Status of vitamins and minerals in children with screening-identified celiac disease: A case-control study.

OBJECTIVES: Micronutrient deficiencies characterize classical "late-diagnosed" celiac disease (CeD). This study aimed to identify the prevalence of micronutrient deficiencies among children with "early-diagnosed" screening-identified CeD to determine the clinical value of routine testing for deficiencies in those patients. METHODS: A case-control study was conducted on screening-identified CeD patients diagnosed during a mass screening study (84 patients, mean age 11.3 ± 2.6 years). The controls (443 children, mean age 10.8 ± 2.5 years) were negative for celiac disease serological screening. Hemoglobin, serum levels of iron, ferritin, folate, vitamin B12, vitamin A, vitamin E, 25-OH vitamin D, zinc, and selenium were measured. RESULTS: The mean serum levels of hemoglobin, iron, ferritin, vitamin D, zinc, copper, and selenium were significantly lower in CeD patients than in healthy controls (hemoglobin 12.56 vs. 13.02 g/dL [p = 0.04]; iron 10.61 vs. 17.6 µmol/L [p < 0.001], ferritin 25.7 vs. 48.3 µg/L [p < 0.001], vitamin D 29.1 vs. 37.5 nmol/L, zinc 11.9 vs. 21.7 µmol/L, copper 18.9 vs. 32.5 µmol/L, selenium 1.04 vs. 1.36 µmol/L; p < 0.001). Patients with celiac and severe intestinal damage (Marsh IIIb and IIIc) had significantly lower serum ferritin and vitamin A levels than patients with mild intestinal damage (Marsh II and IIIa) (ferritin 15 vs. 22 µg/L, p < 0.025; vitamin A 0.85 vs. 1.35 µmol/L, p = 0.007). CONCLUSION: Micronutrient deficiencies are still detectable in "early-diagnosed" screening-identified CeD cases, a clinically relevant result that strongly supports efforts for screening and early diagnosis of CeD.

Clinical and laboratory features of biliary atresia and patterns of management practices: Saudi national study (2000-2018).

BACKGROUND: We utilized the data from the Saudi national biliary atresia (BA) study (2000-2018) to describe the clinical, biochemical, imaging, and histopathological features of BA and the perioperative clinical practices among local pediatric gastroenterologists. METHODS: This is a retrospective, multicenter, nationwide study that included 10 tertiary care governmental hospitals including the four liver transplant (LT) centers in different regions across Saudi Arabia. RESULTS: BA was diagnosed in 204 infants (106 females; 10% preterm). The median age at referral was 65 days. Congenital anomalies were present in 68 patients (33%); 22 were splenic malformation (10.8%). The medians of laboratory investigations were total bilirubin (189 µmol/l), direct bilirubin (139 µmol/l), ALT (164 u/l), and GGT (472 u/l). The level of serum GGT was normal in 26 cases (12.7%). The ultrasound findings included hypoplastic or atrophic gall bladder (GB) (65%), normal GB (30%), and cord sign (5%). A HIDA scan was performed in 99 cases (48.52%). Magnetic resonance cholangiopancreatography (MRCP) was performed in 27 cases (13%). A total of 179 liver biopsies (88%) were obtained. The most common histopathologic findings were bile duct proliferation (92%), canalicular cholestasis (96%), bile plugs (84%), and portal fibrosis (95%). Cholangiography was performed in 139 cases (68%): operative in 122 (60%) and percutaneous in 17 (8%). A total of 143 children (70%) underwent Kasai portoenterostomy (KPE) at a median age of 70 days. After KPE, steroid was used in 37% of the cases and 100 cases (70%) were prescribed prophylactic antibiotics for variable duration (ranging between 3 and 12 months). CONCLUSION: Our data show marked variation in the diagnostic evaluation and perioperative management of BA cases among the different tertiary centers. There is a need to establish a national BA registry in Saudi Arabia aiming to standardize pre- and postoperative clinical practices. Additionally, normal serum GGT level, normal GB size on ultrasound, and being a premature baby should not preclude the diagnostic workup for BA.

Celiac Disease and Intussusception: A Common Association in Children.

OBJECTIVES: In young childhood, intestinal intussusception (IS) is the most common cause of small bowel obstruction. A lead point such as Meckel diverticulum, polyps, tumors, enlarged lymph nodes, cystic fibrosis, and Schoenlein-Henoch purpura are recognized causes. Association between celiac disease (CD) and IS has been well recognized in adults but rarely in children. Data on causes and outcome of intussusception among Saudi children are lacking in the literature. Our objectives were to characterize the pattern of IS among Saudi children and investigate the frequency, clinical presentation, and outcome of intussusception among children with CD. METHODS: We searched the hospital's picture archiving and communications system for abdominal imaging studies (ultrasound, magnetic resonance imaging, computed tomography scan, and barium contrast studies), performed between 2008 and 2019, using "intussusception" as a search key word. The hospital medical records of the identified cases of intussusception (aged 0-14 years) were then retrospectively reviewed to collect demographic, clinical, laboratory and imaging findings, management, and outcome. RESULTS: During the study period, 57 cases were identified as confirmed IS (31 boys, median age 1.95 years, range 0.33-11 years). Abdominal ultrasound was the diagnostic imaging study in 93%. An underlying cause (secondary IS) could be identified in 19 (33.3%) cases: CD in 6, malignancy and Henoch-Schoenlein purpura, 5 each, and Meckel diverticulum in 3; the remaining 38 (66.6%) cases of IS were idiopathic (primary IS). The presence of hypoalbuminemia and abdominal distension were significantly associated with secondary IS as compared with primary IS (P < 0.001, P = 0.006, respectively). All of the 6 cases of IS associated with CD resolved spontaneously, but 3 were recurrent. CONCLUSIONS: Secondary causes contributed to a large proportion of IS in our study cohort (33%) as compared with 5% to 10% in the literature. Celiac disease is an underrecognized cause of IS among children. A child with IS and hypoalbuminemia, anemia, or chronic diarrhea needs to be investigated for CD to avoid unnecessary surgery.

Predictors of biliary atresia outcome: Saudi National Study (2000 - 2018).

Background: Outcomes in biliary atresia (BA) have been well-documented in large national cohorts from Europe, North America, and East Asia. Understanding the challenges that preclude success of the Kasai portoenterostomy (KPE) is the key to improve the overall outcomes of BA and implementing intervention strategies. Here, we analyzed the data from the Saudi national BA study (204 BA cases diagnosed between 2000 and 2018) to identify the prognostic factors of BA outcomes. Methods: One hundred and forty-three cases underwent KPE. Several prognostic factors (center case load, congenital anomalies, serum gamma-glutamyl transferase, use of steroids, ascending cholangitis post-operatively, and degree of portal fibrosis at time of KPE) were investigated and correlated with the primary outcomes of interest: 1) success of KPE (clearance of jaundice and total serum bilirubin <20 mmol/l after KPE), 2) survival with native liver (SNL), and 3) overall survival. Results: Use of steroids after KPE was associated with clearance of jaundice, 68% vs. 36.8% in the BA cases that did not receive steroids (P = 0.013; odds ratio 2.5) and a significantly better SNL rate at 2 - and 10-year of 62.22% and 57.77% vs. 39.47% and 31.57%, respectively (P = 0.01). A better 10-year SNL was observed in centers with caseload <1/year (group 1) as compared to centers that performed ≥1/year (group 2) [45.34% vs. 26.66%, respectively; P = 0.047]. On comparison of the 2 groups, cases in group 1 had KPE at significantly earlier age (median 59.5 vs. 75 days, P = 0.006) and received steroids after KPE more frequently than group 2 (69% vs. 31%, P < 0.001). None of the remaining prognostic variables were identified as being significantly related to BA outcome. Conclusion: Steroids use post-KPE predicted clearance of jaundice and better short- and long-term SNL. There is a need to establish a national BA registry in Saudi Arabia aiming to standardize the pre- and post-operative clinical practices and facilitate clinical and basic research to evaluate factors that influence BA outcome.

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.

Vitamin D and iron deficiencies among Saudi children and adolescents: A persistent problem in the 21st century.

BACKGROUND: Although several studies have reported on the prevalence of micronutrients in Saudi Arabia, most frequently vitamin D and iron, they are either old or hospital- or primary health care center-based. The objectives of our study were to provide more updated data on the prevalence rate of micronutrients deficiency among the Saudi general pediatric population and to determine if there is an association between micronutrients deficiency and undernutrition. METHODS: The present study is part of a cross-sectional mass screening study, "Exploring the Iceberg of Celiacs in Saudi Arabia" conducted among school-aged children (6-16 years) in 2014-2015. A sample of 7,931 children aged 6-16 years was randomly selected. We identified thin children [body mass index (BMI) z-score <-2 SD, for age and gender], using the WHO reference 2007. A case-control study was performed, where the sera of 182 thin children (cases) and 393 normal BMI children (controls) were tested for levels of iron, ferritin, vitamin D, zinc, selenium, and copper. RESULTS: The prevalence of thinness was 3.5%. The two most common micronutrients deficient among Saudi children with normal BMI were iron (20%) and vitamin D (78%). Vitamin D levels were significantly higher among boys as compared to girls (39.6 nmol/L vs. 31.15 nmol/L; P < 0.001). Deficiency of copper, zinc, and selenium occurred in 0.25%, 1%, and 7.4% of the children with normal BMI. Comparisons between the cases and controls did not show statistically significant differences. CONCLUSION: Vitamin D and iron deficiencies are still common forms of malnutrition in the Saudi community, that have remained unchanged over the past 20-30 years, while the intake of trace elements (zinc, copper, and selenium) is adequate as evident by normal serum levels in the vast majority of the investigated children. We could not observe a correlation between undernutrition and micronutrient deficiencies.

Diagnosing Coeliac Disease During Mass-Screening of General Paediatric Population: Is Biopsy Avoidable?

OBJECTIVES: Studies evaluating the correlation between tissue transglutaminase immunoglobulin antibody (TGA-IgA) levels and the degree of enteropathy in screening-detected coeliac disease (CD) patients from the general childhood population are scarce. The objectives of our study were to evaluate the correlation between the TGA-IgA titre and the degree of enteropathy and to evaluate whether the no-biopsy approach to diagnose CD in symptomatic patients proposed by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition could be extended to asymptomatic CD patients diagnosed during mass screening studies. METHODS: The present study is a sub-study of a cross-sectional mass screening study, "Exploring the Iceberg of Coeliacs in Saudi Arabia", conducted among school-aged children (6-15 years) in 2014-2015. The 93 biopsy-confirmed CD patients constituted the study cohort of the present study (mean age 11.4 ±â€Š2.6 years; 24 males). TGA-IgA titres and endomysial antibodies (EMA) at the time of biopsy and grade of enteropathy were assessed, and human leukocyte antigen DQ 2.2/2.5/8 genotyping was performed. RESULTS: Thirty-four patients had TGA-IgA titres >10× upper limit of normal (ULN; 36%); all had villous atrophy with positive EMA and DQ 2.2/2.5/8. The sensitivity and specificity of a TGA-IgA titre >10× ULN in correctly diagnosing CD was 100%. There was a significant positive correlation between the anti-TGA-IgA titre and the severity of enteropathy (P < 0.001). There was no significant difference in the TGA-IgA titre between the asymptomatic and symptomatic CD patients. CONCLUSIONS: Our results provide evidence that a TGA-IgA titre >10× ULN correlates with villous atrophy in CD patients detected by mass screening.

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.

Role of percutaneous liver biopsy in infantile cholestasis: cohort from Arabs.

BACKGROUND: Investigators from different parts of the world are calling for a re-evaluation of the role of liver biopsy (LB) in the evaluation of infantile cholestasis (IC), especially in the light of emerging non-invasive diagnostic technologies. Therefore, this retrospective single-center study was conducted to determine the impact of LB on the diagnosis and management of IC in a cohort from Arabs. METHODS: From 2007 until 2019, 533 cases of IC were referred for evaluation. All infants who underwent LB were included in the study. We categorized the yield of LB into: (1) defined specific diagnosis; (2) excluded an important diagnosis. A single pathologist reviewed and made the histology report. RESULTS: 122 LB specimens met the inclusion criteria. The main indication for LB was a high suspicion of biliary atresia (BA) [high gamma-glutamyl transferase (GGT) cholestasis and pale stool] in 46 cases (37.8%). Liver biopsy had sensitivity of 86.4%, specificity (66.7%), PPV (70.4%), NPV (84.2%) in diagnosing BA. LB had a direct impact on clinical management in 52 cases (42.6%): (1) The true diagnosis was suggested by LB in 36 cases; (2) LB excluded BA and avoided intraoperative cholangiogram in 16 cases with high suspicion of BA. Among the 76 cases with low suspicion of BA, LB suggested the true diagnosis or helped to initiate specific management in 8 cases only (10.5%). In contrast, molecular testing confirmed the diagnosis in 48 (63%). CONCLUSION: LB continues to be an important tool in the workup of cases with a high suspicion of BA. The low yield of LB in cases with low suspicion of BA calls for a re-evaluation of its role in these cases in whom early incorporation of cholestasis sequencing gene  panels can have a better diagnostic yield.

Deamidated Gliadin Antibodies: Do They Add to Tissue Transglutaminase-IgA Assay in Screening for Celiac Disease?

OBJECTIVES: Use of deamidated gliadin peptide (DGP) test kits as adjunctive to tissue-transglutaminase-IgA (TTG-IgA) for the diagnosis of celiac disease (CD) has been a controversial issue. The objectives of our study were to evaluate the diagnostic performance of DGP antibodies compared with TTG-IgA and to evaluate the correlation between DGP-antibody titers and degree of enteropathy. METHODS: We included children who underwent endoscopy and biopsies because of positivity of any of the serology tests in the "celiac profile" (TTG-IgA, DGP-IgA, and DGP-IgG) from 2012 to 2019. We divided children into clinically suspected cases of CD (group 1) and asymptomatic cases screened as they were from a high-risk group (group 2). RESULTS: Group 1 constituted 52 children and group 2 included 81 children (76 type-1 diabetes [T1D]). The sensitivity and positive-predictive value (PPV) of DGP-IgG in group 1 (90%, 98%) and group 2 (91%, 85.5%) were comparable with TTG-IgA (98%, 92% in group 1; 100%, 80% in group 2). By adding DGP-IgG to TTG-IgA, the performance of TTG-IgA has improved marginally in group 1 (sensitivity 100%, PPV 92.3%). All cases with DGP-IgG titer 2 times ULN in group 1, and >4 times ULN in group 2 had villous atrophy. All T1D patients with TTG IgA >10 times ULN had villous atrophy. CONCLUSIONS: DGP-IgG assay did not add to the performance of TTG-IgA. DGP-IgG titer correlated with enteropathy. The diagnosis of CD can be made in asymptomatic T1D child with TTG-IgA titer >10 times ULN and positive endomyseal antibodies.

Liver Failure Among Young Saudi Infants: Etiology, Clinical Presentation, and Outcome.

OBJECTIVES: The published data on early infantile liver failure (EILF) are scarce and limited to Caucasians. We conducted this study to describe the etiology and outcome of EILF among Arabs and identify prognostic factors. METHODS: We retrospectively reviewed our database of 524 infants presenting with liver impairment from 2008 to 2018, and identified cases of EILF defined as presence of biochemical pattern of liver disease and INR ≥2 (unresponsive to vitamin K) with onset before 3 months of life. Primary outcomes included death or liver transplantation (LT) (poor outcome group) and survival with native liver (good outcome group). RESULTS: Forty-two cases of EILF (22 girls) were identified (8%). The etiology was indeterminate in 14 (33.3%) and established in 27 (64.3%): galactosemia (7 cases, 16.6%), tyrosinemia (5, 12%), neonatal hemochromatosis (NH), and hemophagocytic lymphohistiocytosis (HLH) (4 each, 9.5%]) mitochondrial hepatopathy (3, 7%), and miscellaneous (5, 12%). LF resolved in 15 cases (35.7%), either spontaneously or in response to specific therapy, 23 (54.7%) died, and 4 underwent LT (9.5%). ROC analysis for the best cut-off value of serum total bilirubin for prediction of study outcomes was 120 µmol/L (sensitivity 81.5%, specificity 80%). Among the diagnostic groups, galactosemia and tyrosinemia predicted good outcome, whereas the idiopathic diagnosis predicted poor outcome (OR = 13). CONCLUSIONS: Similar to Western countries, galactosemia, tyrosinemia, NH, HLH, and mitochondrial hepatopathy are the main players in EILF in Saudi Arabia. Galactosemia and tyrosinemia predict good prognosis and idiopathic diagnosis predicts poor prognosis.

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.

Mass Screening for Celiac Disease Among School-aged Children: Toward Exploring Celiac Iceberg in Saudi Arabia.

OBJECTIVES: We conducted this mass screening study to determine the prevalence of celiac disease (CD) and characterize the celiac iceberg among Saudi pediatric population in Riyadh, the capital city of Saudi Arabia. METHODS: During the study period (January 2014-June 2016), we have conducted a cross-sectional, mass screening, immunoglobulin A-tissue transglutaminase (TTG-IgA)-based study on 7930 Saudi students from primary and intermediate schools in Riyadh. Students with positive TTG-IgA (>20 U/L) were called in the hospital to undergo a repeat of TTG-IgA; in those with borderline positive TTG-IgA (20-60 U/L), IgA-endomyseal antibody (EMA-IgA) test was performed. Children with TTG-IgA >60 U/L and children with borderline positive TTG-IgA and positive EMA-IgA were advised to undergo upper endoscopy and intestinal biopsies. RESULTS: We identified 221 students with positive TTG-IgA (2.8%). CD was diagnosed in 119 cases (1.5%, 1:67 Saudi children) (mean age 11.5 ±â€Š2.62 years; girls 81 [68%]). Another 51 children had persistently borderline positive TTG-IgA but negative EMA (0.64%) and the remaining 51 had transiently positive TTG-IgA. We have identified 3 clinical patterns in the screening-identified cases with CD: a silent form (37%), a mild symptomatic form characterized by gastrointestinal symptoms in presence of normal growth or overweight/obesity (48%), and gastrointestinal symptoms associated with impaired growth in 15%. CONCLUSIONS: Our study provided evidence of a high prevalence of CD among Saudi children (1.5%), a rate that is at least twice the average prevalence rate in Europe and North America.