Biliary strictures post pediatric liver transplantation-incidence and risk factors in a single tertiary referral transplant center.

BACKGROUND: Biliary strictures are a significant cause of morbidity and graft loss in pediatric liver transplant recipients. Risk factors for the development of biliary strictures are not fully established. We aimed to evaluate the incidence of biliary strictures and treatment modalities outcomes and to identify potential risk factors for occurrence. METHODS: Pediatric patients who underwent liver transplantation in the single tertiary pediatric liver transplant center in Israel were evaluated. We compared demographics, presentation, laboratory results, imaging, treatment, and outcomes between patients with and without biliary stricture. Multivariate regression analyses were used to identify risk factors for biliary strictures. RESULTS: Among 121 pediatric liver transplant patients, 65 (53.7%) were males; the median age at the time of liver transplantation was 43 (3-215) months. Fifteen patients (12.4%) had biliary strictures following transplantation. One (7%) patient with biliary stricture was treated via endoscopic retrograde cholangiopancreatography, and 12 patients (80%) underwent interventions via a percutaneous transhepatic approach. Nine of the 12 patients were treated successfully, requiring one or multiple procedures, while the remaining had surgery or laser therapy. Risk factors for the development of biliary strictures were biliary leak, acute cellular rejection, and the presence of two biliary anastomoses. CONCLUSIONS: In our cohort, the presence of two biliary anastomoses and post-transplant complications including acute cellular rejection and early biliary leaks were associated with biliary strictures in pediatric liver transplantation recipients. Percutaneous transhepatic interventions result in good outcomes in most patients.

A significant increase in anthropometric indices during long-term follow-up of pediatric patients with celiac disease, with no endocrine disorders.

Celiac disease (CeD) is likely to be associated with growth impairment and poor weight gain. However, long-term growth patterns following diagnosis are poorly characterized. We evaluated long-term anthropometric changes in a large cohort of pediatric patients with CeD. A retrospective chart review of patients diagnosed with CeD between 1999 and 2018 was conducted. Demographic and clinical data were collected, and anthropometrics were analyzed from diagnosis and throughout follow-up. The study included 500 patients (59.8% females, median (IQR) age at diagnosis 5.7 (3.7-8.9) years), with a mean follow-up of 5.5 (range 1.5-16.2) years. Weight, height, and BMI Z-score-for-age (WAZ, HAZ, and BMIZ) increased significantly from a mean (± SD) of - 0.82 (± 1.21), - 0.73 (± 1.16), and - 0.32 (± 1.11) at diagnosis to - 0.41 (± 1.23), - 0.45(± 1.16), and - 0.17 (± 1.14) at last follow-up, respectively (p < 0.001 for WAZ and HAZ and p = 0.002 for BMIZ). The largest improvements were observed in patients diagnosed before 3 years of age (p < 0.01). Patients for whom the final adult height was available (n = 86) improved from HAZ mean (± SD) - 0.89 ± 1.37 at diagnosis to - 0.51 ± 1.28 at adulthood measurement, p < 0.05. Wasting was present in 19.7% and stunting in 16.4% of the cohort at diagnosis and normalized in 77.3% and 64.8%, respectively, within a median (IQR) time of 0.79 (0.42-4.24) and 2.3 (0.72-6.02) years, respectively. Gluten-free diet adherence and frequency of visits were not associated with normalization of wasting or stunting in all age groups.  Conclusion: Over a long-term follow-up, pediatric patients with CeD demonstrate significant increases in weight, height, and BMI-for-age. Younger age at diagnosis is associated with greater improvement in weight and linear growth, emphasizing the importance of early diagnosis of CeD. What is Known: • Celiac disease (СeD) is likely to be associated with growth impairment and poor weight gain. • Long-term changes in anthropometric indices after diagnosis of CeD are not well characterized. What is New: • Over a long-term follow-up, pediatric patients with CeD demonstrate significant increases in weight, height, and BMI-for-age. • Young age at diagnosis is associated with larger improvement in weight and linear growth.

Clinical profile of re-hospitalizations in pediatric kidney and liver transplant recipients.

BACKGROUND: Solid organ transplantation has evolved in recent decades, resulting in a rise in patient and graft survival. Frequent hospitalizations affect graft function, patients' health, and quality of life. This study characterizes the frequency and causes of post-transplant hospitalizations among pediatric recipients. METHODS: This is a retrospective observational study evaluating pediatric kidney transplant recipients (KTR) and liver transplant recipients (LTR) aged 0-21 years, followed at a tertiary pediatric center in Israel from 2012 to 2017. Data were collected starting at 60 days post-transplantation. Diagnoses of admissions were based on clinical, laboratory, and radiographic findings. RESULTS: Forty-nine KTR experienced 199 all-cause re-hospitalizations (median number of re-hospitalizations per patient - 3 (IQR [interquartile range] 1-5.5), while 351 re-hospitalizations were recorded in 56 LTR (median - 5 [IQR 2-8.8]). Median follow-up time was 2.2 years for KTR (IQR 1-3.9) and 3 years for LTR (IQR 2.1-4.1). The most common cause for hospitalization for both cohorts was infection (50.8% and 62%, respectively). Gram-negative bacteria were the most common pathogens identified in KTR, while viral pathogens were more common in LTR (51% and 57% of pathogen-identified cases, respectively). CONCLUSIONS: This is the largest study to describe rehospitalizations for pediatric solid organ recipients. The hospital admission rate was higher in LTR in comparison to KTR. Infections were the most common cause of hospitalization throughout the whole study period in both populations. Frequent hospitalizations impose a heavy burden on patients and their families; better understanding of hospitalization causes may help to minimize their frequency.

Cell-based BSEP trans-inhibition: A novel, non-invasive test for diagnosis of antibody-induced BSEP deficiency.

Background & Aims: Antibody-induced bile salt export pump deficiency (AIBD) is an acquired form of intrahepatic cholestasis, which may develop following orthotopic liver transplantation (OLT) for progressive familial intrahepatic cholestasis type 2 (PFIC-2). Approximately 8-33% of patients with PFIC-2 who underwent a transplant develop bile salt export pump (BSEP) antibodies, which trans-inhibit this bile salt transporter from the extracellular, biliary side. AIBD is diagnosed by demonstration of BSEP-reactive and BSEP-inhibitory antibodies in patient serum. We developed a cell-based test directly measuring BSEP trans-inhibition by antibodies in serum samples to confirm AIBD diagnosis. Methods: Sera from healthy controls and cholestatic non-AIBD or AIBD cases were tested (1) for anticanalicular reactivity by immunofluorescence staining of human liver cryosections, (2) for anti-BSEP reactivity by immunofluorescence staining of human embryonic kidney 293 (HEK293) cells expressing BSEP-enhanced yellow fluorescent protein (EYFP) and immunodetection of BSEP-EYFP on Western blot, and (3) for BSEP trans-inhibition using HEK293 cells stably expressing Na+/taurocholate cotransporting polypeptide (NTCP)-mCherry and BSEP-EYFP. The trans-inhibition test uses [3H]-taurocholate as substrate and is divided into an uptake phase dominated by NTCP followed by BSEP-mediated export. For functional analysis, sera were bile salt depleted. Results: We found BSEP trans-inhibition by seven sera containing anti-BSEP antibodies, but not by five cholestatic or nine control sera, all lacking BSEP reactivity. Prospective screening of a patient with PFIC-2 post OLT showed seroconversion to AIBD, and the novel test method allowed monitoring of treatment response. Notably, we identified a patient with PFIC-2 post OLT with anti-BSEP antibodies yet without BSEP trans-inhibition activity, in line with asymptomatic presentation at serum sampling. Conclusions: Our cell-based assay is the first direct functional test for AIBD and allows confirmation of diagnosis as well as monitoring under therapy. We propose an updated workflow for AIBD diagnosis including this functional assay. Impact and Implications: Antibody-induced BSEP deficiency (AIBD) is a potentially serious complication that may affect patients with PFIC-2 after liver transplantation. To improve its early diagnosis and thus immediate treatment, we developed a novel functional assay to confirm AIBD diagnosis using a patient's serum and propose an updated diagnostic algorithm for AIBD.

Adaptive immune response to BNT162b2 mRNA vaccine in immunocompromised adolescent patients.

Protective immunity against COVID-19 is orchestrated by an intricate network of innate and adaptive anti-viral immune responses. Several vaccines have been rapidly developed to combat the destructive effects of COVID-19, which initiate an immunological cascade that results in the generation of neutralizing antibodies and effector T cells towards the SARS-CoV-2 spike protein. Developing optimal vaccine-induced anti-SARS- CoV-2 protective immunity depends on a fully competent immune response. Some evidence was gathered on the effects of vaccination outcomes in immunocompromised adult individuals. Nonetheless, protective immunity elicited by the Pfizer Biontech BNT162b2 vaccine in immunocompromised adolescents received less attention and was mainly focused on the antibody response and their neutralization potential. The overall immune response, including T-cell activities, was largely understudied. In this study, we characterized the immune response of vaccinated immunocompromised adolescents. We found that immunocompromised adolescents, which may fail to elicit a humoral response and develop antibodies, may still develop cellular T-cell immunity towards SARS-CoV-2 infections. Furthermore, most immunocompromised adolescents due to genetic disorders or drugs (Kidney and liver transplantation) still develop either humoral, cellular or both arms of immunity towards SARS-CoV-2 infections. We also demonstrate that most patients could mount a cellular or humoral response even after six months post 2nd vaccination. The findings that adolescents immunocompromised patients respond to some extent to vaccination are promising. Finally, they question the necessity for additional vaccination boosting regimens for this population who are not at high risk for severe disease, without further testing of their post-vaccination immune status.

Prehospital Tranexamic Acid Administration in Pediatric Trauma Patients: A Propensity-Matched Analysis of the Israeli Defense Forces Registry.

OBJECTIVES: Tranexamic acid (TXA) administration confers a survival benefit in bleeding trauma patients; however, data regarding its use in pediatric patients are limited. This study evaluates the prehospital treatment with TXA in pediatric trauma patients treated by the Israel Defense Forces Medical Corps (IDF-MC). DESIGN: Retrospective, cohort study using the Israel Defense Forces registry, 2011-2021. PATIENTS: Pediatric trauma patients less than 18 years old. We excluded patients pronounced dead at the scene. INTERVENTIONS: None. SETTING: All cases of pediatric trauma in the registry were assessed for treatment with TXA. Propensity score matching was used to assess the association between prehospital TXA administration and mortality. MEASUREMENTS AND MAIN RESULTS: Overall, 911 pediatric trauma patients were treated with TXA by the IDF-MC teams; the median (interquartile) age was 10 years (5-15 yr), and 72.8% were male. Seventy patients (7.6%) received TXA, with 52 of 70 (74%) receiving a 1,000 mg dose (range 200-1,000 mg). There were no prehospital adverse events associated with the use of TXA (upper limit of 95% CI for 0/70 is 4.3%). Compared with pediatric patients who did not receive TXA, patients receiving TXA were more likely to suffer from shock (40% vs 10.7%; p < 0.001), sustain more penetrating injuries (72.9% vs 31.7%; p < 0.001), be treated with plasma or crystalloids (62.9% vs 11.4%; p < 0.001), and undergo more lifesaving interventions (24.3% vs 6.2%; p < 0.001). The propensity score matching failed to identify an association between TXA and lesser odds of mortality, although a lack of effect (or even adverse effect) could not be excluded (non-TXA: 7.1% vs TXA: 4.3%, odds ratio = 0.584; 95% CI 0.084-3.143; p = 0.718). CONCLUSIONS: Although prehospital TXA administration in the pediatric population is feasible with adverse event rate under 5%, more research is needed to determine the appropriate approach to pediatric hemostatic resuscitation and the role of TXA in this population.

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.

Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants.

PURPOSE: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. METHODS: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. RESULTS: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. CONCLUSION: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.

Acute Hepatitis of Unknown Etiology Among Young Children: Research Agenda by the ESPGHAN Hepatology Committee.

In April 2022, an increased incidence of acute hepatitis cases of unknown etiology among previously healthy children across the United Kingdom was described. Since, more than 270 cases from the United Kingdom and hundreds more from all across the world have been reported. The majority of affected children were younger than 6 years of age. The clinical presentation was nonspecific with diarrhea and vomiting usually preceding the appearance of jaundice, abdominal pain, nausea, and malaise. Approximately 5% have required liver transplantation. An infectious etiology has been considered likely given the epidemiological and clinical features of the reported cases. Between 50 and 60% of the children tested were diagnosed with adenovirus infection although a clear etiological connection has still to be demonstrated. No link with SARS-CoV-2 infection and COVID-19 vaccine was found. What is not clear to date is whether the high number of acute hepatitis cases reported is related to a true increase in incidence or heightened awareness following on from the initial reports from the United Kingdom. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) developed a paper on the current outbreak of acute hepatitis of unknown etiology recognizing its importance and the need of approaching the current situation with a scientifically rigorous approach. The aims of the article are to summarize the current knowledge and to identify the most pertinent issues regarding the diagnosis and management of this condition and the research questions raised.

Long COVID-19 Liver Manifestation in Children.

OBJECTIVES: Severe acute respiratory syndrome coronavirus 2, the novel coronavirus responsible for coronavirus disease (COVID-19), has been a major cause of morbidity and mortality worldwide. Gastrointestinal and hepatic manifestations during acute disease have been reported extensively in the literature. Post-COVID-19 cholangiopathy has been increasingly reported in adults. In children, data are sparse. Our aim was to describe pediatric patients who recovered from COVID-19 and later presented with liver injury. METHODS: This is a retrospective case series study of pediatric patients with post-COVID-19 liver manifestations. We collected data on demographics, medical history, clinical presentation, laboratory results, imaging, histology, treatment, and outcome. RESULTS: We report 5 pediatric patients who recovered from COVID-19 and later presented with liver injury. Two types of clinical presentation were distinguishable. Two infants aged 3 and 5 months, previously healthy, presented with acute liver failure that rapidly progressed to liver transplantation. Their liver explant showed massive necrosis with cholangiolar proliferation and lymphocytic infiltrate. Three children, 2 aged 8 years and 1 aged 13 years, presented with hepatitis with cholestasis. Two children had a liver biopsy significant for lymphocytic portal and parenchyma inflammation, along with bile duct proliferations. All 3 were started on steroid treatment; liver enzymes improved, and they were weaned successfully from treatment. For all 5 patients, extensive etiology workup for infectious and metabolic etiologies was negative. CONCLUSIONS: We report 2 distinct patterns of potentially long COVID-19 liver manifestations in children with common clinical, radiological, and histopathological characteristics after a thorough workup excluded other known etiologies.

Portal plate bile duct diameter in biliary atresia is associated with long-term outcome.

PURPOSE: Kasai portoenterostomy (KPE) is the only treatment currently available for biliary atresia (BA). Age at KPE and surgical experience are prognostic factors for a successful KPE. Here, we aimed to assess whether the size of bile ductules at the porta hepatis during KPE correlates with KPE success and transplant-free survival (TFS). METHODS: A retrospective analysis of patients diagnosed with BA during 2000-2019. Porta hepatis biopsies were reviewed for diameters of five representative ducts, and a mean ductal diameter (MDD) was calculated. Laboratory values including pre- and postoperative bilirubin levels were analyzed. RESULTS: The cohort included 77 patients; for 33, ductal plate biopsy was available. KPE was successful in six of eight patients with MDD ≥ 50 µm, and in five of 25 with MDD < 50 µm, p = 0.008, OR = 12.0 (95% CI 1.83-78.3). Ten-year survival with native liver was higher in patients with MDD ≥ 50 µm than in patients with MDD < 50 µm, p < 0.001, HR 0.038 (95% CI 0.007-0.207). Direct bilirubin < 1 mg/dl 3 months post-KPE was associated with improved 2-year post-KPE TFS (27.7% vs. 13.9%, p < 0.0001). CONCLUSIONS: MDD ≥ 50 µm correlates with KPE success and a higher rate of TFS. Direct bilirubin < 1 mg/dl 3 months post-operation may serve as a marker of successful biliary excretion, and a predictor of 2-year TFS.

Treatment adherence and behavior of pediatric liver transplant recipients during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has affected medical care worldwide. Thus, we aimed to assess the impact of the COVID-19 pandemic on pediatric LT recipients. METHODS: A cross-sectional study based on a structured internet or telephone survey was conducted among pediatric LT recipients. Survey results were compared with results of a survey conducted among pediatric patients with IBD. RESULTS: Seventy-six pediatric LT patients participated in the study. Of them, 58 (76.3%) reported fear of severe COVID-19 infection due to LT or LT-associated medications. Half of the patients reported needing emotional support. Most patients (51, 67.1%) reported strictly following official guidance, while more stringent protective measures were taken by 64 (84.2%) patients. None of the patients discontinued their medications due to COVID-19. Compared to pediatric patients with IBD, a higher proportion of pediatric LT recipients reported fears of contracting severe COVID-19 infection due to their illness or medications (45, 59.2% vs. 110, 45.1%). CONCLUSION: Among pediatric LT recipients a higher proportion reported fear of severe COVID-19 infection, implemented additional protective measures and expressed a need for emotional support, compared to patients with IBD. Medical teams should provide adequate information and offer a support system for this vulnerable population.

Body composition correlates with laboratory parameters and disease severity in infants with biliary atresia.

AIM: Infants with biliary atresia (BA) generally have chronic malnutrition. However, the best anthropometric measure to assess malnutrition and its correlation with disease severity is unknown. We aimed to assess correlations of various anthropometric measurements, including air displacement plethysmography (ADP), with laboratory parameters and with the pediatric end-stage liver disease (PELD) score in infants with BA. METHODS: Infants with BA were followed at a pediatric liver transplantation center during 2014-2018. Follow-up comprised laboratory tests and nutritional assessment by a dietitian including dietary intake, weight, height, mid-upper arm circumference (MUAC), and skin-fold thickness. Fat-free mass (FFM) and fat mass (FM) were measured by ADP. RESULTS: Forty-three nutritional evaluations were performed in 28 infants with BA (13 boys, 44.4%). The median age was 20.7 weeks (IQR: 13-25.9). Based on the various anthropometry modalities, infants with BA were found to be malnourished on most of the visits; 63% had a MUAC-Z score lower than -2 standard deviations. High serum bilirubin level predicted lower weight for age, length for age, and MUAC-Z. Lower MUAC-Z was associated with a higher PELD score. Neither FM mass nor FFM correlated with PELD or with serum bilirubin level. However, FM correlated with skin-fold thickness-Z and was low in most patients. CONCLUSIONS: The majority of BA infants suffer from malnutrition as assessed by most anthropometrics modalities; low MUAC correlated best with disease severity and serum bilirubin level. Further studies are warranted to determine the contribution of FM measurement by ADP to the anthropometric assessment of infants with BA.

Clinical Outcomes and Antibody Response in COVID-19-Positive Pediatric Solid Organ Transplant Recipients.

We describe the clinical and laboratory manifestations and outcomes of 25 pediatric solid organ transplant recipients who tested positive for severe acute respiratory coronavirus-2. Twenty-one (84%) developed a mild disease; 22 of 23 (96%) had a positive serologic response. Two patients (8%), both kidney transplant recipients with additional comorbidities, developed a severe disease. The findings emphasize the need for close monitoring of this population.

Age-Dependent Trends in the Celiac Disease: A Tertiary Center Experience.

OBJECTIVES: Celiac disease (CD) is a common intestinal autoimmune disorder with diverse presenting features. We aimed to determine age-dependent patterns in CD presentation, diagnosis and management at a large tertiary referral center. METHODS: A retrospective review of electronic medical records of pediatric patients diagnosed with CD between January 1999 and December 2018 at Schneider Children's Medical Center of Israel. We compared demographics, clinical and laboratory parameters between four age groups at CD presentation. RESULTS: A cohort of 932 children was divided into four groups by age (in years) at diagnosis: 0-3 (17.9%), 3-6 (31.8%), 6-12 (34.5%), 12-18 (15.8%). The youngest age group presented more frequently with diarrhea, weight loss, abdominal distention, vomiting and lower weight z scores, P < 0.01. Hypoalbuminemia and zinc deficiency were also more frequent in this age group, compared to older patients (P < 0.05, each). Rates of anemia were higher in younger age groups (0-3 and 3-6 years), compared to older age groups, P < 0.05. Patients in the younger age groups (0-3 and 3-6 years) presented more frequently with tissue transglutaminase (TTG) levels above 10 times the upper limit of normal (ULN; P < 0.05), and more often normalized their CD serologies by 24 months of gluten-free diets (GFD) compared to older age groups (P < 0.05). CONCLUSION: There is an age-dependent variation in CD presentation during childhood. Younger patients present more often with malabsorptive features, and higher TTG levels, yet normalize TTG while on GFD more rapidly than older patients. Clinicians should be aware of the diversity in CD presentation and course at the various presentation age.

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.

Clinical and Esophagogastroduodenoscopy Findings in Pediatric Patients With Severe Obesity Evaluated Before Bariatric Surgery.

OBJECTIVES: Severe obesity in the pediatric population has lifelong consequences. Bariatric surgery has been suggested for selected adolescents with severe obesity after careful evaluation. The indications for preoperative esophagogastroduodenoscopy (EGD) in this age group are not clear, despite its established usefulness in adults. We aimed to assess the usefulness of EGD before bariatric surgery in pediatric patients with severe obesity and metabolic comorbidities. METHODS: We conducted a retrospective chart review in a single tertiary pediatric medical center of adolescents treated during 2011 to 2018. Data collected from electronic medical records included patient demographics, endoscopic findings, and laboratory parameters. RESULTS: A total of 80 patients (40 boys) underwent evaluation. Macroscopic abnormalities were detected in 54% of the endoscopies, including gastritis, esophagitis, and duodenitis in 46%, 16%, and 13%, respectively. Forty-nine percentage of the biopsies showed histological abnormalities; in 35 (44%) patients, Helicobacter pylori was detected. Thirty-three patients (41%) received medical treatment and 2 (2.5%) required a second EGD. Metabolic comorbidities included hypertriglyceridemia (38% of the patients), low high-density lipoprotein (23%), and prediabetic (16%) or diabetic levels of HbA1C (4%). Fifty-five percentage of the cohort had elevated alanine aminotransferase (ALT), suggestive of nonalcoholic fatty liver disease (NAFLD). CONCLUSIONS: Endoscopies performed before bariatric surgeries suggest a higher prevalence of clinically significant findings, many of which required treatment. These findings support incorporating an EGD into the preoperative evaluation of this patient population.

Fetal-TAPSE for Surveillance of Cardiac Function in Growth-Restricted Fetuses With a Portosystemic Shunt.

OBJECTIVES: Congenital portosystemic shunt (CPSS) in a growth-restricted fetus may lead to cardiac overload and ultimately hemodynamic imbalance. The aim of the study was to describe the application of tricuspid annular plane systolic excursion (TAPSE) for surveillance of cardiac function in growth-restricted fetuses diagnosed with CPSS. METHODS: The study group consisted of 7 fetuses with growth restriction diagnosed with CPSS between 2018 and 2020. Patients were followed longitudinally every 2 weeks. Sonographic fetal-TAPSE (f-TAPSE) was performed every 2 weeks. At each visit, the following parameters were recorded: estimated fetal weight, biophysical profile, nonstress test, Doppler flow indices, and fetal cardiothoracic index. Postnatal laboratory and imaging tests were retrieved from the medical files. RESULTS: Mean gestational age at diagnosis of CPSS was 32 + 1 weeks. Cardiomegaly was observed in all cases. All portosystemic shunts were classified as intrahepatic. Values of f-TAPSE were above the 95th percentile in 6/7 fetuses at presentation and throughout follow-up. Gestational age at delivery ranged between 36 + 5 and 38 + 5 weeks. Postnatally, spontaneous closure of the shunt was noted in 2 infants. Transient hyperammonemia was diagnosed in 2 neonates, with no signs of the characteristic complication. CONCLUSIONS: In growth-restricted fetuses diagnosed concomitantly with CPSS, f-TAPSE offers a practical sonographic tool for assessment of cardiac function and may serve as an additional clinical marker for follow-up. The appearance of cardiomegaly in growth-restricted fetuses should prompt a dedicated sonographic evaluation of the fetal portal system.