ATP8B1, ABCB11, and ABCB4 Genes Defects: Novel Mutations Associated with Cholestasis with Different Phenotypes and Outcomes.

OBJECTIVES: To characterize the clinical, laboratory, histologic, molecular features, and outcome of gene-confirmed progressive familial intrahepatic cholestasis (PFIC) 1-3 among Arabs and to evaluate for "genotype-phenotype" correlations. STUDY DESIGN: We retrospectively reviewed charts of 65 children (ATP8B1 defect = 5, ABCB11 = 35, ABCB4 = 25) who presented between 2008 and 2019 with cholestasis. The clinical phenotype of a disease was categorized based on response of cholestasis and itching to ursodeoxycholic acid and ultimate outcome, into mild (complete response), intermediate (partial response, nonprogressive), and severe (progression to end-stage liver disease). RESULTS: Overall, 27 different mutations were identified (ATP8B1, n = 5; ABCB11, n = 11; ABCB4, n = 11), comprising 10 novel ones. Six patients with heterozygous missense mutations (ATP8B1, n = 2; ABCB11, n = 4) had transient cholestasis. Of the remaining 3 patients with PFIC1, 2 developed severe phenotype (splicing and frameshift mutations). Of the remaining 31 patients with PFIC2, 25 developed severe disease (15 due to frameshift and splicing mutations). Of 25 patients with PFIC3, 10 developed a severe phenotype (1 splicing and 3 frameshift mutations; 6 missense). Patients with PFIC2 had significantly shorter survival time and more rapid disease progression than patients with PFIC3 (P < .001). Patients with frameshift mutations in ABCB11 gene (p.Thr127Hisfs∗6) and ABCB4 gene (p.Phe210Serfs∗5) had significantly shorter survival time than missense mutations (P = .011; P = .0039, respectively). CONCLUSIONS: We identified genotype-phenotype correlations among mutations in ABCB11 and ABCB4 genes, which underscore the prognostic value of early genetic diagnosis. The disease course in patients with PFIC3 could be favorably modified by ursodeoxycholic acid therapy.

Occurrence, evaluation, and human health risk assessment of ochratoxin a in infant formula and cereal-based baby food: a global literature systematic review.

This study reviews global levels of ochratoxin A (OTA) in infant formula and cereal-based foods, using Monte Carlo simulation to assess risks. The review found 24 studies on global OTA levels in infant food and cereal-based products, using databases including PubMed, Scopus, Web of Science and Embase until March 2024. We estimated OTA exposure in infant food based on concentration, intake and body weight. The exposure and hazard quotient margin were calculated using BMDL10 and TDI values. Monte Carlo simulation evaluated human health risks from OTA in infant formula and cereal-based foods. A global study from 14 countries shows varying levels, surpassing EU limits in Tunisia, Ecuador, the USA, and generally in Africa, notably in infant cereals, which had higher levels than formula. Globally, OTA was present in 29.3% of the 3348 samples analyzed, with Lebanon at 95.2% and Brazil at 0%. Analysis indicates only non-carcinogenic risk for infants. While health risks for infants are mostly low, ongoing research and monitoring are vital to minimize OTA exposure in infant food.

Infant nutrition at risk: a global systematic review of ochratoxin A in human breast milk-human health risk assessment.

Human breast milk is the optimal source of nutrition for newborns, but the potential transfer of contaminants like mycotoxins, particularly ochratoxin A (OTA), from maternal blood to milk remains a concern. This systematic review aims to provide a comprehensive analysis of global OTA levels in human breast milk and assess the associated health risks. We conducted a thorough search of scientific databases, including Web of Science, ScienceDirect, Scopus, Google Scholar and PubMed, using keywords related to OTA in human breast milk. A total of 39 studies met the inclusion criteria for this review. OTA levels compared to limits, estimated infant intake at various ages and health risks assessed using Margin of Exposures (MOEs) and Hazard quotient (HQ). Our findings reveal the widespread presence of OTA in breast milk across different regions, with notably higher levels detected in Africa compared to Asia, South America and Europe. The higher concentrations observed in warmer, humid climates suggest that environmental factors significantly influence OTA contamination. Mature breast milk samples generally exhibited greater OTA exposure. The neoplastic and non-neoplastic effects demonstrate generally low risks globally. The regional differences in OTA levels and associated health risk assessments underscore the need for continued research into the health impacts of OTA exposure in infants. This includes further investigation into multiple sources of exposure, such as infant formula, within the broader context of the exposome framework.

Patterns and unique features of infantile cholestasis among Arabs.

Background: Most of the literature on infantile cholestasis (IC) originated from Caucasian and Asian populations. The differential diagnosis of IC is very broad, and identification of etiology is challenging to clinicians because the list includes many entities with overlapping clinical, biochemical, and histological features. Thus, a structured, stepwise diagnostic approach is required to help early recognition and prompt evaluation and management of treatable causes of cholestasis. Objective: (1) To determine the differential diagnosis of IC among Saudi population and (2) to evaluate the usefulness of a diagnostic algorithm that has been tailored by the authors to the local practice. Methods: All infants with onset of cholestasis before 12 months of age (2007 and 2020) were identified and included if they underwent extensive work up to exclude infectious, structural, metabolic, endocrine, infiltrative, and familial causes. Results: Our diagnostic pathway allowed a definite diagnosis in 373 of the included 533 cases; 160 (30%) were labelled as "idiopathic neonatal hepatitis" (INH) [i.e., overall 70% detection rate]. However, when considering the cases that underwent extensive investigations including advanced gene testing (415 of the 533), the yield of the diagnostic algorithm was 90% (373/415). Familial cholestasis group was the most common in 20% (107/533), and biliary atresia and neonatal-onset Dubin Johnson syndrome contributed to 6% each. The genetic/hereditary causes of cholestasis contributed to 58% of the diagnosed cases (217/373). No single case of alpha-1 antitrypsin deficiency was diagnosed. Forty-nine infants with cholestasis presented with liver failure (9%). Conclusion: Our study highlights several unique features and causes of IC among Arabs which could have a great impact on the differential diagnosis process and the choice of laboratory tests used in the clinical setting.

Disease patterns among Saudi children undergoing colonoscopy for lower gastrointestinal bleeding: Single tertiary care center experience.

Background: : The yield of colonoscopy in cases presenting with lower gastrointestinal bleeding (LGIB) in previously published studies varies according to several factors, including endoscopic skills, histopathological experience, and pattern of colonic pathology in different countries. The local literature is limited to a single small 20-year-old study. Our objective was to provide updated data on the diagnostic yield of colonoscopy in Saudi children with LGIB in Saudi Arabia. Methods: : This was a retrospective analysis of pediatric patients (0-14 years of age) who underwent colonoscopy for LGIB at the King Fahad Medical City (KFMC), from 2008 to 2018. LGIB was defined as fresh or dark blood per rectum. Results: : During the study period, 175 children underwent colonoscopy for LGIB (99 males, mean age 7.05 ± 3.81 years), which constituted 53.5% of indications for colonoscopy procedures (n = 327) in our center. The terminal ileum was intubated in 81% of the procedures. Overall, inflammatory bowel disease (IBD) was the most commonly identified cause of LGIB (32% ) followed by colonic lymphonodular hyperplasia (CLNH) in 17% and juvenile polyp and rectal mucosal prolapse syndrome (RMPS), 11% each. On sub-analysis, cow's milk protein allergy (CMPA) and CLNH were the most common causes in infants and toddlers, 35% each; IBD (26.5%) and polyps (22.4%) in young children (2-6 years), and IBD (36%), CLNH (14.9%) and RMPS (14%) in older children (6-14 years). In comparing the IBD to the non-IBD group, IBD patients were older (mean 8.37 vs. 6.46 years, P = 0.002) and more likely to have diarrhea, weight loss, high erythrocyte sedimentation rate, anemia, and hypoalbuminemia (odds ratio 24, 11, 10.7, 6.5, and 4, respectively). Colonoscopy had a sensitivity of 97%, specificity of 100%, positive predictive value of 100%, negative predictive value of 81.4%, and accuracy of 97% in diagnosing LGIB. Conclusion: : Colonoscopy is an effective diagnostic tool in children with LGIB with a high diagnostic yield. Besides IBD, CLNH and RMPS are two other important pathologic entities that need to be considered in a child with LGIB.

Antibiofilm Potential and Exoenzyme Inhibition by Elattaria cardamomum Essential Oil in Candida spp. Strains.

Fungal infections caused by Candida species have attracted great interest due to their resistance to commercial antifungal agents. Essential oils from aromatic and medicinal plants have many bioactive compounds that are known for their important biological activities, mainly their antimicrobial effects. In the present study, we aimed to evaluate the antifungal ability of Elettaria cardamomum essential oil (EO) against different clinical Candida isolates. Then, we investigated the anti-phospholipase, anti-protease, and anti-biofilm activity of E. cardamomum EO against the selected isolates. Twenty-four Candida strains (clinical and reference) were tested for virulence factors such as biofilm formation, protease, and phospholipase activity. The minimum inhibitory (MIC) and fungicidal (MFC) concentrations of E. cardamomum were determined, and their effects were tested against all Candida strains. Our results revealed that E. cardamomum EO was rich in α-terpinyl acetate (56.5%), limonene (12.6%), and mentha-2.4(8)-diene (7.65%). The tested EO showed activity against all tested Candida strains in their planktonic form and against exoenzymes and biofilm production. Based on our findings, we promote the use of E. cardamomum EO as a treatment against clinical Candida isolates active on the virulence factors of this fungus.

The Epidemiology and Outcome of Biliary Atresia: Saudi Arabian National Study (2000-2018).

Background: The epidemiology and outcomes of biliary atresia (BA) have been well-documented in national cohorts from two main ethnicities, namely, the Asian Orientals and Caucasians, with incidence ranging from 1 in 5,000 to 1 in 9,000 live births in East Asia and 1 in 15,000 to 19,000 live births in Europe and North America. Objective: We report the first nationwide BA study outside North America, Europe, and East Asia to describe the epidemiology and outcomes of BA in Saudi Arabia. Methods: A national database of BA cases diagnosed between 2000 and 2018 was analyzed. We assessed clearance of jaundice (bilirubin <20 µmol/L) in all cases that underwent Kasai portoenterostomy (KPE). We then estimated survival using the Kaplan-Meier method with endpoints of liver transplantation (LT), death, or survival with native liver (SNL). Results: BA was diagnosed in 204 infants (106 females; 10% pre-term). The incidence of BA was 1 in 44,365, or 2.254 in 100,000 live births (range, 0.5-4 in 100,000). Polysplenia was diagnosed in 22 cases (11%). The median age at referral was 65 days. A total of 146 children (71.5%) underwent KPE at a median age of 70 days. Clearance of jaundice was achieved in 66 of the 146 (45%) infants. The 10-year SNL after KPE was 25.5%, and the overall 10-year estimated survival was 72.5%. The Kaplan-Meier survival curves for patients undergoing KPE at the age of <60, 61-90, and >90 days showed a SNL rate at 51.6, 33, and 12.5%, respectively, at 5 years (P < 0.001). The 2-, 5-, and 10-year post-LT survival rates were 92.5, 90.6, and 90%, respectively. Undergoing an initial KPE did not impact negatively on the overall LT survival rate when compared to BA cases that underwent primary LT (P = 0.88). Conclusion: The incidence rate of BA in Saudi Arabia is lower than the incidence reported elsewhere. Late referral of BA cases remains a problem in Saudi Arabia; as a result, the SNL rate was lower than reported by other national registries. Hence, national policies devoted to timely referral and earlier age at KPE are needed.

HLA-DQ genotypes relative risks for celiac disease in Arabs: A case-control study.

OBJECTIVES: It remains unknown what degree of risk is conferred by celiac disease (CD)-predisposing human leukocyte antigen (HLA)-DQ genotypes in Saudi Arabia compared with in Western countries. In this study, we aimed to determine the CD risk gradient associated with the HLA-DQ genotypes and to compare HLA-DQ genotypes between symptomatic patients with CD and screening-identified asymptomatic CD patients. METHODS: We enrolled three groups of subjects, including 46 CD children diagnosed consecutively over the past 10 years, 54 CD children diagnosed during a mass screening of schoolchildren, and 192 healthy controls. All the participants were typed for the HLA-DQA1 and HLA-DQB1 genes by polymerase chain reaction sequence-specific oligonucleotide probes. RESULTS: Comparing the patients with CD to controls, we identified 5 groups in the CD risk gradient: (i) very high risk associated with the DQ2.5/DQ8 genotype (odds ratio [OR] 46.93); (ii) high risk (homozygous DQ2.5, DQ2.5/DQ2.2; OR 4.12-5.04); (iii) intermediate risk (heterozygous DQ2.5, DQ8/DQ2.2; OR 1.61 and 1.67); (iv) low risk (DQ8, DQ2.2); and (v) very low risk (DQ2.x, DQX.5, DQX.x). Heterozygous DQ8 was more common in screening-identified group compared to symptomatic patients (13.0% vs 2.2%); however, other genotypes were very similar between the two groups. CONCLUSION: The highest risk of developing CD in our Saudi Arabia population is associated with the DQ2.5/DQ8 genotype.