Progressive Familial Intrahepatic Cholestasis Research Articles

Odevixibat (Bylvay)

CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec. This review assesses odevixibat (Bylvay) 200 mcg, 400 mcg, 600 mcg, 1,200 mcg capsules. Indication: For the treatment of pruritus in patients aged 6 months or older with progressive familial intrahepatic cholestasis.

Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC. MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 μg/kg, then escalated to 570 μg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22. Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 μmol/L (95% CI -257 to -94) for maralixibat versus 11 μmol/L (-58 to 80) for placebo, also representing a significant difference of -187 μmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred. Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC. Mirum Pharmaceuticals.

Analysis of clinical characteristic of children with progressive familial intrahepatic cholestasis type 3

Objective: To analyze the clinical manifestations, pathology, and gene variant characteristics in children with progressive familial intrahepatic cholestasis type 3 (PFIC3). Methods: This retrospective study assessed the clinical manifestations, pathological features, gene variants, and prognosis data of 11 children with PFIC3 hospitalized in the Department of Hepatology, Fifth Medical Center, PLA General Hospital, from January 2015 to December 2022. Panel or whole exome sequencing was performed on the probands, followed by Sanger sequencing for verification within the family. Detected pathogenic variants were compared with known disease databases. Additionally, the new variants were predicted the deleteriousness and protein structure using relevant software to evaluate their pathogenicity. Results: Among the 11 PFIC3 children, 8 were boys and 3 were girls. The age of onset was 3.1 (0.2, 15.6) years. The main complaint of onset was different in the 11 patients;5 of them were abnormal liver function, 3 of them were liver and spleen enlargement, 2 of them were abdominal distension, and 1 of them was jaundice. Alanine aminotransferase, asparate aminotransferase and γ-glutamyltransferase increased in all the patients, which were(113±40), (150±44) and (270±156) U/L respectively. Moreover, direct bilirubin increased in 9 patients, and cholestasis was showed in 8 patients. All patients showed liver fibrosis on imaging, and 8 patients had cirrhosis. The pathological features of 8 cases by liver biopsy were as follows: 8 cases of fibrosis in the portal area, 7 cases of small bile duct hyperplasia, 4 cases of positive copper staining, and 5 cases of cirrhosis. A total of 17 ABCB4 gene variants were detected, including 9 new variants: c.589C>T(p.Q197X), c.1230+1G>A(Splicing), c.2914G>A(P.D972N), c.1058G>A(p.C353Y), c.956G>T(p.G319V), c.473T>A(p.L158Q), c.164T>C(p.L55S), c.2493G>C(p.R831S), and c.1150G>C(p.G384R). All 11 patients were treated with ursodeoxycholic acid and followed up for 5.1(0.6, 7.4) years. Among them, 4 cases of cirrhosis progressed continuously, 3 cases had liver transplantations, and the remaining 4 cases were stable after medical treatment. Conclusions: Children with PFIC3 have early onset, diverse clinical manifestations, rapid progression of fibrotic and cholestasis, as well as poor prognosis. Genetic testing helps to confirm the diagnosis.

Transplanting Livers in Young Children – Looking Back at 100 Cases

ABSTRACT Introduction: Despite advances in medical therapy, liver replacement continues to be the only definitive mode of therapy for children with end-stage liver disease (ESLD). However, its acceptance in India has been discouraging more due to financial and logistic reasons than the availability of expertise. This report outlines our journey and highlights issues pertinent to circumstances in an emerging economy like India. Aim: The aim is to review a single center’s 100 case experience with liver transplantation (LT). Materials and Methods: A prospective analysis of all children who underwent LT since 2005 at our institute was done. The data were collated from a maintained structured database. Results: Hundred children underwent LT. Sixty-four were boys. Age ranged from 5 to 144 months, with a median of 17 months. The mean weight of the cohort was 7.5 kg (ranging from 3.7 to 31.5 kg), with 60% of our children weighing between 5 and 10 kg. Biliary atresia is the most common indication (57%); others include metabolic disorders, progressive familial intrahepatic cholestasis, and hepatoblastoma. Two patients were for acute liver failure. Ninety-one children underwent live donor LT (mothers being the majority of the donors). None of the donors had any major postoperative complications. Major intraoperative complications include sepsis (39%), vascular complications (17%), biliary leak (11%), and intestinal complications (11%). Early postoperative deaths occurred in 18% of patients with sepsis being most common cause. The mean follow-up was 8.5 years and the overall survival is 70%. The mean survival is time (months) = 176.1. All surviving patients were followed up and had achieved good catch up growth by 3rd and 5th years posttransplant. The long-term sequalae include recurrent intercurrent infections, graft rejection (9%), posttransplant lymphoproliferative disease (5%), and portal vein stenosis (5%). Conclusion: Our experience demonstrates the feasibility of LT in children with ESLD in India. With longer-living grafts, patients often struggle with other issues such as compliance with follow-up, financial issues, recurrent infections, and neurological problems. Close monitoring with regular follow-up of patients helps in early recognition and treatment of late-onset complications, thus helping the overall long-term outcomes.

Progressive familial intrahepatic cholestasis type 3 or neonatal sclerosing cholangitis? about four Tunisian families

Progressive familial intrahepatic cholestasis type 3 or neonatal sclerosing cholangitis? about four Tunisian families

NR1H4 disease: rapidly progressing neonatal intrahepatic cholestasis and early death.

Clinical studies on progressive familial intrahepatic cholestasis (PFIC) type 5 caused by mutations in NR1H4 are limited. New patients with biallelic NR1H4 variants from our center and all patients from literature were retrospectively analyzed. Three new patients were identified to be carrying five new variants. Liver phenotypes of our patients manifests as low-γ-glutamyl transferase cholestasis, liver failure and related complications. One patient underwent liver transplantation (LT) and survived, and two other patients died without LT. Nine other patients were collected through literature review. Twelve out of 13 patients showed neonatal jaundice, with the median age of onset being 7 days after birth. Reported clinical manifestations included cholestasis (13/13, 100%), elevated AFP (11/11, 100%), coagulopathy (11/11, 100%), hypoglycemia (9/13, 69%), failure to thrive (8/13, 62%), splenomegaly (7/13, 54%), hyperammonemia (7/13, 54%), and hepatomegaly (6/13, 46%). Six of 13 patients received LT at a median age of 6.2 months, and only one patient died of acute infection at one year after LT. Other 7 patients had no LT and died with a median age of 5 months (range 1.2-8). There were 8 patients with homozygous genotype and 5 patients with compound heterozygous genotype. In total, 13 different variants were detected, and 5 out of 12 single or multiple nucleotides variants were located in exon 5. We identified three newly-diagnosed patients and five novel mutations. NR1H4-related PFIC typically cause progressive disease and early death. LT may be the only lifesaving therapy leading to cure.

Clinical and genetic study of ABCB4 gene-related cholestatic liver disease in China: children and adults

BackgroundABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. The correlation between genotype and clinical phenotype still unclear. This study retrospectively analyzed the clinical and pathological characteristics of 23 patients with ABCB4 gene-related cholestatic liver diseases. Next-generation sequencing was used to identify the genetic causes.ResultsThe 23 included patients (15 children and 8 adults) were diagnosed as progressive familial intrahepatic cholestasis type 3 (PFIC3), drug-induced liver injury (DILI), cirrhosis cholestasis, cirrhosis, and mild liver fibrosis. Nineteen patients underwent liver pathological examination of the liver, exhibiting fibrosis, small bile duct hyperplasia, CK7(+), Cu(+), bile duct deletion, and cirrhosis. Thirty ABCB4 variants were identified, including 18 novel variants.ConclusionABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. Biallelic ABCB4 mutation carriers tended to severe PFIC3, which mostly occurs in children; while ABCB4 non-biallelic variants can lead to milder ICP, LACP, DILI or overlapping, mostly in adults. Thus, the ABCB4 genotype has a specific correlation with the phenotype, but there are exceptions. Non-biallelic null mutations can cause severe diseases. The mechanisms underlying this genetic phenotype require further investigation.Graphical

Odevixibat as an adjunctive treatment for refractory pruritus in rare variants of cholestatic liver disease

AbstractObjectivesOdevixibat, a reversible ileal bile acid transport (iBAT) inhibitor, has been shown to reduce serum bile acids (sBA) and pruritus mostly in children with progressive familial intrahepatic cholestasis (PFIC) 1 and 2 in clinical trials and case reports. There are currently no published case reports or series describing its use in rare variants of cholestatic liver disease.MethodsWe describe three children with progressive cholestatic liver disease who developed refractory pruritus, who had a genotypic diagnosis of AKR1D1, ABCB4 variant, and PKHD1 and PKHD2 variants; all being variants of unknown significance as per the American College of Medical Genetics and Genomics guidelines.ResultsOn Odevixibat there was a significant improvement in sBA (absolute change from baseline: −196 and −393 μmol/L) and pruritus in two children with heterozygous AKR1D1 and ABCB4 mutations. The child with ABCB4 variants was found to have features of sclerosing cholangitis along with a diagnosis of Crohn's disease, which represents the first reported usage of Odevixibat in such a case with good response. There was some reported improvement in the third child with PKHD1 and PKHD2 variants; however, we hypothesize that no sustained improvement could be due to severe and progressive nature of the disease. There were no side effects reported and it was well tolerated in all.ConclusionWe suggest that Odevixibat may be used as an adjunctive drug in refractory pruritus and could be started early in the course of disease if clinically and phenotypically indicated.

Primary Bile Acid Disorders: A Largely Unknown Group of Rare Genetic Diseases in Newborns

Primary bile acid disorders (BASD) in newborns are rarely found with a prevalence of 1-9/1,000,000 and include 1-2 % of all cases with neonatal cholestasis. Causes are different gene defects, which lead to liver enzyme defects, which play a major role in both cholic acid pathways, the classical with production of cholic acid and the alternative one with chenodeoxycholic acid. They are found in both genders in the same distribution. Early diagnosis is very important to introduce a bile acid replacement therapy as soon as possible as the treatment of choice to date. Diagnosis will be confirmed by molecular trsting, liver biopsy and different forms of mass spectrometry methods. Differential diagnosis includes progressive familial intrahepatic cholestasis, neonatal hepatitis and biliary atresia. Further gene therapy approaches must be developed, like CRISP Cas9 technology, to repair the spontaneous point mutations on DNA of these patients to cure and not to treat them their whole life finally.

Odevixibat: A Novel Bile Salt Inhibitor Treatment for Pruritus in Progressive Familial Intrahepatic Cholestasis.

Chronic pruritus is defined as an itch lasting greater than six weeks. It can manifest from a wide variety of etiologies, as many different substances can act as pruritogens, such as steroids, histamine, progesterone, endogenous opioids, and serotonin. In the setting of cholestatic liver disease, increased bile acids play a major role in chronic pruritus. The itching in cholestatic liver disease is worsened in intensity at night and localized frequently to the palms, soles, knees, and other pressure sites. It can be hard to manage, affecting the quality of sleep and causing irritability, poor attention, and, in some cases, depression. One such disease that results from chronic pruritus is progressive familial intrahepatic cholestasis (PFIC), a group of uncommon hereditary disorders that affects the formation of bile and its outflow from the liver. Previously, the drug ursodeoxycholic acid was used to help manage pruritus or surgical procedures, e.g., partial external biliary diversion or partial internal biliary diversion, to help control complications of the disease. This literature review will discuss three clinical studies covering the effectiveness of odevixibat in treating pruritus in patients with PFIC. Odevixibat (Bylvay) is an oral drug that has been FDA-approved to treat pruritus in patients three months of age and older with PFIC. Odevixibat prevents the reabsorption of bile salts in the intestines, resulting in decreased levels of bile salts via their excretion in stool. Several studies have determined that the drug is well tolerated and provides a nonsurgical, pharmacological treatment alternative for those with PFIC.

PATTERN OF CHRONIC LIVER DISEASE IN CHILDREN IN A TERTIARY CARE HOSPITAL

The study aimed to identify the different signs, symptoms, and causes of chronic liver disease in children. The study involved patients between the ages of 1 and 12 years who were suspected of having chronic liver disease, excluding those with acute liver disease, congenital anomalies, and liver transplant recipients. The study was conducted in the Department of Pediatrics at Pak Emirates Military Hospital in Rawalpindi from September 2023 to December 2023. The results of the study showed that the most common causes of chronic liver disease in the patients were progressive familial intrahepatic cholestasis, followed by glycogen storage diseases, Hepatitis C, Wilson's disease, and Hepatitis B. Jaundice, abdominal distension, peripheral swelling, ascites, hepatomegaly, and splenomegaly were the most common symptoms of chronic liver disease. Some patients also suffered from variceal bleeding and hepatic encephalopathy. In conclusion, the study found that chronic liver disease in children from Pakistan has a diverse range of causes and symptoms.

Case Report: Intrahepatic cholestasis: a diagnostic dilemma

Cholestasis is an impairment of bile formation or bile flow. The mechanisms of cholestasis can be broadly classified into intrahepatic and extrahepatic. Most of the time, etiology can be determined with proper history, physical examination, and diagnostic testing including laboratory and imaging tests. This is a case report of a patient with severe cholestasis who underwent extensive evaluation to determine the etiology of intrahepatic cholestasis. This Case Report details a 28-year-old male who presented with seven days’ history of yellowish discoloration of eyes, the passage of dark-colored urine, generalized body itching, and the passage of clay-colored stool. The patient had no similar episode in the past. Laboratory investigations showed unconjugated hyperbilirubinemia and increased alkaline phosphatase. Magnetic resonance cholangiopancreaticography was unremarkable and liver biopsy was suggestive of cholestatic pattern and negative for acute hepatitis. The bilirubin level started decreasing after a month. The etiology of intrahepatic cholestasis remained unknown. Genotyping could not be done due to limited available resources. It may have helped to diagnose familial hepatocellular cholestasis such as benign recurrent intrahepatic cholestasis (BRIC) and progressive familial intrahepatic cholestasis. Gamma-glutamyl transferase is normal or mildly elevated in patients with BRIC. A similar picture was seen in our case as well. If the patient presents again with similar symptoms and findings, we can consider the diagnosis of BRIC.

Molecular Insights of Cholestasis in MDR2 Knockout Murine Liver Organoids.

MDR3 (multidrug resistance 3) deficiency in humans (MDR2 in mice) causes progressive familial intrahepatic cholestasis type 3 (PFIC3). PFIC3 is a lethal disease characterized by an early onset of intrahepatic cholestasis progressing to liver cirrhosis, a preneoplastic condition, putting individuals at risk of hepatocellular carcinoma (HCC). Hepatocyte-like organoids from MDR2-deficient mice (MDR2KO) were used in this work to study the molecular alterations caused by the deficiency of this transporter. Proteomic analysis by mass spectrometry allowed characterization of 279 proteins that were differentially expressed in MDR2KO compared with wild-type organoids. Functional enrichment analysis indicated alterations in three main cellular functions: (1) interaction with the extracellular matrix, (2) remodeling intermediary metabolism, and (3) cell proliferation and differentiation. The affected cellular processes were validated by orthogonal molecular biology techniques. Our results point to molecular mechanisms associated with PFIC3 that may drive the progression to liver cirrhosis and HCC and suggest proteins and cellular processes that could be targeted for the development of early detection strategies for these severe liver diseases.

Odevixibat (Bylvay)


 CADTH recommends that Bylvay should be reimbursed by public drug plans for pruritus (itching) in patients aged 6 months or older with progressive familial intrahepatic cholestasis (PFIC) if certain conditions are met.
 Bylvay should only be covered to treat patients aged 6 months or older who have been diagnosed with PFIC type 1 (PFIC1) or PFIC type 2 (PFIC2), have severe itching, and have elevated serum bile acids. The first time Bylvay is prescribed, it should be for a trial period of 3 months to ensure that it improves the patient’s itching before it is renewed.
 Bylvay should only be reimbursed if it is prescribed by specialists in managing PFIC, if patients experience an improvement in their itching after using Bylvay for 3 months, and if the cost of Bylvay is reduced. Bylvay should be stopped if the patient receives a liver transplant.

Odevixibat: A Review of a Bioactive Compound for the Treatment of Pruritus Approved by the FDA.

Odevixibat is synthesized through chemical modification of Benzothiazepine's structure. It is a tiny chemical that inhibits the ileal bile acid transporter and is used to treat a variety of cholestatic illnesses, including progressive familial intrahepatic cholestasis (PFIC). For cholestatic pruritus and liver disease development, bile acid transporter inhibition is a unique treatment strategy. Odevixibat reduces enteric bile acid reuptake. Oral odevixibat was also studied in children with cholestatic liver disease. Odevixibat received its first approval in the European Union (EU) in July 2021 for the treatment of PFIC in patients aged 6 months, followed by approval in the USA in August 2021 for the treatment of pruritus in PFIC patients aged 3 months. Bile acids in the distal ileum can be reabsorbed by the ileal sodium/bile acid cotransporter, a transport glycoprotein. Odevixibat is a sodium/bile acid co-transporter reversible inhibitor. An average 3 mg once-daily dose of odevixibat for a week resulted in a 56% reduction in the area under the curve of bile acid. A daily dose of 1.5 mg resulted in a 43% decrease in the area under the curve for bile acid. Odevixibat is also being evaluated in many countries for the treatment of other cholestatic illnesses, including Alagille syndrome and biliary atresia. This article reviews the updated information on odevixibat with respect to its clinical pharmacology, mechanism of action, pharmacokinetics, pharmacodynamics, metabolism, drug-drug interactions, pre-clinical studies, and clinical trials.

Paediatric Liver Transplant at Army Liver Transplant Unit, Pakistan; A Four-Year Data

Objective: To re-examine the data about survival, prognosis, and complications of twenty-five paediatric liver transplant procedures carried out at Army Liver Transplant Unit, Pak Emirates Military Hospital Rawalpindi, Pakistan. Study Design: Retrospective longitudinal study. Place and Duration of Study: Army Liver Transplant Unit, Pak Emirates Military Hospital, Rawalpindi, Pakistan, from Jan 2016 to Feb 2020. Methodology: The procedural and follow-up data regarding twenty-five pediatric liver transplants was reviewed, and demographic variables, transplant indications and outcomes were documented. Results: The donation was entirely from living donors. Recipients included 12 boys and 13 girls of mean age 5.8±2.00 years. The stay at the hospital averaged 18±5.6 days. Indications in the order of frequency of encounter included 9(36%) cases of Cryptogenic liver cirrhosis, 4(16%) cases of progressive familial intrahepatic cholestasis, 3(12%) cases of Wilson’s disease, 2(8%) cases of Tyrosinemia, congenital hepatic fibrosis and biliary atresia each and one patient (4%) of Criggler-Najjar syndrome, glycogen storage diseases and autoimmune liver disease each. Major complications included viral infections, thrombosis of the portal vein and hepatic artery, bile leak and post-transplant diaphragmatic hernia. 20(80%) recipients were recorded to have survived during the follow-up. Conclusion: Encouraging results are noted, particularly a high survival rate (20 out of 25) and low complications (few and only well-known in this age group).

Expression of miR-34a in Children with Progressive Familial Intrahepatic Cholestasis: A Cross-Sectional Study Based on Shiraz Pediatric Liver Cirrhosis Cohort Study

Background: Progressive familial intrahepatic cholestasis (PFIC) is a rare progressive liver disease associated with portal hypertension leading to liver failure. Most PFIC patients ultimately need liver transplantation. Therefore, identifying a precise, non-invasive biomarker for PFIC is very important. Objectives: This study aimed to investigate the microRNA-34a (miR-34a) expression levels in PFIC patients. Methods: A total of 18 PFIC patients were randomly selected from the Shiraz Pediatric Liver Cirrhosis Cohort Study (SPLCCS), and 18 healthy subjects were enrolled in this study. Blood samples were obtained, and the gene expression of serum miR-34a was analyzed. Results: The results of this study showed that the serum level of miR-34a was significantly increased in PFIC patients, compared to the healthy group (P = 0.0327). However, no association was observed between miR-34a expression and clinical and laboratory findings of PFIC cases. Additionally, the results showed no correlation between miR-34a and serum levels of liver enzymes, albumin, gamma-glutamyl transpeptidase (GGT), and international normalized ratio (INR) among PFIC patients. Conclusions: miR-34a might be a beneficial, non-invasive target for PFIC diagnosis; however, further investigations with a larger population and longer duration are necessary to determine the potential of miR-34a as a diagnostic and therapeutic biomarker for PFIC.

The phospholipid flippase ATP8B1 is involved in the pathogenesis of Ulcerative Colitis via establishment of intestinal barrier function.

Patients with mutations in ATP8B1 develop Progressive Familial Intrahepatic Cholestasis type 1 (PFIC1), a severe liver disease that requires life-saving liver transplantation. PFIC1 patients also present with gastrointestinal problems, including intestinal inflammation and diarrhea, which are aggravated after liver transplantation. Here we investigate the intestinal function of ATP8B1 in relation to inflammatory bowel diseases. ATP8B1 expression was investigated in intestinal samples of patients with Crohn's Disease (CD) or Ulcerative Colitis (UC) as well as in murine models of intestinal inflammation. Colitis was induced in ATP8B1-deficient mice with Dextran Sodium Sulphate (DSS) and intestinal permeability was investigated. Epithelial barrier function was assessed in ATP8B1 knock-down Caco2-BBE cells. Co-immunoprecipitation experiments were performed in Caco2-BBE cells overexpressing ATP8B1-eGFP. Expression and localization of ATP8B1 and tight junction proteins were investigated in cells and in biopsies of UC and PFIC1 patients. ATP8B1 expression was decreased in UC and DSS-treated mice, and associated with a decreased Tight Junctional pathway transcriptional program. ATP8B1-deficient mice were extremely sensisitve to DSS-induced colitis, evidenced by increased intestinal barrier leakage. ATP8B1 knockdown cells showed delayed barrier establishment that associated with affected Claudin-4 (CLDN4) levels and localization.. CLDN4 immunohistochemistry showed a tight-junctional staining in control tissue, whereas in UC and intestinal PFIC1 samples, CLDN4 was not properly localized. ATP8B1 is important in the establishment of the intestinal barrier Downregulation of ATP8B1 levels in UC, and subsequent altered localization of tight junctional proteins, including CLDN4, might therefore be an important mechanism in UC pathophysiology.

Simultaneous total internal biliary diversion during liver transplantation for progressive familial intrahepatic cholestasis type 1: Standard of care?

Patients post liver transplant (LT) with progressive familial intrahepatic cholestasis type 1 (PFIC-1) often develop progressive graft steatohepatitis, intractable diarrhea, and growth failure. A total internal biliary diversion (TIBD) during an LT may prevent or reverse these adverse events. Children with PFIC-1 who underwent an LT at our institute were divided into 2 groups, A and B based on the timeline where we started offering a TIBD in association with LT. Pre-LT parameters, intraoperative details, and posttransplant complications like graft steatosis and diarrhea were also analyzed between the 2 groups, and their growth velocity was measured in the follow-up period. Of 550 pediatric LT performed between 2011 and 2022, 13 children underwent LT for PFIC-1. Group A had 7 patients (A1-A7) and group B had 6 (B1-B6). Patients A1, A4, B4, and B5 had a failed partial internal biliary diversion before offering them an LT. Patients A1, A2, and A6 in group A died in the post-LT period (2 early allograft dysfunction and 1 posttransplant lymphoproliferative disorder) whereas A3, A4, and A5 had graft steatosis in the follow-up period. A4 was offered a TIBD 4 years after LT following which the graft steatosis fully resolved. In group B, B1, B2, B5, and B6 underwent TIBD during LT, and B3 and B4 had it 24 and 5 months subsequently for intractable diarrhea and graft steatosis. None of the patients in group B demonstrated graft steatosis or diarrhea and had good growth catch-up during follow-up. We demonstrate that simultaneous TIBD in patients undergoing LT should be a standard practice as it helps dramatically improve outcomes in PFIC-1 as it prevents graft steatosis and/or fibrosis, diarrhea, and improves growth catch-up.

A286 MYO5B MUTATIONS AS A CAUSE OF CHOLESTASIS IN A CHILD WITHOUT MICROVILLOUS INCLUSION DISEASE

Abstract Background Biallelic Myosin Vb (MYO5B) mutations are identified in the majority of patients with microvillus inclusion disease (MVID) that requires life-long parenteral nutrition and eventually cholestatic liver disease. Biallelic MYO5B mutations have also been reported in a few children with predominant early-onset cholestatic liver disease. Aims To report on a patient with MYO5B mutations and progressive familial intrahepatic cholestasis PFIC-like phenotype and normal serum GGT without intestinal disease. Methods We describe a 2-year and 8-month-old girl, who is the first child of healthy non- consanguineous parents from the Phillipines with no family history of liver disease. She presented at the age of 10 months for evaluation of mild jaundice, which was noticed at the age of 6 months. Other symptoms included pruritus, slowly weight gain, intermittent pale stools and dark urine. Laboratory investigations revealed AST 99, ALT 87, GGT 27, conjugated bilirubin 13 and INR 0.8. Fasting abdominal ultrasound was normal apart from a possibly hypoplastic gallbladder and mild splenomegaly. Additional investigations revealed normal thyroid-stimulating hormone, cortisol, galactosemia screening and sweat chloride, but bile acids were elevated 391.6 umol/L. A liver biopsy was performed and a cholestasis genetic panel sent. The patient was started on ursodiol, hydroxyzine, rifampicin and vitamin D. Results Liver biopsy revealed moderate hepato-canalicular cholestasis, bile duct injury without prominent ductopenia, small caliber bile ducts with no features of obstructive cholangiopathy, mild periportal and pericentral fibrosis stage 1-2/ 4. Electron microscopy demonstrated cytoplasmic and canalicular bile accumulation. The bile canaliculi were variably distended by coarse granular bile. Immunohistochemical staining for BSEP and MDR3, showed canalicular staining in zones 1 and absence of staining in zones 2 and 3. Genetic analysis revealed one pathogenic variant and one variant of uncertain significance in MYO5B. No mutations in ABCB11 or ATP8B1 genes were identified. On follow-up, the jaundice improved, pruritus was managed with the medications described above. Her growth has improved and she is growing on the 25th centiles. She has not developed any gastrointestinal symptoms. Conclusions We present a patient with MYO5B mutations who presented with normal GGT cholestasis and a liver biopsy consistent with PFIC, without any evidence of intestinal disease. Because MYO5B mutations disrupt the intracellular trafficking of brush border proteins in the intestine, it has been assumed that it similarly disrupts the trafficking of the canalicular bile acid transporting and bilirubin transporting proteins in the liver. This case highlights the broad phenotype associated with MYO5B variants. Funding Agencies None