進行性家族性肝内胆汁うっ滞症

Cholestasis is caused by genetic disorders in 25% of cases. Our study aimed to describe the clinical and genetic profile of cholestasis and to demonstrate the importance of next-generation sequencing (NGS) in the etiologic diagnosis of genetic cholestasis. We included patients referred for cholestasis over a 10-year period. Molecular studies using NGS consisted of a 292-gene panel and/or whole exome sequencing. Our cohort included 70 patients from 66 unrelated families. A genetic diagnosis was established in 70% of the families. The most common diagnoses were Type 2 progressive familial intrahepatic cholestasis (n = 12), neonatal sclerosing cholangitis (n = 4), low phospholipid-associated cholelithiasis syndrome (n = 4), and Alagille syndrome (n = 4). The ABCB11 gene was most frequently mutated (15/46), with two recurrent variants, c.1062T>A (p.Tyr354*) and c.1826_1827dup (p.Ile610Glnfs*45), found in six and four families, respectively. Our results showed a 62% diagnostic yield of molecular testing using NGS in cholestasis. An accurate diagnosis was key to providing appropriate genetic counseling, guiding screening of variant carriers, and prenatal diagnosis.

Progressive Familial Intrahepatic Cholestasis type 1 (PFIC1) is a multisystem disorder. Although liver transplant (LT) resolves the hepatic disease, post-LT complications may occur, including severe enteropathy and graft steatosis caused by impaired bile acids handling by the native intestine. Surgical biliary diversion (SBD) is commonly used to alleviate these complications but may result in long-term morbidity, such as fat-soluble vitamin deficiency and essential fatty acids malabsorption. We report a PFIC1 patient who developed post-LT protein-losing enteropathy, initially managed with SBD. While effective, SBD led to severe fat malabsorption requiring intravenous lipid supplementation. After initiation of ileal bile acid transport inhibitor (IBATi) therapy, SBD was surgically reversed without recurrence of enteropathy. This case highlights IBATi as a potential alternative to SBD and as a strategy to reverse prior surgical interventions and improve quality of life.

Biliary atresia (BA) is the most common cause of cholestasis in infants, and pruritus may be a prominent and debilitating complication. Maralixibat is the first US Food and Drug Administration-approved drug for the treatment of cholestatic pruritus in children with Alagille syndrome and has been subsequently approved for treatment of progressive familial intrahepatic cholestasis as well. Several patients with BA have received maralixibat as part of a compassionate use program. We report the use of maralixibat for the treatment of cholestatic pruritus in BA for six patients. Demographics, past medical history, laboratory markers, and medications were collected. Pruritus was assessed using the Clinician Scratch Scale (CSS) at baseline and last clinical follow-up. All patients reported improved CSS with no increased usage of other antipruritic medications, and the medication was well tolerated.

BACKGROUND: Cholestatic liver diseases are the leading indication for pediatric liver transplantation, and low recipient body weight remains a major concern in pediatric living donor liver transplantation (LDLT) because of perceived higher technical complexity and poorer outcomes creating controversy over optimal timing for transplantation. OBJECTIVE: To evaluate the effect of recipient body weight on postoperative complications and survival after LDLT for cholestatic liver diseases in children. METHODS: This retrospective cohort study included 102 pediatric recipients younger than 18 years who underwent LDLT for cholestatic liver diseases between August 2015 and June 2024 at two Cairo transplant centers. Recipients were stratified into three body weight groups: less than 10 kg (n=28), 10-15 kg (n=26), and more than 15 kg (n=48). Demographic, operative, postoperative, and survival outcomes were compared across groups using appropriate statistical tests, and survival was assessed by Kaplan-Meier analysis with log-rank testing. RESULTS: Median age was 6 years and median body weight was 15 kg; 59.8% of recipients were male. Biliary atresia (38.3%) and progressive familial intrahepatic cholestasis (34.3%) were the leading indications for transplantation. Left lateral segment grafts were used in 60.8% of cases, and the median graft-to-recipient weight ratio was 2.11. Recipients weighing less than 10 kg had significantly higher postoperative pneumonia rates (51.7%) and portal vein thrombosis rates (14.3%). Biliary complications occurred across all groups, with bile leak in 9.8 % and biliary stricture in 12.7% bile leak followed by stricture in 5.8 %, without significant between-group differences. Early mortality rates were 25.0%, 19.2%, and 14.6% in the less than 10 kg, 10-15 kg, and more than 15 kg groups, respectively, without significant difference. One-year survival was 71.4%, 76.9%, and 87.5%, and three-year survival was 71.4%, 76.9%, and 81.3%, respectively, also without significant differences. CONCLUSIONS: Children weighing less than 10 kg at the time of LDLT have higher postoperative morbidity, particularly pneumonia and portal vein thrombosis, but achieve survival comparable to that of heavier recipients. Low body weight alone should not be considered a contraindication to pediatric LDLT in experienced centers.