Background & AimsCongenital diarrheal disorders are rare inherited intestinal disorders characterized by intractable, sometimes life-threatening, diarrhea and nutrient malabsorption; some have been associated with mutations in diacylglycerol-acyltransferase 1 (DGAT1), which catalyzes formation of triacylglycerol from diacylglycerol and acyl-CoA. We investigated the mechanisms by which DGAT1 deficiency contributes to intestinal failure using patient-derived organoids.MethodsWe collected blood samples from 10 patients, from 6 unrelated pedigrees, who presented with early-onset severe diarrhea and/or vomiting, hypoalbuminemia, and/or (fatal) protein-losing enteropathy with intestinal failure; we performed next-generation sequencing analysis of DNA from 8 patients. Organoids were generated from duodenal biopsies from 3 patients and 3 healthy individuals (controls). Caco-2 cells and patient-derived dermal fibroblasts were transfected or transduced with vectors that express full-length or mutant forms of DGAT1 or full-length DGAT2. We performed CRISPR/Cas9-guided disruption of DGAT1 in control intestinal organoids. Cells and organoids were analyzed by immunoblot, immunofluorescence, flow cytometry, chromatography, quantitative real-time polymerase chain reaction, and for the activity of caspases 3 and 7.ResultsIn the 10 patients, we identified 5 bi-allelic loss-of-function mutations in DGAT1. In patient-derived fibroblasts and organoids, the mutations reduced expression of DGAT1 protein and altered triacylglycerol metabolism, resulting in decreased lipid droplet formation after oleic acid addition. Expression of full-length DGAT2 in patient-derived fibroblasts restored formation of lipid droplets. Organoids derived from patients with DGAT1 mutations were more susceptible to lipid-induced cell death than control organoids.ConclusionsWe identified a large cohort of patients with congenital diarrheal disorders with mutations in DGAT1 that reduced expression of its product; dermal fibroblasts and intestinal organoids derived from these patients had altered lipid metabolism and were susceptible to lipid-induced cell death. Expression of full-length wildtype DGAT1 or DGAT2 restored normal lipid metabolism in these cells. These findings indicate the importance of DGAT1 in fat metabolism and lipotoxicity in the intestinal epithelium. A fat-free diet might serve as the first line of therapy for patients with reduced DGAT1 expression. It is important to identify genetic variants associated with congenital diarrheal disorders for proper diagnosis and selection of treatment strategies.

Introduction: When transaminase levels (Alanine aminotransferase: ALT, Aspartate aminotransferase: AST) are high, a causal investigation is necessary. Although the etiology and frequency of hypertransaminasemia have been examined at length in the adult population, research addressing pediatric patients is far from being sufficient in number. The objective of this study is to investigate the causes the hypertransaminasemia. We think that knowing the most common causes of hypertransaminasemia in children will help primary care physicians with diagnosis and follow-up. Methods: The patients who were admitted to the pediatric gastroenterology policlinic between 2018-2019 with ALT> 45 IU /L and/or AST> 50 IU /L levels were the subjects of this study. They all displayed elevated liver function test (LFT) results due to various conditions including liverrelated ones and others. The medical records of the patients, who were between 6 months and 18 years of age, were analyzed. Results: Of 237 patients included in the study, 127 (54%) were male and 110 (46%) were female. The mean age of the patients was 75.40 ± 60.50 months. 5.06% of the patients had fever, 11.39% had hepatomegaly, 7.59% suffered from loss of appetite and 7.59% had abdominal pain. The obesity rate was at 9.70% while splenomegaly was detected in 2.11% of the patients. Elevation of liver enzymes was found to be related with idiopathic causes 35% (n=83), viral infections 21% (n=50), hepatosteatosis 15% (n=38), and medication 8.80% (n=21). Conclusion: Hypertransaminasemia may be an outcome of primary diseases of the liver and it may also be aggravated due to secondary effects. NAFLD (non-alcoholic fatty liver disease, viral infections, and medication continue to be among the most common causes. NAFLD constitutes an important cause of hypertransaminemia in children.

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Purpose Sleep disturbances are common in patients with celiac disease (CD), but their response to a gluten-free diet (GFD) treatment remains scarce. This study investigated the alteration in sleep disturbances within 6 months of starting a GFD in children with CD. Patients and Methods A total of 103 children initially diagnosed with CD, with no psychiatric diagnosis and not receiving psychotropic medication, were included in this study. Sociodemographic data were collected, and the Children’s Sleep Habits Questionnaire (CSHQ) was completed both before and after six months of initiating a GFD. Results Overall, the total average CSHQ score was 46; after starting the GFD, this decreased to 40, which was under the clinically significant cutoff level for sleep disturbance (p < 0.001). A total of 74 patients (71.8%) had a CSHQ score above the clinically significant cutoff before treatment, which decreased to 40 patients (38.8%) six months after GFD (p < 0.001). A significant improvement was detected in all CSHQ subscale scores and in the total CSHQ score after starting the GFD (p < 0.001). Parasomnia and the total CSHQ score were higher in children who were diagnosed incidentally compared to symptomatic children but did not differ after GFD (p < 0.005). In 39 patients (37.8%), the total CSHQ score remained high 6 months after starting the GFD. Maternal and paternal ages were significantly higher in children whose scores remained high (p < 0.05). Conclusion A significant improvement in sleep scores was detected after starting a GFD, regardless of initial age, sex, and symptom status. With a GFD, children may fall asleep more easily and sleep for longer with less interruptions. GFD may help to reduce sleep disturbances in CD, but future studies should investigate the certain conditions in patients who do not respond to a GFD.

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