Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC. METHODS: MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 µg/kg, then escalated to 570 µg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22. FINDINGS: Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 µmol/L (95% CI -257 to -94) for maralixibat versus 11 µmol/L (-58 to 80) for placebo, also representing a significant difference of -187 µmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred. INTERPRETATION: Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC. FUNDING: Mirum Pharmaceuticals.

TASL Practice Guidance on the Clinical Assessment and Management of Patients with Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a multisystem disease and is significantly associated with obesity, insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular disease. NAFLD has become the most prevalent chronic liver disease in Western countries, and the proportion of NAFLD-related cirrhosis among patients on liver transplantation waiting lists has increased. In light of the accumulated data about NAFLD, and to provide a common approach with multi-disciplines dealing with the subject, it has become necessary to create new guidance for diagnosing and treating NAFLD. This guidance was prepared following an interdisciplinary study under the leadership of the Turkish Association for the Study of the Liver (TASL), Fatty Liver Special Interest Group. This new TASL Guidance is a practical application guide on NAFLD and was prepared to standardize the clinical approach to diagnosing and treating NAFLD patients. This guidance reflects many advances in the field of NAFLD. The proposals in this guidance are meant to aid decision-making in clinical practice. The guidance is primarily intended for gastroenterology, endocrinology, metabolism diseases, cardiology, internal medicine, pediatric specialists, and family medicine specialists.

Hepatocellular Carcinoma in ADA-SCID Patient After Hematopoietic Stem Cell Transplantation.

Adenosine deaminase (ADA) deficiency is one of the most prevalent forms of severe combined immunodeficiency and results in the accumulation of toxic substrates which creates a systemic metabolic disease. It predisposes patients to the development of malignancies, most commonly lymphoma. We report an 8-month-old infant with ADA deficient severe combined immunodeficiency who developed progressive liver dysfunction and hepatocellular carcinoma after successful hematopoietic stem cell transplantation. This is the first case report of an ADA-deficient patient who presented with hepatocellular carcinoma and gives an insight into the complex etiology that can lie behind liver dysfunction in these patients.

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.

Liver fibrosis in children: a comprehensive review of mechanisms, diagnosis, and therapy.

Chronic liver disease incidence is increasing among children worldwide due to a multitude of epidemiological changes. Most of these chronic insults to the pediatric liver progress to fibrosis and cirrhosis to different degrees. Liver and immune physiology differs significantly in children from adults. Because most of pediatric liver diseases have no definitive therapy, a better understanding of population and disease-specific fibrogenesis is mandatory. Furthermore, fibrosis development has prognostic significance and often guide treatment. Evaluation of liver fibrosis continues to rely on the gold-standard liver biopsy. However, many high-quality studies put forward the high diagnostic accuracy of numerous diagnostic modalities in this setting. Herein, we summarize and discuss the recent literature on fibrogenesis with an emphasis on pediatric physiology along with a detailed outline of disease-specific signatures, noninvasive diagnostic modalities, and the potential for antifibrotic therapies.

Therapeutic Management of Idiosyncratic Drug-Induced Liver Injury and Acetaminophen Hepatotoxicity in the Paediatric Population: A Systematic Review.

INTRODUCTION: Drug-induced liver injury (DILI) is a rare but serious adverse event that can progress to acute liver failure (ALF). The evidence for treatment of DILI in children is scarce. OBJECTIVE: We aimed to comprehensively review the available literature on the therapies for both acetaminophen overdose (APAP) and idiosyncratic DILI in the paediatric population. METHODS: We included original articles conducted in a paediatric population (< 18 years) in which a therapeutic intervention was described to manage APAP or idiosyncratic DILI. Findings were summarized based on age groups (preterm newborn neonates, term and post-term neonates, infants, children and adolescents). RESULTS: Overall, 25 publications (fifteen case reports, six case series and four retrospective cohort studies) were included, including a total of 140 paediatric DILI cases, from preterm newborn neonates to adolescents. N-acetylcysteine was used to treat 19 APAP cases. N-acetylcysteine (n = 14), ursodeoxycholic acid (n = 3), corticosteroids (n = 31), carnitine (n = 16) and the combination of glycyrrhizin, reduced glutathione, polyene phosphatidylcholine and S-adenosylmethionine (n = 31) were the therapeutic options for treating idiosyncratic DILI. The molecular adsorbent recirculating system was used in the management of either APAP (n = 4) or idiosyncratic DILI (n = 2), while 20 paediatric ALF cases received continuous renal replacement therapy. CONCLUSIONS: This systematic review identified DILI in the paediatric population who have received specific treatment. These interventions appear to be mainly extrapolated from low-quality evidence from the adult population. Thus, there is a need for high-quality studies to test the efficacy of known and novel therapies to treat DILI specifically addressed to the paediatric population. PROSPERO registration number CRD42021214702.

SERPINB11 variant-related liver injury in STEC-HUS: case reports and literature review.

BACKGROUND: Liver damage is uncommon in Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS). Herein, we present two cases with a diagnosis of STEC-HUS that progressed to liver damage, with findings presumably related to the SERPINB11 gene c.268G > T (p.Glu90Ter) variant. CASE-DIAGNOSIS/TREATMENT: Two boys aged 3 and 2 years, respectively, were referred to our clinic with a preliminary diagnosis of STEC-HUS. The patients had low hemoglobin, thrombocyte, and haptoglobin levels but high levels of lactic dehydrogenase, urea, creatinine, and schistocytes in peripheral smears. Escherichia coli O157:H7 was detected in their stool samples. The patients underwent hemodialysis, plasma exchange, and supportive treatments. Meanwhile, cholestasis developed in the patients, resulting in elevated total bilirubin levels. During the follow-up period, kidney function recovered completely; however, liver function did not improve, and one patient developed chronic liver damage. Gene mutations that may cause liver damage were investigated, and c.268G > T (p.Glu90Ter) homozygous and heterozygous variants were detected in exon 9 of the SERPINB11 gene in the patients. CONCLUSIONS: Our patients presented with kidney impairment and liver malfunction. Hepatic involvement in STEC-HUS may result from ischemia, hemolysis, and endothelial damage in the hepatic vessels. Liver injury in STEC-HUS cases may be associated with the homozygous SERPINB11 gene c.268G > T (p.Glu90Ter) variant.

Risk factors and outcomes associated with recurrent autoimmune hepatitis following liver transplantation.

BACKGROUND & AIMS: Autoimmune hepatitis can recur after liver transplantation (LT), though the impact of recurrence on patient and graft survival has not been well characterized. We evaluated a large, international, multicenter cohort to identify the probability and risk factors associated with recurrent AIH and the association between recurrent disease and patient and graft survival. METHODS: We included 736 patients (77% female, mean age 42±1 years) with AIH who underwent LT from January 1987 through June 2020, among 33 centers in North America, South America, Europe and Asia. Clinical data before and after LT, biochemical data within the first 12 months after LT, and immunosuppression after LT were analyzed to identify patients at higher risk of AIH recurrence based on histological diagnosis. RESULTS: AIH recurred in 20% of patients after 5 years and 31% after 10 years. Age at LT ≤42 years (hazard ratio [HR] 3.15; 95% CI 1.22-8.16; p = 0.02), use of mycophenolate mofetil post-LT (HR 3.06; 95% CI 1.39-6.73; p = 0.005), donor and recipient sex mismatch (HR 2.57; 95% CI 1.39-4.76; p = 0.003) and high IgG pre-LT (HR 1.04; 95% CI 1.01-1.06; p = 0.004) were associated with higher risk of AIH recurrence after adjusting for other confounders. In multivariate Cox regression, recurrent AIH (as a time-dependent covariate) was significantly associated with graft loss (HR 10.79, 95% CI 5.37-21.66, p <0.001) and death (HR 2.53, 95% CI 1.48-4.33, p = 0.001). CONCLUSION: Recurrence of AIH following transplant is frequent and is associated with younger age at LT, use of mycophenolate mofetil post-LT, sex mismatch and high IgG pre-LT. We demonstrate an association between disease recurrence and impaired graft and overall survival in patients with AIH, highlighting the importance of ongoing efforts to better characterize, prevent and treat recurrent AIH. LAY SUMMARY: Recurrent autoimmune hepatitis following liver transplant is frequent and is associated with some recipient features and the type of immunosuppressive medications use. Recurrent autoimmune hepatitis negatively affects outcomes after liver transplantation. Thus, improved measures are required to prevent and treat this condition.

Telemedicine in monitoring pediatric LT patients before and during COVID-19 pandemic.

BACKGROUND: The delivery of healthcare services by telemedicine decreases costs of traveling for patients, is less time-consuming, and most importantly permits the connection between highly skilled specialists and patients. However, whether the use of telemedicine (text messaging) for LT patients was affected by the COVID-19 pandemic is unknown. METHODS: We collected data (following consent from patients and parents) from 57 patients (33 male/24 female) with a median age of 47 (IQR: 9-91) months, whom we followed up with text messaging between September 2019 and September 2020, spanning the 6 months prior to COVID-19 and during this period. RESULTS: In total, 723 text message mediated consultations occurred during this period, henceforth simply referred to as "messages." Three hundred and twenty-eight (45%) messages occurred during the 6 months up to the start of the pandemic. Following the COVID-19 outbreak, the number of messages increased to 395 (55%). The three most common reasons of messaging were post-liver-LT follow-up messages (n = 215/723, 29.7%), consultations for drug use (n = 157/723, 21.7%), and medication prescriptions (n = 113/723, 15.6%). Protocol biopsy discussions (n = 33/723, 4.6%) and fever (n = 27/723, 3.7%) were among others (vaccination, rash, diarrhea, cough, fatigue, acne). During the COVID-19 outbreak, only post-LT follow-up messages increased significantly to 132/395 (33%) from 83/328 (25%) (p-value: .02). CONCLUSIONS: We found that the pandemic resulted in an increase in the total number of text message mediated consultations and specifically for the use of post-LT follow-up. Messaging was effective for post-LT follow-ups and all patients were at least satisfied.

Examining the Hepatic Immune System in Children With Liver Disease With Fine Needle Aspiration.

OBJECTIVES: Liver biopsy is the standard in diagnosing liver diseases. Yet, it provides little space to perform comprehensive immune profiling of the liver. Hence, we explored whether fine needle aspirates (FNAs) could be used to elucidate the hepatic immunity in children. METHODS: We enrolled 74 children undergoing diagnostic (n = 17) or protocol biopsy (n = 57) following liver transplantation (LT). Matched blood and FNAs were obtained. Additionally, explant liver tissue was collected from children (n = 14) undergoing LT. Immune cells were isolated from peripheral blood, FNAs and explanted livers. Immune-phenotypical profiling was done by flow cytometry. RESULTS: Biopsied patients (58% female) were at a median age of 46 months (interquartile range [IQR]: 12-118) and LT patients (71% female) were 48 months (IQR: 21-134, P = 0.78) old. CD69+, a hallmark of tissue-resident immune cells was expressed in 1.3% of CD3+ T cells from blood being higher in FNA (20%) and tissue (49%, P < 0.001). CD4+ T-cell frequencies in tissue (13%) and FNAs (20%) were lower compared to blood (35%, P < 0.001) whereas CD8+ T cells in tissue (33.5%) and FNA (32%) were higher than in blood (25%, P < 0.01). Mucosal associated invariant T cells were enriched in liver tissue (8.8%) and in the FNA (4.4%) compared to blood (1.7%, P < 0.001). Whereas the percentage of total Tregs (CD4+CD25+FOXP3+CD127low/-) decreased, the proportion of activated Tregs (CD4+CD45RA-FOXP3high) increased in FNA and explant. Breg (CD19+CD20+CD24highCD38high) frequencies were similar in all groups. CONCLUSION: FNA is a practical method to sample the liver immune system collecting even small cell subsets such as regulatory T/B cells.

Turkish Translation, Validation, and Reliability Analysis of Pediatric Eosinophilic Esophagitis Symptom Severity Module Version 2.0.

The Paediatric Eosinophilic Esophagitis Symptom Severity Modules Version 2.0 (T-PEESv2.0) was developed in English as a valid, reliable questionnaire for follow up. This work aimed to develop a Turkish version of T-PEESv2.0 via translation and cultural adaptation and then to test its validation and reliability. Methods: The PEESv2.0 was translated into Turkish by standardized procedural steps completed in cooperation with the Mapi Research Trust. The final version of the questionnaire was submitted to eosinophilic oesophagitis patients or their parents at 2 times point separated by 1 week. An age-matched control group was used to test the discriminant validity. Construct validity was tested using the Wilcoxon test, and internal consistency was tested using Cronbach's alpha. Test-retest reliability was measured with Cohen's kappa and intraclass correlation coefficient. Results: One hundred twenty-eight participants (70 patients, 58 parents) were enrolled. Fifty-eight (39.1%) of them completed T-PEESv2.0-parent by proxy and 70 (54.7%) were T-PEESv2.0. The Cronbach's alpha coefficient and intraclass correlation coefficient for test-retest reliability were >0.70 for both questionnaires and for all domain (frequency and severity) and total scores. For discriminant validity analysis, subscale (frequency and domain) and total scores of the patient group were compared with those of the control group. The subscale and total scores were significantly different between the groups (P < 0.05). Conclusion: T-PEESv2.0 appeared to be valid and reliable, ready to be introduced as a clinical and research tool for the assessment of patients with eosinophilic oesophagitis.

Standard immunosuppressive treatment reduces regulatory B cells in children with autoimmune liver disease.

Introduction: Autoimmune hepatitis (AIH) is a chronic liver disease caused by a perturbed immune system. The scarcity of short- and long-term immune monitoring of AIH hampered us to comprehend the interaction between immunosuppressive medication and immune homeostasis. Methods and patients: We recruited children with AIH at the time of diagnosis and at the 1st, 3rd, 6th, 12th, 18th, and 24th months of immunosuppression (IS). We also enrolled children with AIH being on IS for >2 years. Children with drug-induced liver injury (DILI), and those receiving tacrolimus after liver transplantation (LT), were enrolled as disease/IS control subjects. Healthy children (HC) were also recruited. Peripheral blood mononuclear cells (PBMCs) were isolated from all participants. Healthy liver tissue from adult donors and from livers without inflammation were obtained from children with hepatoblastoma. By using flow cytometry, we performed multi-parametric immune profiling of PBMCs and intrahepatic lymphocytes. Additionally, after IS with prednisolone, tacrolimus, rapamycin, or 6-mercaptopurine, we carried out an in vitro cytokine stimulation assay. Finally, a Lifecodes SSO typing kit was used to type HLA-DRB1 and Luminex was used to analyze the results. Results: Untreated AIH patients had lower total CD8 T-cell frequencies than HC, but these cells were more naïve. While the percentage of naïve regulatory T cells (Tregs) (CD4+FOXP3lowCD45RA+) and regulatory B cells (Bregs, CD20+CD24+CD38+) was similar, AIH patients had fewer activated Tregs (CD4+FOXP3highCD45RA - ) compared to HC. Mucosal-associated-invariant-T-cells (MAIT) were also lower in these patients. Following the initiation of IS, the immune profiles demonstrated fluctuations. Bregs frequency decreased substantially at 1 month and did not recover anymore. Additionally, the frequency of intrahepatic Bregs in treated AIH patients was lower, compared to control livers, DILI, and LT patients. Following in vitro IS drugs incubation, only the frequency of IL-10-producing total B-cells increased with tacrolimus and 6MP. Lastly, 70% of AIH patients possessed HLA-DR11, whereas HLA-DR03/DR07/DR13 was present in only some patients. Conclusion: HLA-DR11 was prominent in our AIH cohort. Activated Tregs and MAIT cell frequencies were lower before IS. Importantly, we discovered a previously unrecognized and long-lasting Bregs scarcity in AIH patients after IS. Tacrolimus and 6MP increased IL-10+ B-cells in vitro.

Liver involvement in neuroblastoma amplified sequence gene deficiency is not limited to acute injury: Fibrosis silently continues.

Biallelic mutations in neuroblastoma amplified sequence gene (NBAS) is a rare disease which is characterized by recurrent liver failure (RALF). We reported the novel mutations, clinical characteristics and long-term outcomes of 5 patients with novel biallelic NBAS variants. Four patients (80%) had acute, episodic liver crises (LC) triggered by fever, with a median age of onset of 8.5 months. The median age in the last episode was 34 months. Median number of liver episodes was 4. The course of ALF was complicated by hepatic encephalopathy and hypoglycaemia in all patients with ALF. Two patients recovered with conservative treatment, 2 required liver transplantation (LT) and 1 died during the fourth episode. Long-term post-transplant follow-up showed normal liver function and histology. There is no hepatic or extrahepatic recurrence after LT. Non-transplanted patients exhibited fibrosis in either biopsy or elastography. Despite a reduction in the frequency of clinically significant episodes, patients may exhibit ongoing liver injury and fibrosis. An acute on chronic liver failure with predominant cholestasis can be an alternative presentation.

Course of vitamin D levels before and after liver transplantation in pediatric patients.

BACKGROUND: 25-hydroxy VD insufficiency is known in children undergoing LT but the serial post-transplant VD course and supplementation modalities in the peri-transplant period are lacking. We aimed to determine the pre-VD status and the post-transplant VD status course following VD supplementation and to elucidate its relationship with post-transplant outcome parameters such as infection and survival. METHODS: Pre- and post-VD levels were monitored in parallel with interventions to adjust VD levels in LT patients. VD status was categorized as circulating levels <30-21 ng/ml (insufficiency), 20-10 ng/ml (deficiency), and <10 ng/ml (severe deficiency). Patients received stoss (300000IU) VD3 within the pretransplant period if serum levels were <20 ng/ml. RESULTS: 135 transplanted children were included. The age at LT was 22 months (IQR: 8-60). The pretransplant median VD level was 14 ng/ml. Despite stoss dose, post-transplant median VD level was 1.8 ng/ml (day one), 4 ng/ml (week one), 19 ng/ml (month one), 33 ng/ml (month three), 38 ng/ml (months 6-12), and 40 ng/ml (month 24). After 6 months, VD status reached >30 ng/ml in 98% of patients. Only at pre-LT, higher infection rate (18.7%) in the severe VD deficiency group was observed compared to the VD deficiency group (2.9%, p = .04). Survival was not affected by serum VD levels. CONCLUSION: VD levels fell substantially after LT but are rectifiable by stoss dose, which was well tolerated. Only the infection rate was associated with the VD status.

A single-center report of COVID-19 disease course and management in liver transplanted pediatric patients.

BACKGROUND: In 2019, SARS-CoV-2 causing COVID-19 emerged. Severe COVID-19 symptoms may evolve by virtue of hyperactivation of the immune system. Equally, immunocompromised patients may be at increased risk to develop COVID-19. However, treatment guidelines for children following liver transplantation are elusive. METHODS: As a liver transplantation center, we diagnosed and followed up 10 children (male/female: 8/2) with a median age of 8.5 years (IQR: 5.2-11.0), with COVID-19 post-liver transplant between March 2019 and December 2020. COVID-19 diagnosis was based on PCR test and or florid X-ray findings compatible with COVID-19 in the absence of other cause. We retrospectively collected clinical and laboratory data from electronic patient records following written consent from patients/parents. RESULTS: Nine patients were diagnosed as definitive (PCR positive) with one patient being diagnosed as probable COVID-19. Seven patients recovered without any support whereas three were admitted for non-invasive oxygenation. Lymphopenia and/or high levels of serum IL-6 were detected in four patients. Six patients mounted anti-SARS-CoV-2 antibodies at median 30 days (IQR: 26.5-119.0) following COVID-19 diagnosis. Antibiotic therapy, favipiravir, anakinra, and IVIG were used as treatment in 4,1,1 and 2 patients, respectively. Furthermore, we kept the tacrolimus with or without everolimus but stopped MMF in 2 patients. Importantly, liver allograft function was retained in all patients. CONCLUSIONS: We found that being immunocompromised did not affect disease severity nor survival. Stopping MMF yet continuing with tacrolimus was an apt treatment modality in these patients.

Gastroesophageal reflux with children requiring adenotonsillectomy.

BACKGROUND: Our aim is to determine the incidence of reflux in children older than 3 years requiring adenotonsillectomy and relationship between GER and diagnostic tests. METHODS: Forty-four patients, who were listed for adenoidectomy/tonsillectomy at Pediatric Ear Nose Throat department due to severe hypertrophy, were evaluated for accompanying GER (Group 1). GER was diagnosed as having at least one positive GER test result (including esophagitis or pH monitoring). Twenty children without reflux symptoms were used as healthy control group (Group 2) and LPR was held. RESULTS: Reflux was detected in 32 children requiring adenotonsillectomy (72.7%). LPR score was negative in all patients in Group 2. There was no correlation between pH monitoring and histopathological evaluation of esophagus. There was a correlation between the LPR score and histological esophagitis in the proximal esophagus. CONCLUSIONS: GER was high in patients with adenotonsillary hypertrophy. LPR score and the history of patients are as effective as invasive techniques like pH monitorization and endoscopy in determining GER disease.

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.

A novel insight into the pathophysiology of autoimmune hepatitis: An immune activator mutation in the FLT3 receptor.

Autoimmune hepatitis (AIH) is a chronic progressive autoimmune liver disease characterized by hypergammaglobulinemia, interface hepatitis, a female preponderance, and the presence of autoantibodies in most patients. The presence of HLA-DR3/DR4 and functional impairment in regulatory T cells are associated with AIH. However, AIH is a multifactorial complex disease. This report is a description of a case of seronegative AIH in a girl with chronic hepatitis, a high immunoglobulin E (IgE) level, perforating nodular dermatitis, and sheer eosinophilia. To re-evaluate the diagnosis, whole exon sequencing was performed. It was determined that the patient had ancestral haplotype A1-B8-DR3, which is associated with autoimmunity. Importantly, it was also noted that an undocumented point mutation (Ala627Thr) of the FMS-like tyrosine 3 kinase (FLT3) receptor was present. This FLT3 receptor gain-of-function mutation is associated with the activation of the mechanistic target of rapamycin (mTOR), and dendritic cell activation. In addition, a loss-of-function mutation in the melanocortin-3 receptor gene, which inhibits interleukin 4, was detected. The constellation of these immune deregulatory factors may have propagated auto-aggression of the liver, causing chronic hepatitis with AIH features. The findings of seronegativity with eosinophilia and a high IgE level led us to hypothesize that the pathognomonic mechanism in this case was unlike that of classic AIH pathophysiology. Since mTOR is constitutively activated, mTOR inhibitors may be a useful option to treat AIH and dermatitis.

Long-Term Follow-Up of Tufting Enteropathy Caused by EPCAM Mutation p.Asp253Asn and Absent EPCAM Expression.

Tufting enteropathy (TE) is caused by recessive epithelial cell adhesion molecule (EPCAM) mutations, features congenital intractable diarrhea, growth retardation, and a characteristic disorganization of surface enterocytes. TE generally requires parenteral nutrition (PN) throughout childhood and into adulthood or a small bowel transplantation. We report 2 siblings with TE; a 3-year-old patient 1 intermittently receives partial PN, monthly somatostatin therapy, tolerates a normal diet and has a normal stool output. However, she is the sixth patient of 90 TE patients in literature, to develop a chronic arthritis. A 12-year-old patient 2 is on a normal diet, and did not require PN for the past 8 years. Duodenal biopsies showed characteristic tufts, and a complete lack of EPCAM staining. Both siblings were homozygous for EPCAM mutation c.757G>A (p.Asp253Asn). This observation shows that an overall favorable outcome can be obtained in TE, even with abrogated intestinal EPCAM expression.