Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis.

Background & Aims: PEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis. Methods: PEDFIC 2 enrolled and dosed 69 patients across two cohorts; all received odevixibat 120 µg/kg per day. Cohort 1 comprised children from PEDFIC 1, and cohort 2 comprised new patients (any age). We report data through 15 July 2020, with Week 24 of PEDFIC 2 the main time point analysed. This represents up to 48 weeks of cumulative exposure for patients treated with odevixibat from the 24-week PEDFIC 1 study (cohort 1A) and up to 24 weeks of treatment for those who initiated odevixibat in PEDFIC 2 (patients who received placebo in PEDFIC 1 [cohort 1B] or cohort 2 patients). Primary endpoints for this prespecified interim analysis were change from baseline to Weeks 22-24 in serum bile acids (sBAs) and proportion of positive pruritus assessments (≥1-point drop from PEDFIC 2 baseline in pruritus on a 0-4 scale or score ≤1) over the 24-week period. Safety monitoring included evaluating treatment-emergent adverse events (TEAEs). Results: In cohort 1A, mean change from PEDFIC 1 baseline to Weeks 22-24 of PEDFIC 2 in sBAs was -201 µmol/L (p <0.0001). For cohort 1B and cohort 2, mean changes from odevixibat initiation to weeks 22-24 in sBAs were -144 and -104 µmol/L, respectively. The proportion of positive pruritus assessments in the first 24-week period of PEDFIC 2 was 33%, 56%, and 62% in cohorts 1A, 1B, and 2, respectively. Most TEAEs were mild or moderate. No drug-related serious TEAEs occurred. Conclusions: Odevixibat in patients with progressive familial intrahepatic cholestasis was generally well tolerated and associated with sustained reductions in sBAs and pruritus. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT03659916). Impact and Implications: Disrupted bile flow is a hallmark feature of patients with progressive familial intrahepatic cholestasis and can result in build-up of bile constituents in the liver with spill over into the bloodstream; other effects that patients can experience include extremely itchy skin, and because not enough bile reaches the gut, patients can have problems digesting food, which may lead to poor growth. Odevixibat is an orally administered medication that shunts bile acids away from the liver. The current study, called PEDFIC 2, suggested that odevixibat can improve the problematic signs and symptoms of progressive familial intrahepatic cholestasis and was generally safe for patients.

Long-term results of liver transplantation for maple syrup urine disease: A single-center experience in Turkey.

OBJECTIVES: Maple syrup urine disease (MSUD) is an autosomal recessive inherited disorder. Despite the advances in medical nutrition therapies, classical phenotype causes severe neurological disorders and sudden death. It is known that MSUD patients do not experience metabolic attacks despite their free diet after liver transplantation (LT). This study aims to reveal the long-term results, development, mental, motor, intellectual and nutritional status of MSUD patients who underwent LT. METHODS: The data of 12 patients who underwent deceased donor (5 recipients) and living donor liver transplantation (7 recipients) were retrospectively analyzed. The age, genotype, psychometric and mental status, development, BCAA values, type of LT, donor-recipient proximity, complications, and survival were assessed. RESULTS: There were 4 (33%) girls and 8 (67%) boys. The mean current age was 9.33 ± 4.58 years. The mean follow-up time was 3 ± 2.5 years. The repeated measures of leucine and isoleucine values revealed that there were no significant differences from the pre-LT to post-LT 1-year. The protein-restricted nutrition was switched to a free diet when oral intake was opened after LT. None of the recipients experienced metabolic attacks after the living donor or deceased donor LT. The 1-, 3-, and 5-year survival rate of the patients is 83.3%. There was no significant difference in survival between living and deceased donor liver transplantation. CONCLUSIONS: Liver transplantation is a treatment option for MSUD in proper conditions to save the patient life, increase the quality of life, and provide essential amino acids with free diet intake for growth and development.

Intestinal Mucormycosis in a Child With Maple Syrup Urine Disease After Orthotopic Liver Transplant.

Mucormycosis can result in serious morbidity and mortality, especially in transplant recipients. In this case report, we present a 3-year-old female patient with maple syrup urine disease who developed mucormycosis infection after deceased donor split liver transplant. Progressive segmental necrosis of the small intestines and new ischemic areas were observed after repeated abdominal surgeries. Microscopic examination of biopsy material revealed mucormycosis. Early recognition is crucial for treatment, and patients with clinical suspicion can be treated empirically with antifungal medicine. However, diagnostic tests with accurate and fast results are needed and more effective therapeutic methods should be developed for better outcomes.

Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of inherited paediatric liver diseases resulting from mutations in genes that impact bile secretion. We aimed to evaluate the effects of odevixibat, an ileal bile acid transporter inhibitor, versus placebo in children with PFIC. METHODS: Patients eligible for this 24-week, randomised, double-blind, completed, phase 3 study were paediatric outpatients diagnosed with PFIC1 or PFIC2 who had pruritus and elevated serum bile acids at screening. Patients were randomly assigned (1:1:1) using an interactive web-based system to once a day oral placebo, odevixibat 40 µg/kg, or odevixibat 120 µg/kg. Randomisation was done in a block size of six and stratified by PFIC type and patient age; patients, clinicians, and study staff were blinded to treatment allocation. Patients were enrolled at one of 33 global sites. Two primary endpoints were evaluated: proportion of positive pruritus assessments (PPAs; ie, scratching score of ≤1 or ≥1-point decrease as assessed by caregivers using the Albireo observer-reported outcome [ObsRO] PRUCISION instrument) over 24 weeks, and proportion of patients with serum bile acid response (ie, serum bile acids reduced by ≥70% from baseline or concentrations of ≤70 µmol/L) at week 24. Efficacy and safety were analysed in randomly allocated patients who received one or more doses of study drug. This study is registered with ClinicalTrials.gov, NCT03566238. FINDINGS: Between June 21, 2018, and Feb 10, 2020, 62 patients (median age 3·2 [range 0·5-15·9] years) were randomly allocated to placebo (n=20), odevixibat 40 µg/kg per day (n=23), or odevixibat 120 µg/kg per day (n=19). Model-adjusted (least squares) mean proportion of PPAs was significantly higher with odevixibat versus placebo (55% [SE 8] in the combined odevixibat group [58% in the 40 µg/kg per day group and 52% in the 120 µg/kg per day group] vs 30% [SE 9] in the placebo group; model-adjusted mean difference 25·0% [95% CI 8·5-41·5]; p=0·0038). The percentage of patients with serum bile acid response was also significantly higher with odevixibat versus placebo (14 [33%] of 42 patients in the combined odevixibat group [10 in the 40 µg/kg per day group and four in the 120 µg/kg per day group] vs none of 20 in the placebo group; adjusting for stratification factor [PFIC type], the proportion difference was 30·7% [95% CI 12·6-48·8; p=0·0030]). The most common treatment-emergent adverse events (TEAEs) were diarrhoea or frequent bowel movements (13 [31%] of 42 for odevixibat vs two [10%] of 20 for placebo) and fever (12 [29%] of 42 vs five [25%] of 20); serious TEAEs occurred in three (7%) of 42 odevixibat-treated patients and in five (25%) of 20 placebo-treated patients. INTERPRETATION: In children with PFIC, odevixibat effectively reduced pruritus and serum bile acids versus placebo and was generally well tolerated. Odevixibat, administered as once a day oral capsules, is a non-surgical, pharmacological option to interrupt the enterohepatic circulation in patients with PFIC. FUNDING: Albireo Pharma.

Exocrine pancreas functions in children with type 1 diabetes mellitus.

BACKGROUND AND STUDY AIM: We evaluated exocrine pancreas functions using a noninvasive indicator in a case-control study conducted on children and adolescents diagnosed with type 1 diabetes mellitus. PATIENTS AND METHODS: Sixty-seven patients who participated in a summer camp were enrolled in this study. Nineteen healthy children in the same age group were assigned to the control group. Fecal pancreatic elastase was assayed using the enzyme-linked immunosorbent assay technique. Values higher than 200 µg/g were considered an indication of sufficient exocrine pancreatic functioning, values between 100 µg/g and 200 µg/g were considered mild exocrine pancreatic insufficiency, and values below 100 µg/g were considered severe exocrine pancreatic insufficiency. RESULTS: The mean concentration of fecal elastase was 158.38 ± 59.67 µg/g. The patients were assigned to three groups according to these values. Thirteen patients (22%) had sufficient fecal elastase levels, whereas 36 patients (62%) had mildly insufficient levels, and nine patients (16%) had severely insufficient fecal elastase concentrations. The levels of fecal elastase, amylase, lipase, and zinc were significantly different between the patients and controls (p < 0.001). Only the duration of diabetes was significantly different between patients with different severities of exocrine pancreatic insufficiency (p = 0.037). Additionally, the group with severe pancreatic insufficiency had more frequent hypoglycemic attacks. CONCLUSION: Exocrine pancreatic insufficiency may develop in children with diabetes, and hypoglycemia attacks are observed more frequently depending on the severity of pancreatic insufficiency.

Familial Mediterranean Fever Mutation Analysis in Pediatric Patients With Inflammatory Bowel Disease: A Multicenter Study.

BACKGROUND: The aim of the study was to evaluate familial Mediterranean fever (FMF) mutation analysis in pediatric patients with inflammatory bowel disease (IBD). The relation between MEFV mutations and chronic inflammatory diseases has been reported previously. METHODS: Children with IBD (334 ulcerative colitis (UC), 224 Crohn's disease (CD), 39 indeterminate colitis (IC)) were tested for FMF mutations in this multicenter study. The distribution of mutations according to disease type, histopathological findings, and disease activity indexes was determined. RESULTS: A total of 597 children (mean age: 10.8 ± 4.6 years, M/F: 1.05) with IBD were included in the study. In this study, 41.9% of the patients had FMF mutations. E148Q was the most common mutation in UC and CD, and M694V in IC (30.5%, 34.5%, 47.1%, respectively). There was a significant difference in terms of endoscopic and histopathological findings according to mutation types (homozygous/ heterozygous) in patients with UC (P < .05). There was a statistically significant difference between colonoscopy findings in patients with or without mutations (P = .031, P = .045, respectively). The patients with UC who had mutations had lower Pediatric Ulcerative Colitis Activity Index (PUCAI) scores than the patients without mutations (P = .007). CONCLUSION: Although FMF mutations are unrelated to CD patients, but observed in UC patients with low PUCAI scores, it was established that mutations do not have a high impact on inflammatory response and clinical outcome of the disease.

Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease.

Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.

Psychopathology, quality of life, and related factors in pediatric liver transplantation candidates and recipients.

BACKGROUND: Liver transplantation (LT) has been accepted as a standard treatment of pediatric liver diseases that can progress to end-stage liver disease or lead to acute liver failure. However, there is a lack of studies clarifying quality of life (QoL) and the characteristics and the prevalence of common psychiatric disorders in children before and/or after LT. Thus, this study aimed to investigate QoL and the prevalence of anxiety, depression, and post-traumatic stress disorder (PTSD) in children and adolescents before and after LT and to compare them with healthy controls. METHODS: The study included 30 children aged 5-18 years who were waiting for LT (pTx group) or had undergone LT (Tx group) as the study groups and 20 children for the control group. The PedsQL was used to evaluate QoL, and SCARED, CDI, and the CPTSD-RI were used to evaluate psychopathology. RESULTS: The QoL scores were higher in the control group compared with the study groups in all or most of the dimensions, depending on the reporter. The mean scores of anxiety, depression, and PTSD of the control group were significantly lower than those of the Tx and pTx groups. A significant positive correlation was found between depression, anxiety, and PTSD scores, and a negative correlation was observed between depression, anxiety, and PTSD scores and QoL. CONCLUSION: Waiting for LT and the transplantation process itself seem to be psychologically traumatic for children. Healthcare providers need to be trained to recognize the symptoms of the main psychiatric disorders.

Role of Soluble Adiponectin Receptor 2 in Non-Alcoholic Fatty Liver Disease in Children.

PURPOSE: The incidence of non-alcoholic fatty liver disease (NAFLD) in children is gradually increasing. The aim of this study was to investigate the use of serum adiponectin and soluble adiponectin receptor 2 (soluble Adipo R2) levels for the diagnosis of fatty liver disease in obese and overweight children. METHODS: The study included 51 obese and overweight children between the ages of 6 and 18 years diagnosed with NAFLD using ultrasonography and 20 children without fatty liver disease. Patients whose alanine transaminase level was two times higher than normal (≥80 U/L) were included in the non-alcoholic steatohepatitis (NASH) group. RESULTS: NASH was observed in 11 (21.6%) of the patients with NAFLD. The incidence of obesity was higher in patients with NASH (80% and 45%, p=0.021). While the adiponectin levels were similar in patients with NAFLD and those without, they were below the normal level in the whole study group. Adiponectin and soluble Adipo R2 levels of patients with NASH were lower than those in patients without NASH; however, this difference was not statistically significant (p=0.064 and p=0.463). Soluble Adipo R2 levels in obese patients with NAFLD were higher than those in obese children without NAFLD (p<0.001). CONCLUSION: Soluble adiponectin receptor 2 level is a noninvasive marker that can be used for the diagnosis of NAFLD in obese children.

Liver transplantation from a live donor to a patient with maple syrup urine disease: Two case reports.

Liver transplantation were reported in patients with classic maple syrup urine disease in the literature. Branched chain alpha keto acid dehydrogenase activity can be improved in patients after transplant, and a protein-restricted diet is usually not needed. The first patient was a boy aged 2,5 years who presented with frequent ketosis attacks and epileptic seizures, and the second patient was an 11-month-old boy who also presented with frequent ketosis episodes, both despite adherence to diet therapy. Both patients received liver transplantations from live donors. A low protein diet was no longer required and no decline in cognitive functions was observed in either patient in the follow-up. We wanted to present these cases to show that despite a normal diet, plasma levels of branched- chain amino acids remained normal without any decline in cognitive function after liver transplantation in patients with classic maple syrup urine disease patients.

Gastritis Associated with Initially Pediatric Crohn's Disease and Ulcerative Colitis.

PURPOSE: The aim of this study is to determine the involvement of the upper gastrointestinal system (GIS) in patients diagnosed with Crohn's disease (CD), ulcerative colitis (UC), and non-inflammatory bowel disease (IBD) and to compare their differences. METHODS: This study included patients aged between 2 and 18 years who underwent colonoscopy and esophagogastroduodenoscopy (EGD) for the first time due to the prediagnosis of IBD. In EGD, samples were taken from duodenum, antrum, corpus, and esophagus; and gastritis, duodenitis, and esophagitis were identified through histopathologic examination. The data gathered the ends of the research were compared between IBD with non-IBD groups and between CD-UC with non-IBD groups, and the presence of significant differences between groups were determined. RESULTS: In our study, 16 patients were diagnosed with CD, 13 with UC, 3 with undeterminate colitis, and 13 with non-IBD. In the histopathological examination of the groups, GIS involvement was found in 94.1% of patients diagnosed with IBD and in 38.5% of non-IBD patients. Moreover, the difference was found to be statistically significant (p=0.032). No significant difference was found between the CD and UC groups. Gastritis was mostly observed in 93.8% of CD-diagnosed patients, 76.8% of UC-diagnosed patients, 81.2% of IBD-diagnosed patients, and 38.5% of non-IBD-diagnosed patients. On the other hand, significant differences were found between CD and non-IBD groups (p=0.03), UC and non-IBD groups (p=0.047), and IBD and non-IBD groups (p=0.03). CONCLUSION: The results of the study show that gastritis was highly observed in UC- and CD-diagnosed patients than in non-IBD-diagnosed patients.

Investigation of Efficacy of Lidocaine Spray for Sedated Esophagogastroduodenoscopy in Children.

PURPOSE: Our aim in this study is to investigate efficacy of topical lidocaine spray for sedated esophagogastroduodenoscopy (EGD) in children. METHODS: The endoscopy of children aged between 3-18 years who underwent EGD in our endoscopy unit. Intravenous (IV) midazolam and ketamine were used for sedation. Prior to sedation, endoscopy nurse applied topical lidocaine 10% with pump spray at 1 mg/kg dose in group 1, and distilled water via identically scaled pump spray in group 2, in a double blinded fashion. RESULTS: Sedation was not applied in 24.1% of the cases in topical lidocaine spray group (LS group) and in 5.7% of the cases in distilled water spray group (DS group). Gag reflex was observed in 6.5% of cases in LS group and 33.3% of cases in DS group (p=0.024), increased oral secretion was observed in 9.3% of cases in LS group and 51.7% of cases in DS group (p=0.038), sore throat was observed in 3.7% of cases in LS group and 35.6% of cases in DS group (p=0.019) and the difference was statistically significant. CONCLUSION: The study showed that topical pharyngeal lidocaine reduces both requirement and amount of IV sedation before EGD in children and sore throat, gag reflex and decreased oral secretion increase.

Investigation of the efficacy of synbiotics in the treatment of functional constipation in children: a randomized double-blind placebo-controlled study.

BACKGROUND/AIMS: The aim of this study was to demonstrate the efficacy of synbiotic (Lactobacillus casei, L. rhamnosus, L. plantarum, and Bifidobacterium lactis and prebiotics [fiber, polydextrose, fructo-oligosaccharides, and galacto-oligosaccharides]) treatment in children with functional constipation. MATERIALS AND METHODS: This study was performed in patients aged 4-18 years, and the patients were diagnosed to have functional constipation according to the Roma III diagnostic criteria. In this prospective study, the first group received synbiotic and the second group received a placebo. At the end of 4 weeks, patients were questioned about the initial symptoms. Patients who showed improvement in the initial symptoms at the end of the 4-week treatment period were considered to completely benefit from the treatment and those with some improvement in initial symptom were considered to partially benefit from the treatment. RESULTS: The synbiotic and placebo groups comprised 72 and 74 patients, respectively. The mean age in the whole study group was 9.18±3.48 years with a male:female ratio of 1:21. After 4 weeks of treatment, significant improvement was not observed in any of the findings in the placebo group. Conversely, a significant improvement was observed in the weekly number of defecations, abdominal pain, painful defecation, and pediatric Bristol scale (p≤0.001) in the synbiotic group. Complete benefit from the treatment was achieved in 48 (66.7%) and 21 (28.3%) patients in the synbiotic and placebo groups, respectively, and a significant difference was observed between the groups (p≤0.001). CONCLUSION: Our studies have shown that the use of synbiotics in the treatment of functional constipation in children is beneficial.

Efficacy and safety of midazolam and ketamine in paediatric upper endoscopy.

BACKGROUND AND STUDY AIM: Upper endoscopy can be successfully carried out in children under deep sedation and anaesthesia. However, the best method of upper endoscopy for children who require gastrointestinal intervention has yet to be defined. The aim of this study is to investigate the efficacy and safety of the sedation induced by intravenous midazolam and ketamine during upper endoscopy in children. PATIENTS AND METHODS: This study included patients ages 3-18years who had undergone upper endoscopy. All subjects received IV midazolam and ketamine. During the intervention, hypoxia, tachycardia, bradycardia, hypertension, and hypotension were recorded. After the intervention, euphoria, dysphoria, vertigo, visual problems (such as diplopia and nystagmus), and emergencies (such as arrhythmia, convulsion, and hallucination), among other findings, were recorded. Older children who were capable of expressing themselves were questioned to help determine these conditions. RESULTS: The mean age of the study group was was 11.9±3.42years; 54% of the patients were females, and 46% were males. During the upper endoscopy, hypoxia occurred in 9% of patients, mild hypertension in 14%, hypotension in 5%, tachycardia in 23%, bradycardia in 8%, and flushing-urticaria in 2%. After the upper endoscopy, one of the most common complications was sore throat, which occurred in 24% of patients. Vomiting was observed in 14% of patients, dizziness in 24%, diplopia in 27%, euphoria in 3% (5 patients), dysphoria in 4%, and hallucination in 4%. Of the total patients, 4% required oxygen supply with a face mask. CONCLUSION: The results of our study showed that the use of IV midazolam and ketamine during upper endoscopy in children was safe and effective.

The incidence of HLA-DQ2/DQ8 in Turkish children with celiac disease and a comparison of the geographical distribution of HLA-DQ.

INTRODUCTION: Celiac disease (CD) is an auto-immune enteropathy that occurs in genetically pre-disposed people as a result of the consumption of gluten-containing foods. AIM: To identify the incidence of HLA-DQ2 and HLA-DQ8 observed in children with CD. MATERIAL AND METHODS: In this study, we focused on children ranging in age from 2 to 18 years and diagnosed with celiac disease. In our patients diagnosed with CD, in addition to tissue transglutaminase antibodies (anti-tTG), we also evaluated HLA-DQ2 B1 and HLA-DQ8 B1 alleles using the method of polymerase chain reaction (PCR)/sequence-specific oligonucleotide probes (Luminex®). The detection of 0201/0202 for HLA-DQ2 allele and 0302 for HLA-DQ8 allele was accepted as a positive result. RESULTS: The mean age of our patients with celiac disease was 7.42 ±3.18 years, and the female/male ratio was 1.5/1. Seventy-six percent of our patients were HLA-DQ2 and/or HLA-DQ8 positive, 67% were HLA-DQ2 positive, and 25% were HLA-DQ8 positive. Nevertheless, 24% of them were HLA-DQ2 and HLA-DQ8 negative. The incidence of HLA-DQ2 in the control group was 18.8% with a significant difference compared to the HLA-DQ2 incidence in the patient group (67%) (p < 0.05). Similarly the HLA-DQ8 incidence in the control group (5.7%) was significantly lower than the incidence in the patient group (25%) (p < 0.05). CONCLUSIONS: The incidence of the patients diagnosed with CD, who are HLA-DQ2 and HLA-DQ8 negative, varies among different populations.

Efficacy of synbiotic, probiotic, and prebiotic treatments for irritable bowel syndrome in children: A randomized controlled trial.

BACKGROUND/AIMS: Irritable bowel syndrome (IBS) is an important health problem that presents serious social burdens and high costs. Our study investigated the efficacy of synbiotic (Bifidobacterium lactis B94 with inulin), probiotic (B. lactis B94), and prebiotic (inulin) treatment for IBS in a pediatric age group. MATERIAL AND METHODS: This study was randomized, double-blind, controlled, and prospective in design and included 71 children between the ages of 4 and 16 years who were diagnosed with IBS according to the Rome III criteria. The first group received synbiotic treatment [5×109 colony forming units (CFU) of B. lactis B94 and 900 mg inulin]; the second group received probiotic treatment (5×109 CFU B. lactis B94), and the third group received prebiotic treatment (900 mg inulin) twice daily for 4 weeks. RESULTS: Probiotic treatment improved belching-abdominal fullness (p<0.001), bloating after meals (p=0.016), and constipation (p=0.031), and synbiotic treatment improved belching-abdominal fullness (p=<0.001), bloating after meals (p=0.004), constipation (p=0.021), and mucus in the feces (p=0.021). The synbiotic group had a significantly higher percentage of patients with full recovery than the prebiotic group (39.1% vs. 12.5%, p=0.036). CONCLUSION: Administration of synbiotics and probiotics resulted in significant improvements in initial complaints when compared to prebiotics. Additionally, there was a significantly higher number of patients with full recovery from IBS symptoms in the synbiotic group than in the prebiotic group. Therefore, the twice daily administration of synbiotics is suggested for the treatment of children with IBS.