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.

Determinants of early surgical complications after pediatric liver transplantation: A single center/single surgeon experience over 20 years.

BACKGROUND: The risk of early surgical complications of liver transplantation (LT) is higher in children when compared with adults. The aims of the present retrospective study from a single center cohort/single surgeon were to identify the predictive factors for surgical complications after pediatric LT. METHODS: All children receiving a first LT from October 1990 to October 2010 in our center were included. RESULTS: Included 151 children (boys 55.0%), with a mean age of 4.8 ± 4.8 years, and a mean weight of 17.9 ± 14.4 kg. Thirty-seven patients were transplanted within the first year, and 59 patients had a body weight below 10 kg. The main initial liver disease was biliary atresia (49.0%). Living donor LT was performed in 39 cases (25.8%), cadaveric whole liver LT in 50 cases (33.1%), and cadaveric partial liver LT in 62 cases (41.1%). Early surgical complications included reoperation (37.8%), vascular complications (8.6%), i.e. arterial (3.3%) or portal thrombosis/stenosis (7.3%) within the first month, and biliary complications in the first 90 days occurred in 22.5% of the cases. The main indications for surgical revision were abdominal bleeding, treatment of a biliary complication, and bowel perforation. Multivariate analysis disclosed that only graft type (split and moreover from a living donor) was significantly and independently associated with the occurrence of biliary complication, and that indication for LT, period, graft type, and operative time were significantly and independently associated with the necessity of surgical revision. CONCLUSION: Our results emphasize that surgical complications are frequent and strongly depend on patient/graft characteristics.

Endoscopic management of esophageal mucosal bridges in children with esophageal atresia.

BACKGROUND AND STUDY AIMS: Esophageal mucosal bridge (EMB) may be diagnosed at the anastomotic site in children operated on for esophageal atresia (EA) but so far only a few cases (n = 4) have been reported. This study aimed to characterize EMB in children with EA, risk factors, and treatment. PATIENTS AND METHODS: This retrospective multicenter study recorded patient's characteristics, EMB diagnosis circumstances, endoscopic management, follow-up, and EMB recurrence in children with EA aged less than 18 years, compared with paired EA patients without EMB. RESULTS: Thirty patients were included (60% male, 90% EA/tracheoesophageal fistula, 43% associated malformations). Compared to 44 paired controls, EMB was associated with a history of nasogastric tube feeding (31% vs. 9.1%, p = 0.02) and severe gastroesophageal reflux disease (history of fundoplication: 41.4% vs. 13.6%, p < 0.01). 77% had symptoms (food impaction and/or dysphagia). Endoscopic management was performed in 53% of patients (83% electrocoagulation) with no technical difficulties or complications. 80% of the symptomatic patients with EMB improved after endoscopic treatment, independently of anastomotic stricture dilatation or not. CONCLUSION: EMB endoscopic management by electrocoagulation is safe and often leads to symptom improvement.

Iterative antibody-induced bile salt export pump deficiency after successive liver transplantations successfully treated with plasmapheresis and rituximab.

Post-transplantation evolution of progressive familial intrahepatic cholestasis type 2 patients can be complicated by antibody-induced bile salt export pump deficiency (AIBD). There is no consensus on its management. We describe a patient who presented two episodes, 9 years apart. The first episode was refractory to plasmapheresis and intravenous immunoglobulin (IVIG) started 2 months after AIBD onset, leading to graft loss. The second episode responded to plasmapheresis, IVIG and rituximab initiated less than 2 weeks after the beginning of symptoms, allowing for long-term recovery. This case suggests that intensive treatment with minimum delay after symptoms onset could sponsor a better evolution.

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.

Are protocol graft biopsies after pediatric liver transplantation useful? Experience in a single center over 20 years.

BACKGROUND: The role of protocol liver biopsies (PLB) in the follow-up of pediatric liver transplant recipients remains questionable. This single-center retrospective study aimed to evaluate their clinical impact on the long-term management of pediatric liver transplant recipients. METHODS: We described histopathological lesions and clinical consequences for patient management of PLB performed 1, 5, 10, 15, 20, and 25 years after pediatric liver transplantation (LT). RESULTS: A total of 351 PLB performed on 133 patients between 1992 and 2021 were reviewed. PLB found signs of rejection in 21.7% of cases (76/351), and moderate to severe fibrosis in 26.5% of cases (93/351). Overall, 264 PLB (75.2%) did not cause any changes to patient care. Immunosuppression was enhanced after 63 PLB, including 23 cases of occult rejection. The 1-year PLB triggered significantly more changes, while biopsies at 15, 20, and 25 years produced the lowest rates of subsequent modifications. PLB had a significantly higher probability of inducing therapeutic changes if the patient had abnormal biological or imaging results (odds ratio [OR] 2.82 and 2.06), or a recent history of rejection or bacterial infection (OR 2.22 and 2.03). CONCLUSION: Our results suggest that, although it often does not prompt any treatment changes, PLB could be performed because of its ability to detect silent rejection requiring an increase in immunosuppression. PLB could be carried out 1, 5, and 10 years after LT and then every 10 years in patients with normal biological and imaging results and no recent complications, while other patients could be kept on a 5-year protocol.

NLRC4 GOF Mutations, a Challenging Diagnosis from Neonatal Age to Adulthood.

The NLRC4 inflammasome is part of the human immune innate system. Its activation leads to the cleavage of pro-inflammatory cytokines IL-1ß and IL-18, promoting inflammation. NLRC4 gain-of-function (GOF) mutations have been associated with early-onset recurrent fever, recurrent macrophagic activation syndrome and enterocolitis. Herein, we describe two new patients with NLRC4 mutations. The first case presented with recurrent fever and vasoplegic syndrome, gut symptoms and urticarial rashes initially misdiagnosed as a severe protein-induced enterocolitis syndrome. The second case had recurrent macrophage activation syndrome (MAS) and shock, suggesting severe infection. We identified two NLRC4 mutations, on exon 4, within the nucleotide-binding protein domain (NBD). After a systematic review of NLRC4 GOF mutations, we highlight the wide spectrum of this disease with a limited genotype-phenotype correlation. Vasoplegic shock was only reported in patients with mutation in the NBD. Diagnosing this new entity combined with gastrointestinal symptoms and vasoplegic shocks is challenging. It mimics severe allergic reaction or sepsis. The plasma IL-18 level and genetic screening are instrumental to make a final diagnosis.

Microsporidiosis after liver transplantation: A French nationwide retrospective study.

BACKGROUND: Microsporidiosis has been largely reported in patients with acquired immunodeficiency syndrome, but emerged as a cause of persistent diarrhea in solid organ transplant patients. METHODS: Through the French Microsporidiosis Network and the Groupe français de recherche en greffe de foie, we collected all microsporidiosis cases identified in liver transplant patients between 1995 and 2020 in France. RESULTS: We identified 24 liver transplant recipients with microsporidiosis. Sex ratio was balanced and median age was 58.8 (3.5-83.5) years (there were 4 children). Microsporidiosis occurred at a median time of 3.9 (0.1-18.9) years post-transplant. Median duration of diarrhea before diagnosis was 22 days (12-45). Therapeutic care included immunosuppressive therapy changes in 20 patients, as follows: stop cyclosporine or tacrolimus (n = 2), dose reduction of cyclosporine or tacrolimus (n = 12), stop MMF (n = 5), and dose reduction of corticosteroids (n = 1). In addition, 15 patients received specific therapy against microsporidiosis: fumagillin (n = 11) or albendazole (n = 4). Median duration of treatment was 14 days (8-45 days). Finally, 7 patients had immunosuppressive treatment tapering only. Microsporidiosis was complicated by renal failure in 15 patients, requiring dialysis in one case. Two patients had infection relapse. No patient presented proven rejection within the 3 months after microsporidiosis. None of the patients died within the 3 months after microsporidiosis. CONCLUSIONS: Microsporidiosis is a very rare infection after liver transplantation but can induce severe dehydration and renal failure. Therefore, it must be systematically sought in any case of persistent diarrhea after first line screening of frequent infectious causes.

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.

Covid-19 in liver transplant recipients: the French SOT COVID registry.

BACKGROUND: Notwithstanding the ongoing coronavirus disease-2019 (Covid-19) pandemic, information on its clinical presentation and prognosis in organ transplant recipients remains limited. The aim of this registry-based observational study was to report the characteristics and clinical outcomes of liver transplant (LT) recipients included in the French nationwide Registry of Solid Organ Transplant Recipients with Covid-19. METHODS: COVID-19 was diagnosed in patients who had a positive PCR assay for SARS-CoV-2 or in presence of typical lung lesions on imaging or specific SARS-CoV-2 antibodies. Clinical and laboratory characteristics, management of immunosuppression, treatment for Covid-19, and clinical outcomes (hospitalization, admission to intensive care unit, mechanical ventilation, or death) were recorded. RESULTS: Of the 104 patients, 67 were admitted to hospital and 37 were managed at home (including all 13 children). Hospitalized patients had a median age of 65.2 years (IQR: 58.1 - 73.2 years) and two thirds were men. Most common comorbidities included overweight (67.3%), hypertension (61.2%), diabetes (50.7%), cardiovascular disease (20.9%) and respiratory disease (16.4%). SARS-CoV-2 infection was identified after a median of 92.8 months (IQR: 40.1 - 194.7 months) from LT. During hospitalization, antimetabolites, mTOR inhibitor, and CNIs were withdrawn in 41.9%, 30.0% and 12.5% of patients, respectively. The composite endpoint of severe Covid-19 within 30 days after diagnosis was reached by 33.0% of the adult patients. The 30-day mortality rate was 20.0%, and 28.1% for hospitalized patients. Multivariate analysis identified that age was independently associated with mortality. CONCLUSION: In our large nationwide study, Covid-19 in LT recipients was associated with a high mortality rate.

Congenital absence of the portal vein: Define the portosystemic shunt, avoid liver transplantation.

Liver transplantation has been historically recommended for patients with congenital absence of the portal vein associated with extrahepatic congenital portosystemic shunts. Here, based on a case report of a 2-year-old girl and a thorough review of all published cases from 1974 to 2020, we show that such a diagnosis most often conceals a hypoplastic portal vein, which can be successfully re-permeabilized through the closure of the shunt in order to re-establish a physiological vascular anatomy. This highlights the importance of achieving a detailed anatomical description of extrahepatic congenital portosystemic shunts with a balloon occlusion test in order to plan the best surgical approach and avoid unnecessary liver transplantation.

Hepatocellular carcinoma-associated depletion of the netrin-1 receptor Uncoordinated Phenotype-5A (UNC5A) skews the hepatic unfolded protein response towards prosurvival outcomes.

In the liver, HBV and HCV infections, exposure to toxics, genetic and metabolic disorders may induce endoplasmic reticulum (ER) stress and the unfolding protein response (UPR). The UPR allows cells to reach ER homeostasis after lumen overload, but also fosters survival of damaged cells and therefore HCC onset. Dependence receptors such as UNC5A trigger apoptosis when unbound to their ligands. We have previously shown that the main dependence receptor ligand, netrin-1, could protect cells against UPR-induced apoptosis through sustained translation. In this study, we show that UNC5A is cumulatively downregulated by the UPR at the transcriptional level in vitro and at the translational level both in vitro and in vivo. We have found that the 5'-untranslated region of the UNC5A mRNA shares a certain homology degree with that of netrin-1, suggesting linked translational regulatory mechanisms, at least during the initial stages of the UPR. RNAi and forced expression studies identified UNC5A as a modulator of cell death in the context of the UPR. UNC5A decrease of association with polysomes and expression oriented cells towards UPR-associated hepatocytic survival. Such data indicate that cooperation between the UPR and UNC5A depletion as previously observed by ourselves in HCC patients samples may foster liver cancer development and growth.

Maternal uniparental disomy 14 revealed by alpha 1 antitrypsin deficiency.

UNLABELLED: Alpha 1 antitrypsin deficiency (AATD) is an autosomal co-dominant disease linked to a mutation of the SERPINA1 gene localized to chromosome 14q32. Uniparental disomy (UPD) is known to be a genetic mechanism that causes various syndromes. Maternal UPD14 presents with a Prader-Willi syndrome-like phenotype. No publications to date have dealt with the association of these two syndromes. In this article, we report on two cases of AATD (from different families), which lead to the diagnosis of maternal UPD14. AATD was diagnosed early in both children. Their clinical presentations were typical (chronic cytolysis in patient 1 and neonatal cholestasis in patient 2); serum alpha 1 antitrypsin levels were low (P1 0.33g/L and P2 0.35g/L), and both patients had a Z phenotype. A pedigree study of both families showed that the father had an M phenotype and the mother an MZ phenotype, which was unexpected. On the other hand, both children were born before term and presented with symmetrical growth retardation, early eating difficulties, moderate hypotonia, understated dysmorphic features and moderate psychomotor retardation, suggestive of a Prader-Willi syndrome-like phenotype. Genotyping was performed to explain gene transmission inconsistencies, and highlighted maternal UPD 14 in both families. CONCLUSION: Logically, maternal UPD 14 can induce AATD. In light of these observations, it seems appropriate to search for AATD in patients with maternal UPD 14 in order to prevent a progression of the disease. These cases also underline the significance of maternal UPD 14, which should be suspected in AATD in view of the discordance with Mendel's allelic transmission law.

[Semen cryopreservation in adolescent with cancer: at which age can it be proposed?]. / Cryopréservation de sperme chez l'adolescent atteint de cancer: à partir de quel âge?

The increased incidence of tumors in children and adolescents (Lacour, 2010), as well as therapeutic advances in recent decades, have led to an increase of fertility disorders in young adult cancer survivors. In pubescent boys, the use of cryopreserved sperm and assisted reproductive technology (ART) is a validated preventive option. Currently, there is no consensus on the age at which the semen cryoconservation has to be proposed. There is a wide disparity of care among centers in France. Based on the observation of Nathan,11 years old, in whom semen cryopreservation was performed at his request, we analyze local practices and discuss the indications for cryopreservation of sperm in young teenagers with cancer treated by potentially sterilizing treatment.