Deleterious Variants in ABCC12 are Detected in Idiopathic Chronic Cholestasis and Cause Intrahepatic Bile Duct Loss in Model Organisms.

BACKGROUND & AIMS: The etiology of cholestasis remains unknown in many children. We surveyed the genome of children with chronic cholestasis for variants in genes not previously associated with liver disease and validated their biological relevance in zebrafish and murine models. METHOD: Whole-exome (n = 4) and candidate gene sequencing (n = 89) was completed on 93 children with cholestasis and normal serum γ-glutamyl transferase (GGT) levels without pathogenic variants in genes known to cause low GGT cholestasis such as ABCB11 or ATP8B1. CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 genome editing was used to induce frameshift pathogenic variants in the candidate gene in zebrafish and mice. RESULTS: In a 1-year-old female patient with normal GGT cholestasis and bile duct paucity, we identified a homozygous truncating pathogenic variant (c.198delA, p.Gly67Alafs∗6) in the ABCC12 gene (NM_033226). Five additional rare ABCC12 variants, including a pathogenic one, were detected in our cohort. ABCC12 encodes multidrug resistance-associated protein 9 (MRP9) that belongs to the adenosine 5'-triphosphate-binding cassette transporter C family with unknown function and no previous implication in liver disease. Immunohistochemistry and Western blotting revealed conserved MRP9 protein expression in the bile ducts in human, mouse, and zebrafish. Zebrafish abcc12-null mutants were prone to cholangiocyte apoptosis, which caused progressive bile duct loss during the juvenile stage. MRP9-deficient mice had fewer well-formed interlobular bile ducts and higher serum alkaline phosphatase levels compared with wild-type mice. They exhibited aggravated cholangiocyte apoptosis, hyperbilirubinemia, and liver fibrosis upon cholic acid challenge. CONCLUSIONS: Our work connects MRP9 with bile duct homeostasis and cholestatic liver disease for the first time. It identifies a potential therapeutic target to attenuate bile acid-induced cholangiocyte injury.

Percutaneous endoscopic gastrostomy in children: A single center experience in Saudi Arabia.

OBJECTIVES: To evaluate the demographic data and complications in children who had undergone percutaneous endoscopic gastrostomy (PEG) over 9 years period. METHODS: The demographic data, complications, length of hospital admission related to PEG insertion and follow-up findings of 39 patients who had undergone percutaneous endoscopic gastrostomy using the standard pull-through technique between 2011 and 2020 were examined. The study took place at the Gastroenterology Division, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia RESULTS: The most common indications of feeding with a gastrostomy tube include neurological diseases (n=30, 76.9%), followed by metabolic disorders (n=3, 7.69%), chronic diarrhea (n=2, 5.1%), chronic kidney diseases (n=2, 5.1%), cystic fibrosis (n=1, 2.56%), feeding aversion fibrosis (n=1, 2.56%). Out of the 39 patients, 20 (51%) did not have any complications. However, minor complication are expected. Most common complications included local infection (n=14, 35.89%) followed by granulation tissue (n=6, 15.38%), "buried bumper syndrome" developed in one. CONCLUSION: Percutaneous endoscopic gastrostomy tube is the desirable method for patients who are unable to feed orally, feeding is not adequate for demands, has special feeding requirements, or swallowing dysfunction. The technique has become more widespread because of its simplicity, safety, and low cost. Major complications are rare. The procedure is safe and effective and could be carried out by pediatric gastroenterologists after training.

Incidence of pediatric inflammatory bowel disease in Saudi Arabia: a multicenter national study.

BACKGROUND: Pediatric inflammatory bowel disease (IBD) is increasingly recognized in developing countries; however, the incidence and trend over time have not been reported. METHODS: This retrospective study included children diagnosed with IBD in gastroenterology centers in the Kingdom of Saudi Arabia between 2003 and 2012. The date of birth, date and age at diagnosis, gender, and final diagnosis were collected on special forms. Clinical, laboratory, imaging, endoscopy, and histopathology results were reviewed to confirm the final diagnosis. Descriptive statistics were used to compare ulcerative colitis and Crohn's disease in different age groups, and significance was assessed by the chi-square test. Incidence rates and trend over time were analyzed with the assumption of Poisson distribution. The incidence rate over time was compared in 2 periods (2003-2007 and 2008-2012). A P value of <0.05 and 95% confidence intervals were used to assess the significance and precision of the estimates. RESULTS: A total of 340 Saudi Arabian children aged 0 to 14 years were diagnosed. The mean incidence rate per 100,000 individuals was 0.2, 0.27, and 0.47 for ulcerative colitis, Crohn's disease, and IBD, respectively. Except for the 0- to 4-year age group, there was a significant increase in incidence over time. CONCLUSIONS: Although the incidence of pediatric IBD in Saudi Arabian children is lower than suggested in the Western literature, there is a significantly increasing trend over time. However, decreased trend in the younger age group over time is identified. Prospective studies will be important to identify the risk factors for IBD in different age groups.

Differences in presentation and progression between severe FIC1 and BSEP deficiencies.

BACKGROUND & AIMS: Progressive familial intrahepatic cholestasis (PFIC) with normal serum levels of gamma-glutamyltranspeptidase can result from mutations in ATP8B1 (encoding familial intrahepatic cholestasis 1 [FIC1]) or ABCB11 (encoding bile salt export pump [BSEP]). We evaluated clinical and laboratory features of disease in patients diagnosed with PFIC, who carried mutations in ATP8B1 (FIC1 deficiency) or ABCB11 (BSEP deficiency). Our goal was to identify features that distinguish presentation and course of these two disorders, thus facilitating diagnosis and elucidating the differing consequences of ATP8B1 and ABCB11 mutations. METHODS: A retrospective multi-center study was conducted, using questionnaires and chart review. Available clinical and biochemical data from 145 PFIC patients with mutations in either ATP8B1 (61 "FIC1 patients") or ABCB11 (84 "BSEP patients") were evaluated. RESULTS: At presentation, serum aminotransferase and bile salt levels were higher in BSEP patients; serum alkaline phosphatase values were higher, and serum albumin values were lower, in FIC1 patients. Elevated white blood cell counts, and giant or multinucleate cells at liver biopsy, were more common in BSEP patients. BSEP patients more often had gallstones and portal hypertension. Diarrhea, pancreatic disease, rickets, pneumonia, abnormal sweat tests, hearing impairment, and poor growth were more common in FIC1 patients. Among BSEP patients, the course of disease was less rapidly progressive in patients bearing the D482G mutation. CONCLUSIONS: Severe forms of FIC1 and BSEP deficiency differed. BSEP patients manifested more severe hepatobiliary disease, while FIC1 patients showed greater evidence of extrahepatic disease.

Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families.

BACKGROUND & AIMS: Patients with severe bile salt export pump (BSEP) deficiency present as infants with progressive cholestatic liver disease. We characterized mutations of ABCB11 (encoding BSEP) in such patients and correlated genotypes with residual protein detection and risk of malignancy. METHODS: Patients with intrahepatic cholestasis suggestive of BSEP deficiency were investigated by single-strand conformation polymorphism analysis and sequencing of ABCB11. Genotypes sorted by likely phenotypic severity were correlated with data on BSEP immunohistochemistry and clinical outcome. RESULTS: Eighty-two different mutations (52 novel) were identified in 109 families (9 nonsense mutations, 10 small insertions and deletions, 15 splice-site changes, 3 whole-gene deletions, 45 missense changes). In 7 families, only a single heterozygous mutation was identified despite complete sequence analysis. Thirty-two percent of mutations occurred in >1 family, with E297G and/or D482G present in 58% of European families (52/89). On immunohistochemical analysis (88 patients), 93% had abnormal or absent BSEP staining. Expression varied most for E297G and D482G, with some BSEP detected in 45% of patients (19/42) with these mutations. Hepatocellular carcinoma or cholangiocarcinoma developed in 15% of patients (19/128). Two protein-truncating mutations conferred particular risk; 38% (8/21) of such patients developed malignancy versus 10% (11/107) with potentially less severe genotypes (relative risk, 3.7 [confidence limits, 1.7-8.1; P = .003]). CONCLUSIONS: With this study, >100 ABCB11 mutations are now identified. Immunohistochemically detectable BSEP is typically absent, or much reduced, in severe disease. BSEP deficiency confers risk of hepatobiliary malignancy. Close surveillance of BSEP-deficient patients retaining their native liver, particularly those carrying 2 null mutations, is essential.

Donor experience and outcome of pediatric living-related liver transplantation in Saudi Arabia.

BACKGROUND/PURPOSE: The purpose of this article is to present the first series of living donation of liver grafts in Saudi Arabia, as well as in the Arab World, and to report the morbidity and mortality of the living donors after such procedures. METHODS: A retrospective review of the medical charts of 37 living donors who were involved in the procedure of living-related liver transplantation (LRLT), that took place in Riyadh Armed Forces Hospital in the period between November 1998 and July 2002, is conducted. RESULTS: The age of living donors ranged between 21 and 41 years, and there were 22 women and 15 men. All donors are first-degree relatives, apart from 2 donors who were the cousins of the recipients. There was no mortality among the donors. The morbidity was minimal, including 3 cases of biliary leakage and 1 of incisional hernia. Of 39 pediatric liver transplantations that have been done over the above period, only 2 cases had cadaveric liver transplantation and these were excluded from this study. All donors had left lateral segment donation, apart from one who had right lobe, segments V-VIII donation to a 14-year-old recipient. CONCLUSION: Living donation of hepatic graft is a safe procedure for the donors with an excellent outcome. Living-related liver transplantation is the optimal treatment for end-stage liver disease and the solution for the scarcity of cadaveric liver grafts. The level of acceptance of living donation of hepatic grafts among the Saudi people is favorable.

Pediatric living-related liver transplantation in Saudi Arabia.

OBJECTIVE: The purpose of this paper is to report our experience of the first 29 consecutive living-related liver transplants in pediatric recipients and to demonstrate the feasibility of living-related liver transplantation in the Arab World. The first living-related liver transplantation in the Kingdom of Saudi Arabia was performed in November 1998 by Bassas et al following an appropriate period of multi-disciplinary preparation. METHODS: This study was carried out at the Armed Forces Hospital, Riyadh, Kingdom of Saudi Arabia, during the period November 1998 through to October 2001. A review of the data of the transplanted children and adult donors was carried out. The data recorded for recipients included age, sex, patient's weight, preoperative diagnosis, intraoperative surgical complications, graft size and weight, medical and surgical postoperative complications, immunosuppression, rejection and overall survival rate. Data recorded for the donors included age, sex and any postoperative complications. RESULTS: The most frequent indication for living-related liver transplantation in our series was metabolic liver disease. Post-operative complications included biliary leaks in 10% (N=3), vascular occlusion in 13% (N=4), acute cellular rejection in 38% (N=11), positive cytomegalovirus PP65 antigen in 38% (N=11), wound infection in 3.4% (N=one), and systemic infections in 14% (N=4). One urgent retransplantation was necessary due to thrombosis of the hepatic artery. Patient and graft survival rates are 96% and 93%. One patient, treated for acute liver failure, died 2 months post-transplant. CONCLUSION: Our experience has shown pediatric living-related liver transplantation to be a success whilst alleviating the need for sending Saudi patients overseas for treatment and providing a solution to organ shortages for pediatric patients. In general, this endeavor has broadened the spectrum of our experience in surgery, anesthetics, intensive care and pediatrics.