Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency.

BACKGROUND AND AIMS: Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date. APPROACH AND RESULTS: This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication), FIC1-A (n = 67; no PPTMs), FIC1-B (n = 29; one PPTM), or FIC1-C (n = 34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs < 194 µmol/L: 49% vs. sBAs ≥ 194 µmol/L: 15%; P = 0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] µmol/L; P = 0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65 µmol/L (P = 0.05) tended to be associated with improved NLS. CONCLUSIONS: Less than half of patients with FIC1 deficiency reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.

Genotype correlates with the natural history of severe bile salt export pump deficiency.

BACKGROUND & AIMS: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date. METHODS: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category. RESULTS: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27-0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 µmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001). CONCLUSIONS: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS. LAY SUMMARY: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease.

Unique presentation of neonatal liver failure: A case report.

BACKGROUND: Acute fulminant liver failure rarely occurs in the neonatal period. The etiologies include viral infection (15%), metabolic/genetic disease (10%), hematologic disorders (15%), and ischemic injury (5%). Gestational alloimmune liver disease usually manifests as severe neonatal liver failure, with extensive hepatic and extrahepatic iron overload, sparing the reticuloendothelial system. Empty liver failure is a rare cause of liver failure where a patient presents with liver failure in the neonatal period with no hepatocytes in liver biopsy. CASE SUMMARY: A 5-week-old male presented with jaundice. Physical examination revealed an alert but deeply icteric infant. Laboratory data demonstrated direct hyperbilirubinemia, a severely deranged coagulation profile, normal transaminase, and normal ammonia. Magnetic resonance imaging of the abdomen was suggestive of perinatal hemochromatosis. Liver biopsy showed histiocytic infiltration with an absence of hepatocytes. No hemosiderin deposition was identified in a buccal mucosa biopsy. CONCLUSION: Neonatal liver failure in the absence of hepatocellular regeneration potentially reflects an acquired or inborn defect in the regulation of hepatic regeneration.

Expert Recommendations on the Diagnosis of Eosinophilic Esophagitis in the United Arab Emirates.

Eosinophilic esophagitis (EoE) is a chronic, progressive, type 2 inflammatory esophageal disease presenting as dysphagia to solid food and non-obstructive food impaction. Knowledge gaps exist in its diagnosis and management. These expert recommendations focused on the diagnosis of EoE in the United Arab Emirates. An electronic search of PubMed and Embase databases was used to gather evidence from systematic reviews, randomized controlled trials, consensus papers, and expert opinions from the last five years on the diagnosis of EoE. The evidence was graded using the Oxford system. Literature search findings were shared with the expert panel. A 5-point scale (strongly agree, agree, neither agree nor disagree, disagree, and strongly disagree) was used, and a concordance rate of >75% among experts indicated agreement. Using a modified Delphi technique, 18 qualified experts provided 17 recommendations. Eleven statements achieved high agreement, four got moderate agreement, and two got low agreement. Challenges exist in diagnosing EoE, particularly in children. Esophageal biopsies were crucial in diagnosis, irrespective of visible mucosal changes. Further research on diagnostic tools like endoscopic mucosal impedance and biomarkers is needed. Diagnosis relies on esophageal biopsies and symptom-histology correlation; however, tools like EoE assessment questionnaires and endoscopic mucosal impedance could enhance the accuracy and efficiency of EoE diagnosis. The diagnosis of EoE is challenging since the symptoms seldom correlate with the histological findings. Currently, diagnosis is based on patient symptoms and endoscopic and histological findings. Further research into mucosal impedance tests and the role of biomarkers is needed to facilitate diagnosis.

An international multidisciplinary consensus on pediatric metabolic dysfunction-associated fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in children and adolescents, particularly those with obesity. NAFLD is considered a hepatic manifestation of the metabolic syndrome due to its close associations with abdominal obesity, insulin resistance, and atherogenic dyslipidemia. Experts have proposed an alternative terminology, metabolic dysfunction-associated fatty liver disease (MAFLD), to better reflect its pathophysiology. This study aimed to develop consensus statements and recommendations for pediatric MAFLD through collaboration among international experts. METHODS: A group of 65 experts from 35 countries and six continents, including pediatricians, hepatologists, and endocrinologists, participated in a consensus development process. The process encompassed various aspects of pediatric MAFLD, including epidemiology, mechanisms, screening, and management. FINDINGS: In round 1, we received 65 surveys from 35 countries and analyzed these results, which informed us that 73.3% of respondents agreed with 20 draft statements while 23.8% agreed somewhat. The mean percentage of agreement or somewhat agreement increased to 80.85% and 15.75%, respectively, in round 2. The final statements covered a wide range of topics related to epidemiology, pathophysiology, and strategies for screening and managing pediatric MAFLD. CONCLUSIONS: The consensus statements and recommendations developed by an international expert panel serve to optimize clinical outcomes and improve the quality of life for children and adolescents with MAFLD. These findings emphasize the need for standardized approaches in diagnosing and treating pediatric MAFLD. FUNDING: This work was funded by the National Natural Science Foundation of China (82070588, 82370577), the National Key R&D Program of China (2023YFA1800801), National High Level Hospital Clinical Research Funding (2022-PUMCH-C-014), the Wuxi Taihu Talent Plan (DJTD202106), and the Medical Key Discipline Program of Wuxi Health Commission (ZDXK2021007).

Advances and challenges of gastrostomy insertion in children.

When oral feeding cannot provide adequate nutritional support to children, enteral tube feeding becomes a necessity. The overall aim is to ultimately promote appropriate growth, improve the patient's quality of life and increase carer satisfaction. Nasogastric tube feeding is considered appropriate on a short-term basis. Alternatively, gastrostomy feeding offers a more convenient and safer feeding option especially as it does not require frequent replacements, and carries a lower risk of complications. Gastrostomy tube feeding should be considered when nasogastric tube feeding is required for more than 2-3 wk as per the ESPEN guidelines on artificial enteral nutrition. Several techniques can be used to insert gastrostomies in children including endoscopic, image guided and surgical gastrostomy insertion whether open or laparoscopic. Each technique has its own advantages and disadvantages. The timing of gastrostomy insertion, device choice and method of insertion is dependent on the local expertise, patient requirements and family preference, and should be individualized with a multidisciplinary team approach. We aim to review gastrostomy insertion in children including indications, contraindications, history of gastrostomy, insertion techniques and complications.

COVID-19-induced liver injury in infants, children, and adolescents.

Coronavirus disease 2019 (COVID-19) typically presents with fever and respiratory symptoms in children. Most children develop an asymptomatic and mild illness, with a minority requiring specialist medical care. Gastrointestinal manifestations and liver injury can also occur in children following infection. The mechanisms of liver injury may include infection following direct viral hepatic tissue invasion, immune response, or medication effects. Affected children might develop mild liver dysfunction which has a benign course in most children with no pre-existing liver disease. However, the presence of non-alcoholic fatty liver disease or other pre-existing chronic liver disorders is associated with a higher risk of developing severe COVID-19 illness with poor outcomes. On the other hand, the presence of liver manifestations is associated with the severity of COVID-19 disease and is considered an independent prognostic factor. Respiratory, hemodynamic, and nutritional supportive therapies are the mainstay of management. Vaccination of children at increased risk of developing severe COVID-19 disease is indicated. This review describes the liver manifestations in children with COVID-19, detailing its epidemiology, basic mechanisms, clinical expression, management, and prognosis in those with and without pre-existing liver disease and also children who have had earlier liver transplantation.

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency.

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.

Gastrointestinal manifestations in children with COVID-19 infection: Retrospective tertiary center experience.

Objective: The majority of pediatric severe acute respiratory syndrome coronavirus 2 (COVID-19) cases demonstrate asymptomatic, mild or moderate disease. The main symptoms in children with COVID-19 are respiratory symptoms but some patients develop gastrointestinal symptoms and liver injury. We aim to review gastrointestinal symptoms and liver injury in children with confirmed COVID-19 infection. Method: This is a retrospective case note review of children with positive COVID-19 nasal Polymerase Chain Reaction aged 0-18 years admitted to a tertiary pediatric hospital from March 1st till June 1st 2020. Results: 180 children were identified. Mean age was 5 years (Range: 0.01-17), the majority of patients were school aged (30%). Patients were mainly from East Asia 81 (45%) and Arabs 67 (37%). Gastrointestinal symptoms were encountered in 48 (27%) patients and 8 (4%) patients had only Gastrointestinal symptoms with no associated fever or respiratory symptoms. Liver injury was seen in 57 (32%) patients. Patients with fever and cough were more likely to have gastrointestinal symptoms (P = <0.001 and 0.004 respectively). Fever was more likely to be associated with liver injury (P = 0.021). Children with abdominal pain were more likely to have elevated C-Reactive Protein (P = 0.037). Patients with diarrhea and vomiting were more likely to have elevated procalcitonin (P = 0.034 and 0.002 respectively). Children with Gastrointestinal symptoms were not more likely to be admitted to Pediatric Intensive Care Unit (P = 0.57). Conclusion: COVID-19 infection in children can display gastrointestinal symptoms at initial presentation. Additionally, gastrointestinal symptoms can be the only symptoms patients display. We demonstrated that children with gastrointestinal symptoms and liver injury can develop more severe COVID-19 disease and are more likely to have fever, cough, and raised inflammatory markers. Identifying children with gastrointestinal manifestations needs to be part of the initial screening assessment of children.What is known?• Pediatric COVID-19 cases mostly demonstrate asymptomatic, mild or moderate disease.• The symptoms in children are mainly respiratory but some display gastrointestinal symptoms.• Children with COVID-19 display increased gastrointestinal symptoms when compared to adults.What is new?• Children with COVID-19 displaying gastrointestinal symptoms are more likely to have fever, cough and elevated inflammatory markers.• Children with liver injury are more likely to develop fever.• Children with gastrointestinal involvement in COVID-19 are more likely to demonstrate more severe disease but are not more likely to be admitted to PICU.

Is endoscopy beneficial in pediatric laparoscopic gastrostomy insertion; A 9-year comparative study.

Objectives: Advancements in pediatric percutaneous endoscopic gastrostomy placement (PEG), laparoscopic-assisted gastrostomy (LAG) technique, and laparoscopic-assisted percutaneous endoscopic gastrostomy (LAPEG) procedure have opened up new options for gastrostomy tube placement. LAPEG utilizes endoscopy and laparoscopy for gastrostomy insertion. This review compares the outcomes and complications of LAG and LAPEG techniques in children. Methods: All LAG and LAPEG gastrostomy tube placements in children from September 2010 to September 2019 were reviewed retrospectively. Patient demographic, along with procedural and 1-year complication data, were collected. Results: In total, 92/181 of gastrostomies were LAG and 89/181 were LAPEG. The mean age, weight and patient characteristics were comparable. Conversion rate was 1% in both groups (p = 0.74), there was no peritoneal leak in either group, a minor serosal injury to the stomach was seen in 1 patient in LAG with no bowel injury in LAPEG cohort (p = 0.51), need for re-operation was 1 and 2% in LAG and LAPEG, respectively (p = 0.49), early tube dislodgement was in 8 (9%) patients in LAG and 7 (6%) in LAPEG (p = 0.53) and wound infection was 13/92 in LAG and 11/89 in LAPEG (p = 0.8). The median operative time for LAPEG was less than LAG (p < 0.001) by 11 min but the median length of hospital stay was not significantly different (p < 0.096). Conclusion: Both LAG and LAPEG techniques in children are safe with comparable complication rates and length of hospital stay, the addition of endoscopy to LAG allowed for shorter operative time in the LAPEG technique.

Clinical manifestations and outcome in children with COVID-19 infection in Abu Dhabi: a retrospective single-centre study.

We conducted a retrospective cohort review of 180 patients aged 0-18 years with positive COVID-19 nasal PCR swab admitted to the only designated paediatric COVID-19 hospital in Abu Dhabi from 1 March to 1 June 2020. 60 (33%) patients were asymptomatic, 117 (65%) patients had mild or moderate symptoms and 3 patients required intensive care with no mortality reported. Symptoms at presentation were fever in 84 patients, cough in 62 patients and gastrointestinal symptoms in 48 patients.

Prebiotics in the Infant Microbiome: The Past, Present, and Future.

The latest definition of a prebiotic is "a substrate that is selectively utilized by host microorganisms conferring a health benefit"; it now includes non-food elements and is applicable to extra-intestinal tissues. Prebiotics are recognized as a promising tool in the promotion of general health and in the prevention and treatment of numerous juvenile diseases. Prebiotics are considered an immunoactive agent, with the potential for long-lasting effects extending past active administration of the prebiotic. Because of its extremely low risk of serious adverse effects, ease of administration, and strong potential for influencing the composition and function of the microbiota in the gut and beyond, the beneficial clinical applications of prebiotics are expanding. Prebiotics are the third largest component of human breast milk. Preparations including galactooligosaccharides (GOS), fructooligosaccharides (FOS), 2'-fucosyllactose, lacto-N-neo-tetraose are examples of commonly used and studied products for supplementation in baby formula. In particular, the GOS/FOS combination is the most studied. Maintaining a healthy microbiome is essential to promote homeostasis of the gut and other organs. With more than 1,000 different microbial species in the gut, it is likely more feasible to modify the gut microbiota through the use of certain prebiotic mixtures rather than supplementing with a particular probiotic strain. In this review, we discuss the latest clinical evidence regarding prebiotics and its role in gut immunity, allergy, infections, inflammation, and functional gastrointestinal disorders.

Evaluation of Outcomes in Adolescent Inflammatory Bowel Disease Patients Following Transfer From Pediatric to Adult Health Care Services: Case for Transition.

PURPOSE: We aimed to evaluate the impact of a transition service on clinical and developmental outcomes in adolescent Inflammatory Bowel Disease (IBD) patients on transfer to adult health care services. METHODS: We reviewed the records of IBD patients diagnosed in pediatric care following their transfer/attendance to the adult IBD service. The data on patients who attended the transition service were compared with those who did not pass through the transition service. RESULTS: Seventy-two patients were included in the study 41M and 31F. Forty-four patients went through the transition system (Group A), and 28 had no formalized transition arrangement before transfer (Group B). A significantly higher number of Group B patients needed surgery within 2 years of transfer when compared with patients in Group A (46% vs. 25%, p = .01). Sixty-one percent of patients in Group B needed at least one admission within 2 years of transfer when compared with 29% of Group A patients (p = .002). Nonattendance at clinics was higher in Group B patients with 78% having at least one nonattendance, whereas 29% of Group A failed to attend at least one appointment (p = .001). In addition, drug compliance rates were higher in the transition group when compared with Group B (89% and 46%, respectively; p = .002). A higher proportion of transitioned patients achieved their estimated maximum growth potential when completing adolescence. There was a trend toward higher dependence on opiates and smoking in Group B patients. CONCLUSIONS: In adolescent IBD patients, transition care is associated with better disease specific and developmental outcomes. Prospective studies of different models of transition care in IBD are needed.

A pilot open case series of ethyl-EPA supplementation in the treatment of anorexia nervosa.

Anorexia nervosa (AN) carries the highest risk of morbidity and mortality amongst psychiatric disorders. The efficacy of current treatment approaches is limited. Despite the fat-phobic nature of the disease, poly-unsaturated fatty acids (PUFAs) have not received much research attention. Patients who consume western diet, which is rich in n-6 PUFAs and trans-fatty acids, are likely to develop severe n-3 PUFA deficiency during self-induced starvation. Re-feeding programmes do not take into consideration n-3 EFA intake, possibly leading to further n-3 PUFA deficiency during weight restoration, and this might contribute to the maintenance of the disorder. To test this hypothesis, we carried out a systematic case series of E-EPA supplementation in the treatment of AN. Seven young patients received 1g/day E-EPA in addition to standard treatment, and were followed up for 3 months. Three of them recovered and four improved. Randomised controlled trials are warranted to examine the effectiveness of E-EPA in AN further.

Sigmoid volvulus in an adolescent girl: staged management with emergency colonoscopic reduction and decompression followed by elective sigmoid colectomy.

A case of acute sigmoid volvulus in a 14-year-old adolescent girl presenting with acute low large bowel obstruction with a background of chronic constipation has been presented. Abdominal radiograph and CT scan helped in diagnosis. She underwent emergency colonoscopic detorsion and decompression uneventfully. Lower gastrointestinal contrast study showed very redundant sigmoid colonic loop without any transition zone and she subsequently underwent elective sigmoid colectomy with good outcome. The sigmoid volvulus should be considered in the differential diagnosis of paediatric acute abdomen presenting with marked abdominal distention, absolute constipation and pain but without vomiting. Plain abdominal radiograph and the CT scan are helpful to confirm the diagnosis. Early colonoscopic detorsion and decompression allows direct visualisation of the vascular compromise, assessment of band width of the volvulus and can reduce complications and mortality. Associated Hirschsprung's disease should be suspected if clinical and radiological features are suggestive in which case a rectal biopsy before definitive surgery should be considered.

Fulminant pertussis: a multi-center study with new insights into the clinico-pathological mechanisms.

Pertussis carries a high risk of mortality in very young infants. The mechanism of refractory cardio-respiratory failure is complex and not clearly delineated. We aimed to examine the clinico-pathological features and suggest how they may be related to outcome, by multi-center review of clinical records and post-mortem findings of 10 patients with fulminant pertussis (FP). All cases were less than 8 weeks of age, and required ventilation for worsening respiratory symptoms and inotropic support for severe hemodynamic compromise. All died or underwent extra corporeal membrane oxygenation (ECMO) within 1 week. All had increased leukocyte counts (from 54 to 132 x 10(9)/L) with prominent neutrophilia in 9/10. The post-mortem demonstrated necrotizing bronchitis and bronchiolitis with extensive areas of necrosis of the alveolar epithelium. Hyaline membranes were present in those cases with viral co-infection. Pulmonary blood vessels were filled with leukocytes without well-organized thrombi. Immunodepletion of the thymus, spleen, and lymph nodes was a common feature. Other organisms were isolated as follows; 2/10 cases Para influenza type 3, 2/10 Moraxella catarrhalis, 1/10 each with respiratory syncytial virus (RSV), a coliform organism, methicillin-resistant Staphylococcus aureus (MRSA), Haemophilus influenzae, Stenotrophomonas maltophilia, methicillin-sensitive Staphylococcus aureus (MSSA), and candida tropicalis. We postulate that severe hypoxemia and intractable cardiac failure may be due to the effects of pertussis toxin, necrotizing bronchiolitis, extensive damage to the alveolar epithelium, tenacious airway secretions, and possibly leukostasis with activation of the immunological cascade, all contributing to increased pulmonary vascular resistance. Cellular apoptosis appeared to underlay much of these changes. The secondary immuno-compromise may facilitate co-infection.