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Background Congenital portosystemic shunts (CPSS) are rare vascular malformations and can be classified into extrahepatic and intrahepatic shunts. Extrahepatic CPSS, also termed Abernethy malformations are associated with severe long-term complications including portopulmonary hypertension, liver atrophy, hyperammoniemia and hepatic encephalopathy. We report a hitherto undescribed variant of Abernethy malformation requiring an innovative approach for interventional treatment. Case presentation We describe a 31-year-old patient following surgical repair of atrioventricular septal defect at the age of 6 years. In the long-term follow-up he showed persistent pulmonary hypertension which deteriorated despite dual pulmonary vasodilative treatment. When he developed arterial desaturation and symptomatic hyperammoniemia detailed reassessment revealed as underlying cause a hitherto undescribed variant of Abernethy malformation connecting the portal vein with the right lower pulmonary vein. Following interdisciplinary discussions we opted for an interventional approach. Since the malformation was un-accessible to interventional closure via antegrade venous or retrograde arterial access, a transhepatic percutaneous puncture of the portal vein was performed. Temporary balloon occlusion of the malformation revealed only a slight increase in portal venous pressure. Interventional occlusion of the large vascular connection was achieved via this transhepatic approach by successive implantation of two large vascular occluding devices. The postinterventional course was unremarkable and both ammonia levels and arterial saturation normalized at follow-up of 12 months. Conclusions Portal vein anomalies should be included in the differential diagnoses of pulmonary hypertension or pulmonary arterio-venous malformations. Based on careful assessment of the anatomy and testing of portal vein hemodynamics interventional therapy of complex Abernethy malformations can be performed successfully in specialized centers.

The European Reference Network for rare liver diseases (ERN RARE-LIVER) is a Europe-wide network of paediatric and adult hepatologists from expert centres in close collaboration with patient advocates from the various disease-areas covered in our ERN. The ERN is focused on providing more equitable care across Europe and creates a network of both medical specialists and patient experts in rare liver disease. This position paper summarizes the achievements of the first year and plots the route for the near future for ERN RARE-LIVER, as discussed during a strategy meeting that took place 27 and 28 February 2018 in Nijmegen, the Netherlands. ERN RARE-LIVER has established itself as a group with experts, hospitals and patients. One of the tools to improve communication is the clinical patient management system (CPMS) that allows access to expert consultation by European physicians confronted with a patient with rare liver disease. ERN RARE-LIVER will function as the platform to improve healthcare by initiating registries, foster research efforts and coordinate development of clinical guidelines in Europe.

Background. Calcineurin inhibitors (CNI) have significantly improved patient and graft survival in pediatric liver transplantation (pLT). However, CNI toxicity leads to significant morbidity. Moreover, CNIs cannot prevent long-term allograft injury. Mesenchymal stem (stromal) cells (MSC) have potent immunomodulatory properties, which may promote allograft tolerance and ameliorate toxicity of high-dose CNI. The MYSTEP1 trial aims to investigate safety and feasibility of donor-derived MSCs in pLT. Methods/Design. 7 to 10 children undergoing living-donor pLT will be included in this open-label, prospective pilot trial. A dose of 1 × 106 MSCs/kg body weight will be given at two time points: first by intraportal infusion intraoperatively and second by intravenous infusion on postoperative day 2. In addition, participants will receive standard immunosuppressive treatment. Our primary objective is to assess the safety of intraportal and intravenous MSC infusion in pLT recipients. Our secondary objective is to evaluate efficacy of MSC treatment as measured by the individual need for immunosuppression and the incidence of biopsy-proven acute rejection. We will perform detailed immune monitoring to investigate immunomodulatory effects. Discussion. Our study will provide information on the safety of donor-derived MSCs in pediatric living-donor liver transplantation and their effect on immunomodulation and graft survival.

Untreated progressive familial intrahepatic cholestasis (PFIC) type 2, or bile salt exporter protein deficiency, frequently leads to severe pruritus, impaired growth and progressive liver fibrosis with risk of organ failure. We describe a 15-month-old male patient with severe pruritus diagnosed with PFIC type 2 enrolled in an open-label phase 2 study who received 4 weeks of treatment with odevixibat, an ileal bile acid transporter inhibitor under development for cholestatic liver disease treatment. The patient experienced reductions in serum bile acids and improvement in itching and sleep scores, and odevixibat was well tolerated. After the odevixibat study, symptoms returned and the patient underwent partial external biliary diversion (PEBD). Odevixibat treatment and PEBD produced similar normalisation of serum bile acid levels and improvements in pruritus and sleep disruptions. Thus, odevixibat appeared to be as effective as invasive PEBD in treating serum bile acids and cholestatic pruritus in this patient.

Class III multidrug resistance (MDR) P-glycoproteins (P-gp), mdr2 in mice and MDR3 in man, mediate the translocation of phosphatidylcholine across the canalicular membrane of the hepatocyte. Mice with a disrupted mdr2 gene completely lack biliary phospholipid excretion and develop progressive liver disease, characterized histologically by portal inflammation, proliferation of the bile duct epithelium, and fibrosis. This disease phenotype is very similar to a subtype of progressive familial intrahepatic cholestasis, hallmarked by a high serum γ -glutamyltransferase (γ -GT) activity. We report immunohistochemistry for MDR3 P-gp, reverse transcription-coupled PCR sequence analysis, and genomic DNA analysis of MDR3 from two progressive familial intrahepatic cholestasis patients with high serum γ -GT. Canalicular staining for MDR3 P-gp was negative in liver tissue of both patients. Reverse transcription-coupled PCR sequencing of the first patient's sequence demonstrated a homozygous 7-bp deletion, starting at codon 132, which results in a frameshift and introduces a stop codon 29 codons downstream. The second patient is homozygous for a nonsense mutation in codon 957 (C → T that introduces a stop codon (TGA). Our results demonstrate that mutations in the human MDR3 gene lead to progressive familial intrahepatic cholestasis with high serum γ -GT. The histopathological picture in these patients is very similar to that in the corresponding mdr2(-/-) mouse, in which mdr2 P-gp deficiency induces complete absence of phospholipid in bile.

Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical, sodium-dependent, bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in Alagille syndrome. ICONIC was a placebo-controlled, randomised withdrawal period (RWD), phase 2b study with open-label extension in children (aged 1–18 years) with Alagille syndrome (NCT02160782). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 μg/kg once per day, participants were randomly assigned (1:1) to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat until week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 μg/kg twice per day. The primary endpoint was the mean sBA change during the RWD in participants with at least 50% sBA reduction by week 18. Cholestastic pruritus was assessed using observer-rated, patient-rated, and clinician-rated 0–4 scales. The safety population was defined as all participants who had received at least one dose of maralixibat. This trial was registered with ClinicalTrials.gov, NCT02160782, and is closed to recruitment. Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5·4 years [SD 4·25]) were enrolled and 28 analysed at week 48. Of the 29 participants who entered the randomised drug withdrawal period, ten (34%) were female and 19 (66%) were male. In the RWD, participants switched to placebo had significant increases in sBA (94 μmol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference –117 μmol/L, 95% CI –232 to –2). From baseline to week 48, sBA (–96 μmol/L, –162 to –31) and pruritus (–1·6 pts, –2·1 to –1·1) improved. In participants who continued to week 204 (n=15) all improvements were maintained. Maralixibat was generally safe and well tolerated throughout. The most frequent adverse events were gastrointestinal related. Most adverse events were self-limiting in nature and mild-to-moderate in severity. In children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome. Mirum Pharmaceuticals.

IntroductionPatients with progressive familial intrahepatic cholestasis (PFIC) may have continued hepatic damage leading to liver transplantation (LT). Efficacy and safety of odevixibat, an ileal bile acid transporter inhibitor, were assessed in patients with PFIC in the phase 3 PEDFIC 1 and PEDFIC 2 studies. In a pooled analysis of data from these studies, we analysed native liver survival (NLS) in odevixibat-treated patients who met serum bile acid (sBA) treatment response criteria (sBAs reduced ≥70% or levels ≤70 µmol/L at 6 months). NLS was also analysed in partial sBA responders (patients with sBA reductions ≥30% to <70% at 6 months) and nonresponders (patients with sBA reductions <30% at 6 months or who underwent LT or discontinued treatment before 6 months).MethodsPEDFIC 1 was a 24-week, randomised, placebo-controlled study in children with PFIC1 or PFIC2. PEDFIC 2 is an ongoing 72-week extension study in patients of any age with any PFIC type. This pooled analysis spans from patients’ first dose of odevixibat to a cut-off date of 31 January 2022.ResultsOf 98 patients analysed (mean treatment duration, 88 weeks), 35 (36%) were sBA responders, 14 (14%) were partial sBA responders, and 49 (50%) were nonresponders. Mean sBA reductions at 6 months were 87% in responders and 44% in partial responders; there was a mean increase of 27% in nonresponders. All 35 sBA responders and 13 of the 14 partial sBA responders remained transplant free; 8 of the 49 nonresponders underwent LT (figure 1). sBA responders had mean improvements at week 24 of treatment vs baseline in alanine aminotransferase and total bilirubin levels.Conclusions sBA decreases at 6 months were strongly associated with NLS for up to 3 years in odevixibat-treated patients with PFIC.Abstract P7 Figure 1Native liver survival in serum bile acid responders, partial responders, and nonresponders to odevixibat in the PEDFIC studies[Figure omitted. See PDF]

IntroductionPatients with progressive familial intrahepatic cholestasis (PFIC) may present with elevated serum bile acids (sBAs), growth deficits, and impaired hepatic function. The phase 3 PEDFIC 1 and PEDFIC 2 studies evaluated odevixibat, an ileal bile acid transporter inhibitor, in patients with PFIC. Using pooled data from these studies, we describe key outcomes in patients treated with odevixibat for ≥96 weeks.MethodsPEDFIC 1 (NCT03566238) was a 24-week, randomised, placebo-controlled study in children with PFIC1 and PFIC2. PEDFIC 2 (NCT03659916) is an ongoing, 72-week open-label extension study in patients with any PFIC type; an optional extension period follows PEDFIC 2. This pooled analysis spans from patients’ first dose of odevixibat to 31 January 2022. Outcomes included sBAs, hepatic parameters, growth, and safety.ResultsOf the 111 patients in the pooled population (69 ongoing at data cut-off), 36 had ≥96 weeks’ odevixibat exposure and an sBA measurement at week 96 (36% PFIC1, 61% PFIC2, 3% MYO5B deficiency). At baseline, patients had elevated mean sBA, transaminase, and total bilirubin levels, and impaired growth (table 1). At week 96, mean sBA levels were significantly reduced (P<0.001); no changes were observed in bilirubin levels (table 1). All 36 patients (100%) had treatment-emergent adverse events (TEAEs); most were mild or moderate in severity. No drug-related serious TEAEs were reported.ConclusionsOdevixibat treatment for ≥96 weeks was associated with improvements in sBAs, transaminase levels, and growth in patients with PFIC. Odevixibat was generally well tolerated.Abstract O21 Table 1Outcomes in patients with PFIC treated with odevixibat for ≥96 weeks Baseline Week 96a n Mean (SE) n Mean (SE) sBAs, µmol/L 36 266 (22) 36 118 (20)b ALT, U/L 36 102 (23) 32 38 (7) AST, U/L 36 86 (10) 32 49 (5) Total bilirubin, µmol/L 36 56 (13) 32 50 (17) Height Z score 36 −1.5 (0.3) 36 −0.9 (0.2) Weight Z score 36 −0.9 (0.3) 36 −0.2 (0.2) aVisit window spans weeks 94–104; bMean change in sBAs from baseline to week 96, P<0.001.Inferential statistics were not calculated for hepatic parameters or growth.ALT, alanine aminotransferase; AST, aspartate aminotransferase; PFIC, progressive familial intrahepatic cholestasis; sBA, serum bile acid.

Background: Patients with progressive familial intrahepatic cholestasis (PFIC) experience cholestasis-associated symptoms, including severe pruritus. Odevixibat is an ileal bile acid transporter inhibitor indicated for treatment of PFIC in the European Union and for the treatment of pruritus in PFIC in the United States. The aim of the current study was to characterize the real-world effectiveness and safety of odevixibat in patients with PFIC. Methods: This retrospective study included 9 patients with PFIC treated with odevixibat in a single center in Tübingen, Germany. Data were recorded using case report forms. Results: Of the 9 patients (PFIC1, n = 2; PFIC2, n = 7), 5 had improved serum bile acid levels, pruritus, liver function tests, and sleep with odevixibat treatment. Two siblings with periodic relapses of PFIC symptoms also had improved pruritus and sleep within 4 months of treatment. Two siblings with complete loss of bile salt export pump (BSEP) protein did not respond to treatment; both underwent liver transplantation (indications: hepatocellular carcinoma [HCC] manifestation [n = 1] and severe failure to thrive and refractory pruritus [n = 1]). Four patients reported abdominal complaints that were transient or responded to dose reduction; no other safety issues were reported. Conclusions: In this case series, clinical benefits were observed in most patients with PFIC1 and PFIC2 treated with odevixibat. In patients with periodic relapse of PFIC symptoms, ≥3 months of treatment with odevixibat may be required for symptom control. Patients with complete loss of BSEP did not have consistent symptom relief and require careful monitoring. Effectiveness and feasibility results from our cohort demonstrate potential for long-term benefits with odevixibat in real-world treatment of patients with PFIC.