Genetic variants involved in innate immunity modulate the risk of inflammatory bowel diseases in an understudied Malaysian population.

BACKGROUND AND AIM: Inflammatory bowel diseases (IBD) are chronic gastrointestinal inflammatory conditions comprising two major subtypes: Crohn's disease (CD) and ulcerative colitis (UC). The incidence of IBD is increasing in Asian countries including Malaysia. The aim of this study was to determine whether 32 single nucleotide polymorphisms (SNPs) strongly associated with IBD from genome-wide association studies, performed mainly in Caucasian populations, are associated with IBD in a Malaysian population, correlating these findings with local and systemic inflammation. METHODS: Selected SNPs were investigated in a Malaysian cohort comprising 36 IBD patients and 75 controls using customized matrix-assisted laser desorption ionization time-of-flight genotyping. Local mRNA and/or systemic protein levels of IL-10, IL-12, IL-22, IL-23, and TNF-α were measured in these same subjects. RESULTS: ATG16L2 rs11235667 and LINC00824 rs6651252 was significantly associated with increased CD risk while IL12B rs56167332 was a significant protective factor. Three SNPs (SBNO2 rs2024092, CARD9 rs10781499, and rs17085007 between GPR12-USP12) were significantly associated with increased UC risk while NKX2-3 rs4409764 was a significant protective factor. After adjusting for age, gender, and ethnicity, SBNO2 rs2024092, ATG16L2 rs11235667, CARD9 rs10781499, and LINC00824 rs6651252 remained associated with IBD. Interestingly, the risk alleles of IL10 rs3024505, CARD9 rs1078149, and IL12 rs6556412 were associated with higher levels of IL-10, IL-22, and IL-23 in these same subjects, respectively. CONCLUSIONS: This study identified eight SNPs associated with IBD and/or its subtypes in the Malaysia population, significantly advancing our understanding of the genetic contribution to IBD in this understudied population. Three of these SNPs modulated relevant cytokine levels and thus, may directly contribute to IBD pathogenesis.

A Rare Case of von Willebrand Disease Presenting as Hemolacria and Literature Review.

Hemolacria is a rare condition that causes a person to produce tears that are partially composed of blood. It can be a presenting feature of certain ocular and systemic conditions. Here, the authors describe an interesting case of a 12-year-old boy with an underlying beta-thalassemia trait, who presented with a 2-day history of bilateral blood-stained tears, and an episode of epistaxis. Ocular examination was normal, and syringing showed no nasolacrimal duct blockage. Systemic examination was unremarkable. Laboratory investigations confirmed type 2 von Willebrand disease. Management of hemolacria remains a clinical challenge given the rare occurrence of the disease. In this case report, the authors discuss the differential diagnosis and management approach to hemolacria.

Exclusive enteral nutrition is effective and feasible as primary induction and re-induction therapy in Asian children with Crohn's disease.

AIM: We aimed to ascertain the efficacy and feasibility of exclusive enteral nutrition (EEN) as an induction and re-induction therapy in Asian children with Crohn's disease (CD). METHODS: All children diagnosed with CD between 1995 and 2019 were reviewed. Response to induction was compared between EEN and standard immunosuppression (IS) using Paediatric Crohn's Disease Activity Index, growth failure, perianal disease and extra-intestinal manifestations. Two study groups were analysed: (i) primary induction and (ii) re-induction for relapses. RESULTS: Twenty-nine children (mean age (± standard deviation) at diagnosis 9.4 ± 8.5 years old, ileo-colonic 35%, non-stricturing 79%) were studied. At primary induction (group 1; n = 18), no difference was observed in remission rates (9/13 vs. 5/5; P = 0.278), efficacy for improving growth failure (6/8 vs. 0/1; P > 0.999), perianal disease (4/6 vs. 0/2; P > 0.999) and extra-intestinal manifestations (2/2 vs. 0/0; P > 0.999) with EEN or standard IS. Group 2 (n = 38 relapses), no difference was observed in remission rates (16/19 vs. 15/19, P > 0.999), growth failure (0/7 vs. 4/14; P = 0.328), perianal disease (1/10 vs. 7/7; P > 0.999) and extra-intestinal manifestations (0/0 vs. 1/1; P > 0.999) with EEN or standard IS. Both treatment modalities were equally effective as re-induction in relapses in patients previously treated with EEN (P = 0.191). CONCLUSION: As compared to standard IS, EEN was equally effective in primary induction and re-induction for relapse in Asian children with CD and can be repeatedly used for recurrent relapses.

ATG16L1 rs2241880/T300A increases susceptibility to perianal Crohn's disease: An updated meta-analysis on inflammatory bowel disease risk and clinical outcomes.

BACKGROUND: ATG16L1 plays a fundamental role in the degradative intracellular pathway known as autophagy, being a mediator of inflammation and microbial homeostasis. The variant rs2241880 can diminish these capabilities, potentially contributing to inflammatory bowel disease (IBD) pathogenesis. OBJECTIVES: To perform an updated meta-analysis on the association between ATG16L1 rs2241880 and IBD susceptibility by exploring the impact of age, ethnicity, and geography. Moreover, to investigate the association between rs2241880 and clinical features. METHODS: Literature searches up until September 2022 across 7 electronic public databases were performed for all case-control studies on ATG16L1 rs2241880 and IBD. Pooled odds ratios (ORP ) and 95% CI were calculated under the random effects model. RESULTS: Our analyses included a total of 30,606 IBD patients, comprising 21,270 Crohn's disease (CD) and 9336 ulcerative colitis (UC) patients, and 33,329 controls. ATG16L1 rs2241880 was significantly associated with CD susceptibility, where the A allele was protective (ORP : 0.74, 95% CI: 0.72-0.77, p-value: <0.001), while the G allele was a risk factor (ORP : 1.23, 95% CI: 1.09-1.39, p-value: 0.001), depending on the minor allele frequencies observed in this multi-ancestry study sample. rs2241880 was predominantly relevant in Caucasians from North America and Europe, and in Latin American populations. Importantly, CD patients harbouring the G allele were significantly more predisposed to perianal disease (ORP : 1.21, 95% CI: 1.07-1.38, p-value: 0.003). CONCLUSIONS: ATG16L1 rs2241880 (G allele) is a consistent risk factor for IBD in Caucasian cohorts and influences clinical outcomes. As its role in non-Caucasian populations remains ambiguous, further studies in under-reported populations are necessary.

Morbidity and treatment costs of cystic fibrosis in a middle-income country.

Introduction: : Asian children with cystic fibrosis (CF) managed in Malaysia have significant morbidity with limited access to life-sustaining treatments. We determined the morbidity and treatment cost of CF in a resource-limited country. Methods: This cross-sectional study included all children diagnosed with CF in our centre. Data on clinical presentation, genetic mutation, serial spirometry results and complications were collected. Out-of-pocket (OOP) and healthcare costs over 1 year were retrieved for patients who were alive. Cohen's d and odds ratio (OR) were used to determine the effect size. Results: Twenty-four patients were diagnosed with CF. Five patients died at a median (range) age of 18 (0.3-22) years. F508deletion (c. 1521_1523delCTT) was found in 20% of the alleles, while 89% of the variants were detected in nine patients. Body mass index (BMI) Z score was >-1.96 in 70.6% of patients. Two thirds (68%) were colonised with Pseudomonas aeruginosa, and this was associated with lower weight (P = 0.009) and BMI (P = 0.02) Z scores. Only 18% had FEV1 Z scores >-1.96. Early symptom onset (d = 0.74), delayed diagnosis (d = 2.07), a low FEF25-75 Z score (d = 0.82) and a high sweat conductance (d = 1.19) were associated with death. Inpatient cost was mainly from diagnostic tests, while medications contributed to half of the outpatient cost.Healthcare utilisation cost was catastrophic, amounting to 20% of the total income. Conclusion: Asian children with CF suffer significant complications such as low weight, low lung function and shortened lifespan. P. aeruginosa colonisation was frequent and associated with poor growth. Healthcare cost to parents was catastrophic.

Epidemiological characteristics of Asian children with inflammatory bowel disease at diagnosis: Insights from an Asian-Pacific multi-centre registry network.

BACKGROUND: There remains a dearth of Asian epidemiological literature for paediatric inflammatory bowel disease (PIBD). AIM: To describe the presenting features of PIBD from 7 Asia-Pacific pediatric gastroenterology centers via a central standardised electronic data platform. METHODS: Clinical, endoscopic and radiologic data at diagnosis from the registry were extracted between 1st January 1995 to 31st December 2019. Disease phenotypic characteristics were classified as per the Paris classification system. RESULTS: There was a distinct rise in new PIBD cases: Nearly half (48.6%) of the cohort was diagnosed in the most recent 5 years (2015-2019). The ratio of Crohn's disease (CD):Ulcerative colitis (UC):IBD-Unclassified was 55.9%:38.3%:5.8%. The mean age was 9.07 years with a high proportion of very early onset IBD (VEO-IBD) (29.3%) and EO-IBD (52.7%). An over-representation of the Indian/South Asian ethnic group was observed which accounted for 37.0% of the overall Singapore/Malaysia subcohort (6.8%-9.0% Indians in census). Indian/South Asian CD patients were also most likely to present with symptomatic perianal disease (P = 0.003). CD patients presented with significantly more constitutional symptoms (fever, anorexia, malaise/fatigue and muscle-wasting) than UC and higher inflammatory indices (higher C-reactive protein and lower albumin levels). CONCLUSION: We observed a high incidence of VEO-IBD and an over-representation of the Indian ethnicity. South Asian CD patients were more likely to have symptomatic perianal disease.

Nudix Hydroxylase 15 Mutations Strongly Predict Thiopurine-Induced Leukopenia Across Different Asian Ethnicities: Implications for Screening in a Diverse Population.

Background and Aims: Thiopurines, which are immunosuppressive drugs for maintaining remission for inflammatory bowel disease, are known to cause myelotoxicity in patients with Nudix Hydroxylase 15 (NUDT15) genetic variants in some Asian countries with monoethnic populations. We aimed to investigate the association of NUDT15 variants with leukopenia in a multiethnic population in Southeast Asia. Methods: Patients with a confirmed diagnosis of inflammatory bowel disease were recruited. We collected demographic and clinical characteristics and whole blood counts before and after initiating thiopurines. Thiopurine S-methyltransferase (TPMT) and NUDT15 genotypes were analyzed with the single nucleotide polymorphisms (SNPs) genotyping assay. Leukopenia was defined as a white blood cell (WBC) count < 3,000/µl. Results: In this study, 19 (18.6%) of the 102 patients who had adequate thiopurine therapy experienced leukopenia, 11 patients (57.9%) had NUDT15 c.415C > T variants, 2 patients (10.5%) had NUDT15 c.52G > A variants while one (5.3%) had a TPMT variation. Individually, NUDT15 c.415C > T had a sensitivity and specificity of 57.9% and 94.0% (odds ratio [OR] = 21.45, 95% CI 5.94-77.41, p < 0.001), respectively, for predicting thiopurine-induced leukopenia, while NUDT15 c.52G > A was only observed in patients with leukopenia. As compared with patients with wild-type NUDT15, both NUDT15 variations had a combined sensitivity and specificity of 68.4% and 94%, respectively (OR = 33.80, 95% CI 8.99-127.05, p < 0.001), for predicting thiopurine-induced leukopenia as well as a shorter onset to leukopenia (median onset [months] 2.0 vs. 5.5; p = 0.045). Sub-group analysis showed that both NUDT15 variations were strongly associated with leukopenia among the Chinese and Indians but not among the Malays. Conclusion: Nudix Hydroxylase 15 variants strongly predicted thiopurine-induced leukopenia across a multiethnic Southeast Asian population, particularly among the Chinese and Indians.

Etiology, outcome and prognostic indicators of acute liver failure in Asian children.

OBJECTIVE: Outcome of pediatric acute liver failure (PALF) in countries with limited availability of LT is not well described. We evaluated the outcome and prognostic indicators of PALF in Malaysia where emergency LT for ALF is limited. METHODS: In this retrospective review on children < 18 years with PALF, we compared clinical and laboratory parameters between survival after supportive treatment and after LT or succumbed without LT. The predictive values of Liver Injury Unit (LIU; peak laboratory values for international normalized ratio [INR], ammonia, total bilirubin) and upon admission (aLIU) on outcome of PALF was evaluated using receiver operator characteristic (ROC) curves. RESULTS: Of 77 children (39 males [51%]; median age 2.8 years) with PALF, the overall survival was 55% (n = 42); 52% (n = 40) survived with supportive management, 2.6% (n = 2) after LT. As compared to children who survived without LT, children who had LT/died had lower hemoglobin, aspartate transferase, γ-glutamyl transpeptidase (GGT), and higher serum bilirubin, alkaline phosphatase, ammonia, and serum sodium (p < 0.05). On multivariate analysis, significant independent predictor for death or LT were peak bilirubin > 452 µmol/L and peak GGT < 96 IU/L. The C-index of LIU and aLIU score were 0.79 and 0.68, respectively, indicating that LIU score was a good model in predicting outcome of PALF. CONCLUSIONS: Overall survival of PALF remained poor. High peak bilirubin and low GGT predict poor outcome of PALF. LIU score is a good model in predicting outcome of PALF and maybe useful in selecting children for emergency LT.

Role of primary prophylaxis in preventing variceal bleeding in children with gastroesophageal varices.

BACKGROUND: Primary endoscopic prophylaxis in pediatric gastroesophageal varices is not universally practiced. We aimed to determine the role of primary endoscopic prophylaxis in preventing variceal bleeding in gastroesophageal varices in children. METHODS: We reviewed all children with gastroesophageal varices seen in our unit from 2000 to 2019. Primary prophylaxis was defined as endoscopic procedure without a preceding spontaneous bleeding and secondary prophylaxis as preceded by spontaneous bleeding. High-risk varices were defined as presence of grade III esophageal varices, cardia gastric varices or cherry red spots on the varices. Outcome measures (spontaneous rebleeding within 3 months after endoscopic procedure, number of additional procedures to eradicate varices, liver transplant [LT], death) were ascertained. RESULTS: Sixteen of 62 (26%) patients (median [± S.D.] age at diagnosis = 5.0 ± 4.3 years) with varices had primary prophylaxis, 38 (61%) had secondary prophylaxis while 8 (13%) had no prophylaxis. No difference in the proportion of patients with high-risk varices was observed between primary (88%) and secondary (92%; P = 0.62) prophylaxis. As compared to secondary prophylaxis, children who had primary prophylaxis were significantly less likely to have spontaneous rebleeding (6% vs. 38%; P = 0.022) and needed significantly fewer repeated endoscopic procedures (0.9 ± 1.0 vs. 3.1 ± 2.5; P = 0.021). After 8.9 ± 5.5 years of follow-up, overall survival was 85%; survival with native liver was 73%. No statistical difference was observed in the eventual outcome (alive with native liver) between primary and secondary (71% vs. 78%, P = 0.78). CONCLUSION: Children with PHT who had primary prophylaxis had less subsequent spontaneous rebleeding and needed fewer additional endoscopic procedures as compared to secondary prophylaxis but did not have an improved eventual outcome. Screening endoscopy in all children who have signs of PHT and primary prophylaxis in high-risk esophageal varices should be considered before eventual LT.

Low prevalence of infantile functional gastrointestinal disorders (FGIDs) in a multi-ethnic Asian population.

BACKGROUND: Functional gastrointestinal disorders (FGIDs) are common in children. The prevalence of FGIDs varies across the world but is unknown in Malaysia. We aimed to investigate the prevalence of FGIDs in healthy Malaysian infants. METHODS: This was a cross-sectional study involving healthy infants younger than 12 months of age who attended a well-baby clinic. A universal sampling method was adopted. Children with congenital disorders potentially affecting gastrointestinal functions, chronic debilitating diseases and hypothyroidism were excluded. Rome IV criteria were used to define FGIDs. RESULTS: Of the total 534 infants recruited (54% males), 92% were born at term; 85% had normal birth weight [range 2.5-4.0 kg], and the mean (±S.D.) age at interview was 6.8 (±3.4) months. Thirty-six percent were breastfed, 29% were formula-fed, and 35% had mixed feeding. Prevalence of infant regurgitation and rumination syndrome was 10.5% and 1.7%, respectively. Prevalence of infant colic was 1.9% (3/160) (infant < 5 months old) while infant dyschezia, functional constipation and diarrhoea were 1.3%, 1.1% and 0.3%, respectively. No subjects fulfilled diagnostic criteria for cyclic vomiting syndrome. Breastfed infants were less likely to regurgitate, after adjustment for age, gender, ethnicity, birth weight and gestation (adjusted OR 0.25 [95% CI 0.12-0.54]; p < 0.001). No significant differences among other factors (gender, Malays vs. non-Malays, premature vs. term, and birthweight) were noted for other FGIDs. CONCLUSION: With the exception of the lower prevalence of infant colic and functional constipation, the prevalence rates of other FGIDs observed in the present study were similar to those published in the literature. Breastfeeding protects against infant regurgitation.

Parental concern of feeding difficulty predicts poor growth status in their child.

BACKGROUND: Parents often express concerns about feeding difficulties in their child. We hypothesized that these parental concerns were associated with adverse growth status in early childhood. We aimed to determine the prevalence of such concerns and whether these concerns were associated with adverse growth status in early childhood. METHODS: We performed a cross-sectional study among healthy children aged 12-36 months attending three well-baby clinics in three urban areas in Malaysia and Singapore between December 2016 and February 2017. Parents were interviewed for concerns about their child's feeding and presence of behavioral and organic red flags for feeding difficulties. We defined growth faltering as weight-for-age < 3rd centile and short stature as height-for-age < 3rd centile according to World Health Organization Growth Standards. RESULTS: Of the 303 children studied (boys = 160, 52.8%; mean [± SD] chronological age at interview 21.3 [± 4.0] months), 13% (n = 38/292) had growth faltering and 19.5% (n = 50/256) had short stature. Overall, 36.3% (n = 110) of parents expressed concerns about their child's feeding behavior. Sixty-eight percent (n = 206) of parents reported presence of at least one behavioral and 18.5% (n = 56) had at least one organic red flag for feeding difficulties, respectively. 9.9% (n = 30) had both behavioral and organic red flags for feeding difficulties. Growth faltering was significantly associated with parental concern about feeding (odds ratio [OR] 3.049, p < 0.001), food refusal (OR 4.047, p < 0.001) and presence of at least one organic red flag (OR 2.625, p = 0.012). CONCLUSION: We found that parental concerns about their child's feeding to be common. Presence of parental concern, food refusal in the child and presence of organic red flags for feeding difficulties are associated growth faltering in early childhood.