. Um, she did her residency in uh New York Health Science Center, uh, in, in SUNY Upstate Medical University, um, and completed her GI fellowship at the University of Rochester and went on to do an additional year of transplantedpatology to Children's Hospital of Boston, a very important topic which we all see inpatient outpatient. Thank you, Doctor Mohanty for taking time to teach us about neonatal cholestasis this morning. OK. Thank you, Doctor Ali for the introduction and uh thank you for the grand rounds uh team for inviting me today to talk to all of you. So let's get started with our presentation today on neonatal cholestasis. So no one involved in the planning or presentation of this activity has any relevant financial relationships with the commercial interest to disclose. So my objectives for today's talk are to list the etiologies of neonatal cholestasis, to identify the evolving roles of liver biopsy and gene testing, and to explain the mode of action and approved indications for ileal bile acid transporter inhibitors. So here we can see that the mechanism of bile excretion is a complex process, and it depends upon multiple receptors. So in the hepatocytes, the bile acids, they are secreted into the bile cannaliculi by the BEP transport protein. Cholesterol is secreted by ABCG5 and ABCG8, and phospholipids are secreted by MGR3. The bile, the cholesterol, and the phospholipids, they formed mixed in the cells, and then the bile acid is secreted into the small intestinal lumen where it facilitates dietary lipid absorption. The bilaids are absorbed in the terminal ileum. By the apical sodium dependent bile acid transporter or the ASBT. In the enterocytes, the bile acids bind with a binding protein. And at the basal lateral side of the enterocytes, the bile acid efflux is mediated by organic solute transporters. And then these bile acids are transferred via the portal blood back to the liver. In the liver, their uptake is taken by the sodium dependent torocholate polypeptide and the organic anion peptide. A small amount of acids that are not absorbed, then enter the systemic circulation. And the hepatocytes also influx bile acids via the MRP3 and the MRP4 proteins. So as you can see here, there are so many different receptors involved and um an abnormality involving any of them can result in cholestasis. So what is cholestasis? cholestasis is defined physiologically as a measurable decrease in bile flow, pathologically as a histologic presence. In the hepatocytes and bile ducts and clinically as the accumulation in blood and extrapatic tissues of substances that are normally excreted in bile like the bilirubin, bile acids, and cholesterol. So it's important to remember that elevated conjugated bilirubin or direct bilirubin is the predominant characteristic and that is never physiologic or normal. So cholestasis results in impaired bile flow and that leads to liver bile acid accretion. So that has its consequences in the liver, intestine, and systematically. So in the liver, it causes inflammation. The cholestasis can cause apoptosis and over time result in fibrosis, cirrhosis, and rare cancer. Because of the cholestasis, we have fat malabsorption that results in malnutrition, deficiency of fat-soluble vitamins, so ADEK deficiency, and it can lead to an altered microbiome. Because of the presence of the cholestasis, we can have increasing pruritus. It can be associated with other conditions, um, you know, such as cardiac and renal pathologies, depending upon the etiology. It can also result in cirrhosis and complicated. To hypertension and decreased growth. So these were the guidelines that were published in 2016 in um by NASA of the North American Society of Gastroenterology, Hepatology, and Nutrition. And The Recommended that the measurements of serum bilirubin should always be fractionated into unconjugated or conjugated hyperbilirubinemia. And if you see any infant jaundiced after 2 weeks of age, they should be evaluated for cholestasis by measuring the total and the direct serum biarabin. So conjugate the direct bilirubin more than one is considered pathological and warrants diagnostic evaluation. So our role as physicians is to remember that if we see an infant or a neonate um who's jaundiced, it's important that we fractionate it, and if the bilirubin is more than one, we act on that. It's important to visualize the stools always, you know, check the diaper, look at the color of the stool. A good liver and spleen exam is important, and making sure that you're timely following the labs until the direct hyperbilirubinemia is trending down and is normalizing. So the etiologies of neonatal cholestasis can be grouped as hepatocytes and involving the bindups. So if the cause of the cholestasis is because um of hepatitis, we can have that uh be indeterminate where we are unable to determine what is the etiology of the hepatitis, and that is commonly. Natal hepatitis. It could be because of a viral infection, you know, just a, just like HSV or CMV or a bacterial or parasitic infection. The cholestasis can also be due to transporter gene defects. So as we saw, there are so many different transporters involved and so There are conditions called SPI 12, and 3, which are some of these conditions involving transporter defects. Metabolic and storage conditions like galactosemia, thyrosinemia, Niemanic, mitochondrial disorders, alpha one antitrypsin deficiency, OTC deficiency, drug toxicity, these can also cause cholestasis. So galactosemia is our typical baby who would come in with lethargy, poor sucking, breastfed, first month of life, and um, you know, it's important to remember that some of these metabolic conditions can also cause um cholestasis and require intervention. The other etiologies are involving the bile ducts, so they can be classified as those involving the extra hepatic and the intrahepatic bile ducts. So, uh, biliary atresia is one of the conditions that we are going to spend a lot of time today to talk about. Uh, the other conditions involving the extrahepatic bile duct would be instigated bile syndrome, uh, choleocholithiasis, agenesis of the extrahepatic bile ducts, and those involving the intrahepatic bile duct would be allergy syndrome and Talk about Algal syndrome in detail today as well. Other conditions involving the ductive plate malformation can also lead to cholestasis, such as Karoli disease, autosomal recessive polycystic kidney disease, and autosomal dominant polycystic kidney disease, as well as one myber complexes which are, uh, bile hematomas um seen around the biliary. And it's important to also remember that endocrinopathies can also cause neonatal cholestasis, um, like pan hypopituterism, hypothyroidism, neonatal hemochromatosis, and TPN associated cholestasis. So these are also some of the conditions that we see, uh, causing cholestasis. So this is a vast topic today, so, um, because of the time constraint, I'll be focusing mainly on biliatrezia and allergy syndrome. But again, always remember that there are so many different conditions involving the liver and the bile ducts that can cause cholestasis. Remember endocrinopathies, remember metabolic diseases, especially the most common ones that we see like gaoptosemia. you know, presenting to us in the first month of life and then remember vital infections as well as transported defects. So this was um looking at the differential diagnosis of neonatal cholestasis in 2016, so we can see that 25% of the causes of neonatal cholestasis was because of metabolic disease. 25% for was due to intrahepatic cholestasis. 25% was also found to be secondary to biliary atresia. 10% was secondary to neonatal cholestasis, 10% secondary to alpha one antitrypsin deficiency, and 5% of the causes were viral. So when we see a baby who is jaundiced, you know, there are other causes of jaundice as well, like breast, breastfeeding jaundice, physiological jaundice. So it's important to determine whether this jaundice is liver in a collision or not. So in the history, we should ask about is there any history of cardiac disease, any hemolysis, any neurological concerns? Um, any recent illnesses, you know, any vital illnesses, um, any history of being on TPN for a prolonged period of time? What is the color of the stools? What formula or milk is the child feeding? An examination is also important, examining um the liver, checking the spleen, the splenomegaly is a late finding. Um, and then looking for other complications like ascites, um, looking for neuromuscular exam as well is important. So our imaging modalities would be an ultrasound or an MRI that may show a dilated common bile duct or stones in the bile duct, a liver mass or abscess, and may show splenomegaly or if associated with um the syndromic variety may show polysplenia as well. And then our lab work is suggestive of increased direct bilirubin, increased GGT, increased transaminasis. There may be an increase in ammonia and an increase in INR depending upon the synthetic, you know, function of the liver, and there'll be an increase in serum bile acids. So it's important to understand from this slide that what are the signs of urgency. So if we see a baby whose glucose is less than 40, the child is coagulopathic with an INR more than 4, the ammonia is more than 100, you have a very low or very high ALT, massive ascites, respiratory difficulties, or encephalopathy. So these are signs of, you know, an urgent or an emergent intervention. So let's begin to talk about biliatrezia. So biliatrezia is a destructive inflammatory cholangopathy. It is progressive. It involves the intrahepatic and the extrahepatic bile ducts. These ducts are destroyed at varying lengths during the neonatal period and replaced by fibrous scar tissue. Eventually, the scar tissue obliterates the lumen of the bile ducts and impairs the bile flow stasis. So the most common is the acquired form, and that's seen in 85% and 15 to 20% have the embryonic form which is associated with other congenital anomalies like polyschemia and heterotaxy. So infants who have acquired BA, they may be asymptomatic at birth, and as time progresses, we may see them developing jaundice in the first few weeks after birth. As the bile flow diminishes, the stool color loses its normal pigmentation and becomes acolic or clay colored. And the finding of acholic stools in a jaundiced newborn should prompt an urgent evaluation for biliotrezia. So what causes biliatrezia? So there is strong evidence that viruses, toxins, and gene sequence variations, they trigger a pro-inflammatory response that injures the duct epithelium and produces a rapidly progressive cholangopathy, and the immune response also activates the expression of type 2 cytokines that promote epithelial cell proliferation and extracellular matrix production by non-parinal cells. So these are the clinical manifestations where um we see jaundice or the yellowish discoloration of the skin and the eyes, acolic stools, dark urine. You may see the child falling off the growth curve, and then hepatosplenomegaly and complications like ascites. So this was, um, this is an infant stool card which was used in Taiwan and the importance for this was a screening program to pick up children with biliviatresia at a much earlier time. So they would give this infant stool card at the time of neonatal like discharge from the hospital, and they would advise the parents to check their baby's stool every day for the first month after birth to screen them for BA. And if the baby had any of these abnormal stool colors that you can see, uh, labeled as 12, and 3, they were told to contact the provider. And so this study um used the stool color card screen and they found a 46% decrease in very late referrals and a decrease in the Kasai operation occurring more than 90 days. So when we have a baby with neonatal cholestasis, what would be the workup to do? So, The workup is done in multiple tiers because as you saw there are so many different etiologies, so we would have to work through slowly getting all of this done. So initially we would check the bilirubin, so conjugated hyperbilirubinemia is what you would see, a disproportionately increased GGT in biliatrezia. And elevated alkaline phosphatase and mild to moderate increases in serum aminoransis. So you'll see more of an obstructive pattern with increased GTT, alkaline phosphatase, and direct bilirubin. Um, and then if there is coagulopathy, there you will see an increase in the PTINR. Now, you might have seen that recently we have started ordering for this biomarker. It is called as the MMP 7 or the matrix uh metalloprotein A7, and I'll talk a little bit about it in the next few slides, but that is something that you can order on Epic, and the results are available in about 3 to 4 days. Um, a liver ultrasound with Doppler would also be a good initial, um, imaging study to begin with. And then some of the other conditions you could screen for in the first year would be checking for alpha one antitrypsin phenotype, um, checking the thyroid function tests and urine CMV and urine analysis as well as culture. So Biomarkers and deliriat trees, yeah. So this is, you know, currently a hot topic here, and we have a lot of research going on to identify biomarkers that can, um, identify these neonates very early in time so that intervention can also be done much sooner, leading to a better prognosis with the. So the biomarkers that are currently available for clinical application are the MMP 7 as well as the GGT. So, let's talk a little bit in detail about those. So the MMP 7, that is pivotal in the degradation of extracellular matrix proteins involving the tissue remodeling and fibrosis. So if the levels of MMP 7 are elevated, they correlate with the extent of bile duct proliferation and fibrosis, and hence it is an important biomarker for assessing disease severity. The FGF-19 or the fibroblast growth factor 19, that's involved in bile acid regulation and liver growth. So it plays an important role in liver regeneration and in bile acid homeostasis. So it is important in evaluating the liver function and in predicting post Kasai outcomes. The MAC 2 binding protein glycosylation isomer. That correlates with the severity of liver fibrosis in BA patients. Its high sensitivity and specificity for liver fibrosis highlights in its utility in monitoring disease progression. We all use GGT, that's a well established biomarker for liver dysfunction. It serves as an indicator for bile duct obstruction and liver damage. It's also well known that elevated levels of interleukin 68, and 33 TNF alpha have been documented in VA patients reflecting the role of cytokines in immune-mediated bile duct injury and fibrosis. So again, a lot of research going on to look at some of these other. But what we have available now to us is the MMP 7 and the GGT. So in this study done by the author and colleagues published in 2017, they use proteonomics to screen the serum samples obtained from 35 infants with BA and 35 infants with intrahepatic cho cholestasis at the time of diagnosis. 76 proteins were found to be differentially expressed between the two groups. And in logistic regression, we see the combination of serum levels of MMP 7 and GGT differentiated between these two diseases with an area under the receiver. Of 0.98 outperforming all other individual proteins and serum markers. So we're seeing from this slide that ordering MMP 7 and GGT can help us with a higher sensitivity. This study um was accepted in December 2023 looking at the diagnosis. Accuracy of serum MMP 7, as a biomarker of BA and this was a large North American cohort done across a lot of different centers in the United States. And as we can see in this current study, they had a sample size of 399 patients. Um, the area under the curve was 0.90 with a confidence interval of 0.87 to 0.94 at a cutoff of MMP 7 of 52.8. The sensitivity of this marker was found to be 94%, with a specificity of 78%. NPV of 97% and a positive predictive value of 65%. So that was talking about MMP 7 and GGD and their roles as biomarkers. There were also a few studies published by Harpava in pediatrics in 2011 and then in 2016 and 2018 in JPGN, um, and they looked at the level or the value of direct bilirubin at birth. So the study was important because they Found that the direct bilirubin levels are eliminate elevated in that are ultimately diagnosed as biliatresia. So the newborn direct bilirubin levels, they were obtained retrospectively from all of these hospitals, and the subjects with BA were born between 2007 and 2010 were studied. Of the 61 subjects with biliary atresia, 56% of the newborns had their levels of direct bilirubin measured, and all the direct bilirubin levels exceeded the lab norms, and they found that these numbers increased over time. So some of these patients had direct bilirubin levels elevated in the 1st 24 hours of life, and by the 1st 96 hours of life they saw the direct bilirubin numbers. You know, increasing significantly. So at 24 to 48 hours of life, the subjects with biliary atresia had a main direct bilirubin levels significantly higher than that of control, even though their total bilirubin levels remained below phototherapy limits. So despite the elevated direct bilirubin, the majority of patients had like 79% of these actually had normal direct bilirubin and total bilirubin ratios of less than 0.2. They also found that in the BA cohort, all of the infants had elevated concentrations of direct bilirubin, equating to a sensitivity of 100%. And in the non-BA cohort, 8936 infants, they tested below or equal to the lab's upper limit of normal translating to a specificity of 98.2%. So In their study, they suggested that there may be two ways that we can actually improve our current practice. One is to screen all the newborns for elevated direct bilirubin regardless of their clinical appearance, and 2, to follow the elevated bilirubin levels regardless of the total bilirubin levels. So this was an important study, um, so again, very important to fractionate your bilirubin. Very important to know that even though the total bilirubin is normal, the direct bilirubin may be abnormal. So moving on, we spoke about various labs that are, you know, done in the evaluation um of neonatal cholestasis, and now we move on to talk about various imaging studies. So the most common first step for imaging study is doing the abdominal ultrasound. So often the abdominal ultrasound is done to actually rule out other anatomic causes of cholestasis, namely, um, a cholidocal cyst because that can also present uh with obstructive findings of neonatal jaundice. So you can see here that um this is how a normal gallbladder would look. In deliatresia, the gallbladder is shrunken because it is fibrotic. Um, when you see the ultrasound report, it may say that the baby was just fed, you know, and that's why the gallbladder is shrunken or it is partially contracted. So sometimes that makes it a little difficult for us to realize what is the cause of the contracted gallbladder. Is it truly contracted or is it because the baby was just fed within an hour or so? And rarely you can see the triangular cord sign, and that is very specific. It's almost 97% specific for biliary atresia, and that is um fibrotic scar tissue in the porta hepatis. So another study that you see as ordering is the HIDA scan. So a normal HIDA scan will show excretion of contrast into the small intestine and normal liver uptake. And a HIDA scan in a patient with resia, um. will show the normal uptake in the liver and bladder, but there will be failure of excretion of the tracer into the small bowel. We ordered phenobarbital at 5 mg per kg per day in 2 divided doses for about 3 to 5 days prior to the scheduled procedure to optimize the biliary excretion. It's important to know that the HIDA scan is not specific for biliary atresia. However, if you do see extrition into the small bowel that makes biliary atresia unlikely. The HIDA scan has been used to confirm the biliary tract patency in the past, but it is limited because of its very low specificity, which ranges about 68 to 72%. And a non-diagnostic result when the bioflow is limited to a variety of other etiologies, such as intralobular bile ductposity, neonatal hepatitis, low birth weight babies, those on TPN, they all may have non-excreting scans, so the HIDA scan is limited because of its low specificity. Now, a liver biopsy, um, it is performed to differentiate bresia from other causes of cholestasis, and what you see here in the liver biopsy is you see bile duct plugs, cholestasis, um, you see a lot of inflammatory cells, and what you can see staining here as in blue is the collagen that has stained blue, um, because of the trichome staining. And so you're seeing, you know, a lot of fibrosis here, inflammation, as well as bile duct proliferation. So bile duct proliferation, that is the classic finding in biliary atresia. It's also important to know that if you do the liver biopsy too early in infancy, like, let's say in the first two weeks of life, you may get false negative results and you may need to repeat it when they are older. Um, which means by, you know, about 3 to 4 weeks or so would be a good time to proceed with it. So the liver biopsy, it is highly sensitive for billary atresia diagnosis, but the cons are that it is an invasive procedure. It requires general anesthesia. If you perform it too early, you may get false negative results. It involves, you know, a risk, um, and you need an adequate biopsy sample and an experienced pathologist to interpret it. So what is new and what is in discussion right now uh for imaging for biliary atresia is the use of PTCC or percutaneous transpatic cholecysto cholangiography in neonates and an infants presenting with conjugated hyperbilirubinemia. So this study was published by the Toronto Group, and this is something that they commonly use um in their hospitals to um further evaluate the cholestasis. So they did a retrospective study uh over 16 years. They looked at patients with persistent cholestasis. 7373 patients underwent PTCC. And out of them, 55% studies were normal. Among the abnormal studies, um, they identified that 79% were diagnosed with biliatresia and 12% with alleral syndrome, and the most common patterns that they found in biliatreia was non-opacification of the common hepatic duct with a narrowed common bile duct, and that was seen in 42% patients. And an isolated small gallbladder was seen in 38% patients, so these were the most common patterns of biliatoriessia on the PTCC. So, according to their group, um, performing the PTCC is a minimally invasive procedure as compared to the gold standard that is the IOC or the intraoperative cholangiogram. And what goes in favor of PTCC would also be that if it is a normal study, um, then you are preventing a lot of invasive procedures, um, in those patients. So in the intraoperative cholangiogram, um, you know, that's done to determine the patency proximally into the liver and then distilling into the small bowel. You can see here this intrahepatic of the common bile duct, as well as the left and right hepatic ducts. So moving on from the evaluation by Um, the blood work and the various imaging studies, the PTCC, and, um, it's comparison with the IOC, we now move on into the management. So we spoke about the Kasai procedure or the portal info uh stomy, and that is aimed at reestablishing bio flow. So, in this procedure, um, we have the liver capsule which is connected to the small bowel and it helps in the bile flow. And the timing for performing the the side procedure that is critical. So the sooner it is performed, that increases the probability of survival with the native liver. So we can see here that we have the best results if the procedure is performed in less than equal to 30 days of life. And this was a similar findings in another study published in JPGN in 2019. So to optimize the success of the Casa procedure, um, it should ideally be performed within 30 days of life, but definitely in the 1st 60 days of life, if it's done, then 70% of patients will be able to establish bile flow. After 90 days of life, less than 25% of patients will have bile flu. It is important to remember that biliary atresia is a progressive disease, so even after the Casa operation is done and bile flow is restored, most of these patients, they go on to develop, um, you know, inflammatory injury, um, to the intrahepatic bile ducts. And 70 to 80% of these patients with biliata develop fibrosis, cirrhosis, and total hypertension. Bilatrezia, it is the most common cause for liver transplantation in in pediatric patients, and a recent nationwide study reported that 50% of patients who have bilirezia, they required liver transplantation in the first two years after birth, with an overall incidence of liver transplantation of 80% in childhood. The potential complications for Skai, most of these children may develop at least one episode of ascending cholangitis, and that's because of the anatomy with the direct contact between the liver intrahepatic bile ducts and the small intestine. Um, and so that makes them susceptible to developing cholangitis. Uh, the babies who present with cholangitis, they may come in with history of recurrent jaundice, acholic stools, signs of sepsis. And if you have recurrent cholangitis that, you know, may prompt you to think about whether there is an obstruction in the room and why that's causing it. Other complications post-kai as we spoke about is developing progressive disease leading to cirrhosis, portal hypertension, and malignancy. Another rare complication, and I just wanted to mention this here is hepatopulmonary syndrome when there is abnormal shunting of blood in the pulmonary vascular bed leading to hypoxia and platnia. So this is one condition where you'll see that the the smear is actually improved when they are in recumbent position. So you can see in this slide that in cirrhosis, um, and portal hypertension, um, you do have the production of endothelium one and tuber necrosis factor alpha. There's bacterial translocation, um, because of this, uh, the, in the endothelium you have production of vasoactive mediators such as the veg F and the nitric oxide. And these can cause angiogenesis as well as vaso dilatation result in abnormal shunting of blood in these liver or cirrhotic patients. So the post-operative care after Kasai, um, is, it's important to look at what the serum bilirubin level is at 3 months. So if the jaundice resolves by 3 months, that is a good predictor. Um, of the outcome of Kasai. Um, we have these kids on Acagol or the ursodiol, and that helps in improving the bile flow. We typically start them at 10 mg per kg per dose twice a day. And um initially these kids are on antibiotic prophylaxis. Remember, about 40 to 90% of babies develop at least one episode of cholangitis, and they are at risk because of bacterial stasis and their abnormal anatomy. We commonly use TMPSMX at 4 mg per kg per day. And if they do develop um cholangitis, then we treat them with antibiotics for about 4 to 6 weeks. Hello, can you hear me? Oh yeah, I think we lost you for a second. Oh. Yeah me. We can hear you now. I think we heard up to the uh the 4 to 6 weeks of antibiotics. Yes, perfect. Um, Are, are you able to go to the I'm having some issues. Um, I, sorry, I don't have control of the slides. Just give me 1 2nd, I'm just gonna quickly troubleshoot. Yeah, no worries. OK. There we go. OK, there we go. OK. So the take home points um From, you know, this topic that we spoke about biliotrezia, is to, it's important to again understand that you may have elevated direct and conjugated bilirubin at birth. Um, you know, so keep an eye out of what the bilirubin levels are of retina in life and then continue to monitor. Obtain an MMP 7. so again, an important biomarker that you can now order on Epic. And then remember that PTCC is something that we may use often in the future moving forward compared to an IOC. And again, the goal for biliatorresia here is to do the Kasai by 30 days of age. So moving on to our next topic, and that is allergal syndrome. So alleral syndrome is an arteriohepatic dysplasia. You have a, it's an autosomal dominant condition where you have mutation of the jagged 1 gene on chromosome 20 that codes for the ligand of the NO2 receptors. JAG1 mutations are identified in 94% of patients, 60% of these are new mutations in the pro band, and then we often see that there's no good genotype and phenotype correlation and allergy syndrome. AndAG one is expressed in the organs that are typically affected in allergy syndrome. So this is a simplified view of notch signaling. So what we're seeing here is the ligan of JAG that is the JAG1 and the Jag 2, and the delta-like or the DLL families. So these interact with the notch family transmembrane receptors on the adjacent cell. The notch to receptor exists at the cells surface as a proteolytically cle product consisting of a large ecto domain and a membrane tethered intracellular domain. Now this receptor ligan interaction, it results in protelytic cleavage of the intracellular domain. Which then gets free, it translocates to the nucleus, and once it's in the nucleus, it forms a complex with the RBPSUH protein and displaces the core repressor complex from this protein and leads to the transcriptional activation of the notch target genes. Now, in this particular condition, allergies, um, there is repression of the uh transcription process and hence, you know, we do not see the formation of those proteins. So you're seeing suppression of um this signaling pathway in allergy patients. So the diagnostic criteria and allergy syndrome involves bile duct paucity. Um, there are other clinical characteristics like a characteristic facial appearance, ocular abnormalities like posterior embryotoxin, cardiac murmur, skeletal abnormalities, as well as association with other conditions such as renal disease, pancreatic disease, and intracranial hemorrhage. You also have the mutation in Jagged one. So all of these make up the diagnostic criteria in allergy syndrome. So these are the typical faces where you see a prominent forehead and nasal bridge. You see deep eyes with hyperthyism, a small pointed chin, and prominent ears. And you see these facial features evolve over time in these patients with allergy. It's not, uh, in these facial features are not specific. They may also be seen in other conditions of congenital intrahepatic cholestasis. This is a posterior embryotoxin, which is a prominent Schwalbe's line in the anterior chamber of the eye. And you see the butterfly vertebrae where there is failure of fusion of the anterior arches of the vertebrae. You see these xanthomas that are commonly seen in these allergic kits, and they can be very debilitating as well. And then the cardiac, um, you know, malformations that we see here most commonly the peripheral pulmonic stenosis. We also see ASDO, VST, PA, and PVS. So these are the most common, uh, but the PPS is seen 67 to about 80% of patients with Alger syndrome. And then there are other renal disorders that can also be associated, such as a single kidney, a cystic, you know, renal disease, a renal artery stenosis, to name a few. So, uh babies with allergy syndrome, they'll come to you, they'll be cholestatic, um, they'll have a characteristic facial appearance. Their, um, most common symptom would be pruritis or the presence of these anthomas. The labs would again show the obstructive pattern with a high GGT and alkaline phosphatase, high cholesterol, and maybe mild increases in transamylysis. The liver biopsy would show paucity of bile ducts. So in comparison to um uh to biliaties that when you saw bile duct proliferation, here you would see bile duct positive. So what you can see here is a large portal vein, multiple small hepatic artery branches, but you don't see the bile duct. And the portal tract with the bile duct ratio is less than 0.5. So again to remember that the positive bile ducts is not specific to allergies, it's also seen in a lot of other conditions like non-syndromic positive bile ducts, alpha one antitrypsin deficiency. It can be seen in chronic rejection after liver transplantation and Down syndrome and premature babies, so a lot of other conditions also can cause the positive. Now, the advantages of doing genetic testing in cholestasis is to confirm the diagnosis, is to identify other health risks which are associated with syndromic disease, to also allow for targeted testing of other family members and to assist with reproductive planning. This is an example of one of the genetic uh panels. There are multiple panels now available. This is the ER cholestasis panel and you can see again multiple um genes that are commonly involved in producing cholestasis can be tested. So the natural history of allergies is that those with mild disease may not have any disease progression. Cholestasis in infancy mayus unchanged. It may progress to end-stage liver disease, or it may resolve and significantly improve, usually around the ages of 4 to 5 years. So, and then lastly, I wanted to talk about um the new medications which are currently involved in treating pruritus. So, you know, as I mentioned, the pruritus can be uh very disturbing in these patients with allergy syndrome. It is also one of the uh reasons why these kids go on to require a liver transplantation. The pruritus can be so severe, involving their quality of life, they're unable to sleep at night. And the usual medications that we use for pruritis and other kids like antihistaminics don't usually work for these babies. So, let's talk a little bit about IBAT inhibitors. So again, talking about, you know, the intrahepatic circulation of bile acids. So 95% of the intestinal bile acids, they are reabsorbed in the last part of the small intestine. The ileal transporter then binds the bilaids and returns them to the bloodstream. The iPad plays an important role in the intrahepatic circulation facilitating the bile acid return to the portal circulation. And helps involve, you know, and helps to hence, um, you know, regulate the bile acid concentrations in the liver and the bile acid. So the ileal reuptake of bile acids at the apical surface of the enterocyte is coupled with sodium intake. And the IPA inhibitors, they interfere with the uptake of the bile acids and hence they interrupt the intrahepatic circulation and they increase the bile acid excretion. So IPAT inhibitors, they, um, you know, lead to augmented bile acid excretion in stool. They help reducing liver damage in the setting of cholestasis and accumulation of toxic bile acids, and currently they have been approved for allergy syndrome and for the PIC or the PFICs. So the approved IBAT inhibitors in allergys, we have the um Marrilixabat, which is approved now in 3 month old with allergys as well as the oviabat which is approved in 12 months old. Um, in Europe, the Oviabat is also approved in those babies who are more than 6 months of age. Now, the uh Mariliximab is an oral once a day uh suspension, whereas the odeviabat is a pill. So again, these are various different trials that have been done um in for the Madralixipad, we're seeing the itch and the iconic trial which showed that there is a decrease in the serum bile acids and the regression of xanthomas and improved growth in kids with allergy syndrome and the most common side effects that were reported was diarrhea, abdominal pain, and vomiting. And this was a trial, um, a search trial for um the. It was done for over 24 weeks and what they found is a significant improvement in the bilaid count. They also found that there was a significant reduction in instant. And then to fall asleep from a parent um report versus a placebo over the 24 weeks. So the goal for the iPad inhibitor trials was to improve the pruritus. The hepatic fibrosis to reduce the transaminassis and the need for liver transplantation. And the IPA inhibitors, the safety appears good. Um, just one of the things to remember is that may, they may cause fat-soluble vitamin deficiency and some monitoring is needed. So, um, my concluding remarks of the take-home messages from today's presentation would be that hyperbilirubinemia, more than 1 mg a day. That is never normal. So when you see conjugated regularly, that needs prompt referral to a pediatric gastroenterologist or hepatologist. So early detection is crucial early diagnosis and early referral. So these are my references. And again, thank you everyone for your time and hope this presentation was helpful in understanding neonatal cholestasis and especially bilireatresia and all syndrome. Thank you so much, Doctor Mohanti. That was very comprehensive and I feel like we went over a lot of material in a very short amount of time, so I'm very impressed with your efficiency. Um, it doesn't seem like we have questions immediately right now, but we'll give folks a bit of a chance to type them in. Um, I did have a few questions myself too. Though, um, in terms of, uh, primary care and how we should be thinking about these patients long term, I know GI will be carrying the brunt of it, uh, but is there anything that us in the primary care setting or in the hospital setting, uh, that we should be looking out for, um, in these patients whenever we see them for an annual in terms of immunizations, annual testing, things like that? Mhm. Very, very good question. So I think firstly, you know, um, starting right from the beginning, um, you know, primary care, pediatricians play an important role. So, um, when you see a jaundiced baby, I cannot emphasize how important it is again to fractionate that direct bilirubin at 2 weeks of age and continue to follow that and to refer to a pediatric gastroenterologist in a timely manner. And then once these kids are diagnosed and we have a cause for the neonatal cholestasis depending on whether it is due to biliresia or allergies or if it is because of endocrinopathy or other metabolic diseases, once we know the etiology and we have started treatment, um, the. is important. So checking on their nutritional status is also important, uh, from the standpoint of a pediatrician, making sure that they are gaining weight and growing appropriately, um, you know, so nutrition would be a, a key role, monitoring them for fat-soluble vitamin deficiencies, um. And then also talking about immunization. So yes, these kids, like all other babies, um, you know, should be immunized at their regular vaccination schedule. Um, once they have received a liver transplantation, they cannot receive live vaccines, so that's also something important to remember. Um, and, um, You know, I think, uh, a lot of these kids, sometimes they may go on to need like feeding tubes for their nutrition, you know, towards the end stage liver diseases. They may also need like prolonged TPN. So I think we all have to work together as a gastroenterologist and as a pedia. um, you know, as a team to help make sure that these kids are gaining weight well, that they're growing well, and they are of adequate, um, size because most of these BA babies, even after the Kasai procedure, they go on eventually to require a liver transplant. So the Kasai procedure is buying us some time and helping us, you know, with the babies gaining good weight and good growth so that uh we can have a successful liver transplantation. Um, but eventually they go on to require that. And then once they're transplanted, again, we work closely in making sure that they are having a good outcome and um, Yeah, and I hope that answers your question. Perfect. Yeah, that's awesome. Um, there's another question about, um, if there's a conjugated bilirubin that's elevated but not above the one mark, what are the typical causes, and then should we be trending this until it normalizes completely, or um do we just see that there's a trend down and are we happy with that? Yes. So, you know, again, if you have one thing to take from this presentation, that is that conjugated bilirubin is never normal. So there always has to be a cause. So if you're seeing your direct bilirubin level, it's like going up, you know, from 0.4, it's going, you know, it's trending up. You have to monitor that. Um, if it's more than 0.8, you know, we usually begin World Cup to look for all of these other causes, and you need to follow it until it starts down trending and it completely normalizes. So any of the etiologies that we spoke about, like even viral infections or any of these other, you know, genetic or metabolic causes, they can all cause hyperbilirubinemia, right? So, um, you keep monitoring that if it's a vital infection, if it's inspiated bile, it will downturn and it will resolve, but if it does not, then you're looking at all the other eiologies that we spoke about and then we, you know, need to continue to evaluate them and treat accordingly. Perfect. Um, I have another question. Uh, in terms of, uh, we see a 2 week old or older than 2 week old infant, they're jaundiced, we see elevated conjugated, uh, hyperbilirubinemia. We think it's, uh, biliary atresia. We're sending them over to GI. Um, what's that turnaround time look like? Is there anything in the interim that we should, we've gotten a, a fractionatedability? Is there anything else that we should be doing in the interim and what sort of, uh, counseling can we give to the parents? Yes. So, firstly, if you're seeing the two week old having conjugated hyperbole, you know, that's an urgent referral. So, you know, feel free to give us a call or to reach us anytime because these kids need to be seen in our clinic urgently. Um, in the meantime, again, what we need to do is, uh, focus on their nutrition. So again, making sure that they are feeding well, they are, you know, gaining weight, they're growing, whether they need supplementation, um, you can put them on orsodiol which will help with the bile flow. You can put them on DekA plus to help with their multivitamin supplementation. Um, and then, you know, we can also start with the preliminary workup, right? Like doing the all the other labs that we spoke about, um, like to name transaminasis, rebrobin, GGT, alkaline phos, also making sure that you have, you know, an alpha one antitrypsin phenotype at some point just to make sure that that's not the cause of presentation. Um, you could do a UA, new culture, UN C and B, you know, if your history also suggests that. So some of this workup, um, as well as an ultrasound can probably be done in the interim, um, you know, in the 1st 1 or 2 days as soon as you find out about the direct hypervisinemia. That's perfect. That's nice to see, yes, um, I have a question. So thank you for this wonderful talk. So as Jay mentioned, a 2 week old, I actually have a 40 day old in clinic, and how would your evaluation and expedited workup, like, you know, you mentioned some tier one labs, but would that change now that this patient is You know, getting closer to the 60 day mark, which you mentioned is that critical time for, you know, getting them a casai if that's what's needed. So is there something that needs to be done differently if it's a little older baby? Absolutely. So again, um, so Doctor Ali's question here is again for all of us to know and to highlight how important it is for a timely diagnosis for, you know, biliatresia. So when you have a two week old, it's completely different than Having a 6 week old or an 8-week old in terms of urgency. So these kids have to be, you know, immediately admitted to the hospital for a more like a quick and thorough workup. So after, you know, doing the initial labs, the next is to move on to imaging studies. So the gold standard being the liver biopsy and the intraoperative cholangiogram. So we move on to, you know, do this, um, as soon as possible so that we can arrive at the diagnosis, you know, quickly. At the same time as they are doing the liver biopsy and the intraoperative cholangiogram, so on the table, if they see there is no flow of bile into the. Um, a can be done, um, at that time by the surgeons. So, um, I think just expediting this process is very, very, very important in somebody who is, you know, already 6 weeks or 8 weeks because if the the side procedure is not done, uh, within, you know, that time frame, um, you know, the chances of that working as well later on diminishes. Perfect. Thank you so much, um, and thank you for such a nice comprehensive talk that brings us to the top of the hour, unfortunately, so if there's any questions, uh, would it be OK if our, uh, participants could reach out to you? Absolutely. They can reach out at, uh, you know, to me at any point. And then if you could also, you know, maybe email all the residents, um, the 4 or 5 questions that we have to discuss so that they can go over those MCQs and again, if they have any questions regarding that, they can reach out to me. Absolutely, perfect. Thank you so much, Doctor Mati. Have a great day. Again, thank you everyone for your time. Bye-bye. Created by
