Progressive familial intrahepatic cholestasis—outcome and time to transplant after biliary diversion according to genetic subtypes

BackgroundProgressive familial intrahepatic cholestasis (PFIC) is a heterogeneous disease characterized by progressive cholestasis in early childhood. Surgical therapy aims at preventing bile absorption either by external or internal biliary diversion (BD). Several different genetic subtypes encode for defects in bile transport proteins, and new subtypes are being discovered ongoingly. Overall, the literature is scarce, however, accumulating evidence points to PFIC 2 having a more aggressive course and to respond less favorable to BD. With this knowledge, we aimed to retrospectively analyze the long-term outcome of PFIC 2 compared to PFIC 1 following BD in children at our center.MethodsClinical data and laboratory findings of all children with PFIC, who were treated and managed in our hospital between 1993 and 2022, were analyzed retrospectively.ResultsOverall, we treated 40 children with PFIC 1 (n = 10), PFIC 2 (n = 20) and PFIC 3 (n = 10). Biliary diversion was performed in 13 children (PFIC 1, n = 6 and 2, n = 7). Following BD, bile acids (BA) (p = 0.0002), cholesterol (p < 0.0001) and triglyceride (p < 0.0001) levels significantly decreased only in children with PFIC 1 but not in PFIC 2. Three out of 6 children (50%) with PFIC 1 and 4 out of 7 children (57%) with PFIC 2 required liver transplantation despite undergoing BD. On an individual case basis, BA reduction following BD predicted this outcome. Of the 10 children who had PFIC 3, none had biliary diversion and 7 (70%) required liver transplantation.ConclusionIn our cohort, biliary diversion was effective in decreasing bile acids, cholesterol levels as well as triglycerides in the serum only in children with PFIC 1 but not PFIC 2. On an individual case level, a decrease in BA following BD predicted the need for liver transplantation

Genotypic diversity and phenotypic spectrum of infantile liver failure syndrome type 1 due to variants inLARS1

Purpose: Biallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings. Methods: Individuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts. Results: Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro. Conclusion: ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke

Congenital Diarrhea and Cholestatic Liver Disease: Phenotypic Spectrum Associated with MYO5B Mutations

Myosin Vb (MYO5B) is a motor protein that facilitates protein trafficking and recycling in polarized cells by RAB11- and RAB8-dependent mechanisms. Biallelic MYO5B mutations are identified in the majority of patients with microvillus inclusion disease (MVID). MVID is an intractable diarrhea of infantile onset with characteristic histopathologic findings that requires life-long parenteral nutrition or intestinal transplantation. A large number of such patients eventually develop cholestatic liver disease. Bi-allelic MYO5B mutations are also identified in a subset of patients with predominant early-onset cholestatic liver disease. We present here the compilation of 114 patients with disease-causing MYO5B genotypes, including 44 novel patients as well as 35 novel MYO5B mutations, and an analysis of MYO5B mutations with regard to functional consequences. Our data support the concept that (1) a complete lack of MYO5B protein or early MYO5B truncation causes predominant intestinal disease (MYO5B-MVID), (2) the expression of full-length mutant MYO5B proteins with residual function causes predominant cholestatic liver disease (MYO5B-PFIC), and (3) the expression of mutant MYO5B proteins without residual function causes both intestinal and hepatic disease (MYO5B-MIXED). Genotype-phenotype data are deposited in the existing open MYO5B database in order to improve disease diagnosis, prognosis, and genetic counseling.This research was funded by Jubiläumsfonds der Österreichischen Nationalbank, grant no.16678 (to A.R.J.), grant no. 18019 (to G.-F.V.) and Tiroler Wissenschaftsfonds, grant No. 0404/2386 (toG.-F.V.).info:eu-repo/semantics/publishedVersio

Genetic landscape of pediatric acute liver failure of indeterminate origin.

BACKGROUND AIMS Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, main causes are viral infections (12-16%) and inherited metabolic diseases (14-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. METHODS With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF (RALF). WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (46%), and in children with RALF (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8) and DGUOK (n=7) were the most frequent findings. When categorizing, most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%) and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplants. CONCLUSION This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics

Isolation and identification of adenosineguanosinetriphosphate, adenosineguanosinepentaphosphate and diguanosinediphosphate from human parathyroid glands

Die Ätiologie der essentiellen Hypertonie ist multifaktoriell; viele der involvierten Faktoren sind bislang noch unbekannt. Gründe für eine Erhöhung des arteriellen Blutdrucks könnten unter anderem endogene bisher unbekannte vasoaktive Mediatoren sein. Die Nebenschilddrüse ist Ort der Synthese und Sekretion unterschiedlicher Hormone. So ist das in der Nebenschilddrüse gebildete Parathormon für die Regulation des Calciumhaushalts verantwortlich. Patienten mit primärem Hyperparathyreoidismus entwickeln eine arterielle Hypertonie. Nachdem in vorhergehenden Studien gezeigt worden war, dass Parathormon nicht ursächlich für eine Erhöhung des arteriellen Blutdrucks bei Patienten mit Hyperparathyreoidismus war, konnte in Tierversuchen ein Zusammenhang zwischen dem hypothetischen „Parathyroid Hypertensive Factor“ (PHF) und der arteriellen Hypertonie nachgewiesen werden. Der „Parathyroid Hypertensive Factor“ wurde in seiner Struktur bisher nicht genau identifiziert, obwohl mehrere Hypothesen zur Form und Größe der Substanz aufgestellt wurden. In den letzten Jahren sind Dinukleosidpolyphosphate, eine Gruppe endogener Mediatoren, aus tierischen und menschlichen Geweben isoliert worden. Dinukleosidpolyphosphate haben einen Einfluss auf den Tonus und die Proliferationsrate glatter Gefäßmuskelzellen. Dinukleosid-polyphosphate könnten somit einen Einfluss auf die Pathogenese der arteriellen Hypertonie haben. In der vorliegenden Arbeit wurden Dinukleosidpolyphosphate aus Nebenschilddrüsengewebe isoliert. Das Nebenschilddrüsengewebe entstammte Patienten, die aufgrund eines primären Hyperparathyreoidismus parathyreoidektomiert wurden. Nach mechanischer Desintegration und Deproteinierung wurden mittels unterschiedlicher chromatographischer Verfahren homogene Fraktionen erhalten. Die zu Grunde liegenden Substanzen wurden mittels Massenspektrometrie, Vergleich der Retentionszeiten mit den authentischen Substanzen und enzymatischer Analytik analysiert. Mit diesen Methoden konnten die Dinukleosidpolyphosphate Ap3G, Ap5G und Gp2G in menschlichem Nebenschilddrüsengewebe nachgewiesen werden. Aufgrund dieser Arbeit kann vermutet werden, dass diese Dinukleosidpolyphosphate bei einem Teil der Patienten mit Hyperparathyreoidismus für die arterielle Hypertonie verantwortlich sein könnten. In weiterführenden Studien sollte der Gehalt der Dinukleosidpolyphosphate Ap3G, Ap5G und Gp2G bei Patienten mit und ohne Hyperparathyreoidismus bestimmt werden. Hierdurch könnte möglicherweise ein neuer therapeutischer Ansatz zur Therapie der arteriellen Hypertonie entwickelt werden.The aetiology of essential hypertension is diverse. Many of the causative factors are unknown. New endogenous vasoactive mediators could be responsible for arterial hypertension. The parathyroid gland is place for synthesis and secretion of a variety of hormones. Parathormone, which is produced in the parathyroid gland, is responsible for the regulation of the calcium homoeostasis. Patients with primary hyperparathyroidism develop arterial hypertension. Studies could show that parathormone unlikely causes arterial hypertension. Animal studies showed that there is a link between the hypothetical “parathyroid hypertensive factor” (PHF) and arterial hypertension. The exact structure of the PHF molecule has not been clearly identified, even though there are hypothesis for size and shape of the substance. Within the last years, a group of endogenous mediators, dinucleosidepolyphosphates, have been isolated from animal and human tissue. Dinuclesidepolyphosphates are known to influence the tonus of vascular smooth muscle cells as well as its proliferation rate. Therefore, dinucleosidepolyphosphates could influence the pathogenesis of arterial hypertension. In the present work, dinucleosidepolyphosphates have been isolated from human parathyroid glands. The tissue was taken from patients who underwent parathyroidectomy due to primary hyperparathyroidism. After mechanical disintegration and deproteinization, homogenous fractions were obtained through liquid chromatography. The analysis of the substances was made by mass spectrometry, enzymatic analysis and comparison of the retention times with the authentic substances. Like this, the dinucleosidepolyphosphates Ap3G, Ap5G and Gp2G could be found in human parathyroid tissue. This work shows that dinucleosidepolyphosphates could be responsible for arterial hypertension in patients with hyperparathyroidism. In further studies, the quantity of these dinucleosidepolyphosphates should me measured in patients with or without hyperparathyroidism to evaluate their influence in arterial hypertension in this group

Mutation in ITCH Gene Can Cause Syndromic Multisystem Autoimmune Disease With Acute Liver Failure

Pediatric intractable autoimmune hepatitis is rare and may be responsible for acute liver failure. Mutations in the itchy E3 ubiquitin protein ligase (ITCH) gene (located on chromosome 20q11.22) can lead to a deficiency of the encoded protein, resulting in increased T-cell activity with lack of immune tolerance and manifestation of a complex systemic autoimmune disease. A 1-year-old girl of consanguineous parents received a liver transplant (LT) because of acute liver failure attributed to a drug-induced hypereosinophilic syndrome with positive liver-kidney-mikrosome-2 antibodies. Notable findings were syndromic features, dystrophy, short stature, psychomotor retardation, and muscular hypotonia. Later, we saw corticosteroid-sensitive rejections as well as a systemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia). Histologically, liver cirrhosis with lobular inflammatory infiltrates, giant-cell hepatitis, and ductopenia was verified in chronic cholestasis. Shortly after a second LT, a comparable liver histology could be detected, and viral, bacterial, and mycotic infections deteriorated the general health condition. Because of refractory pancytopenia related to portal hypertension and hypersplenism, a posttransplant lymphoproliferative disorder was excluded. One year after the second LT, epidural and subdural bleeding occurred. Three months afterward, the girl died of sepsis. Postmortem, whole-exome sequencing revealed a homozygous mutation in the ITCH gene. A biallelic mutation in ITCH can cause a severe syndromic multisystem autoimmune disease with the above phenotypic characteristics and acute liver failure because of autoimmune hepatitis. This case reveals the importance of ubiquitin pathways for regulation of the immune system

Etiology, outcome and prognostic factors of childhood acute liver failure in a German Single Center

Pediatric acute liver failure (PALF) is a progressive, potentially fatal clinical syndrome occurring in previously healthy children. Our study aimed to determine the current leading causes of PALF in a single center in Germany, identifying possible prognostic markers. Thirty-seven pediatric patients with PALF were included. Medical records were reviewed for demographic, laboratory and clinical data. Laboratory results on admission and at peak value, PELD and MELD score on admission, and intensive care support were assessed. Fifteen patients recovered spontaneously, 14 died without transplantation, and 8 received a liver transplant. Patients who survived were significantly older than patients who died. Specific causes of PALF could be identified as infectious diseases (16%), metabolic diseases (14%), toxic liver injury (11%), immunologic diseases (8%), or vascular diseases (8%). Causes of PALF remained indeterminate in 43%. High ammonia, low albumin, and low ALT levels on admission were associated with worse outcome. Absence of need of ventilation, hemodialysis, and circulatory support predicted spontaneous recovery. In conclusion, infections are the most common known cause of PALF. However, in a large proportion of patients the cause for PALF remains cryptic. Ammonia and albumin levels may be of prognostic value to predict outcomes

Prevalence of hepatitis E virus infection in pediatric solid organ transplant recipients - A single-center experience

HEV infection appears to be an emerging disease in industrialized countries. The aim of this study was to evaluate the prevalence of HEV infection in pediatric solid organ transplant recipients. One hundred and twenty‐four pediatric recipients of liver (n = 41) or kidney (n = 83) transplants aged between one and 18 yr were screened for anti‐HEV IgG antibodies. Patients were tested for fecal HEV RNA excretion if they showed anti‐HEV seropositivity. As a control group, 108 immunocompetent pediatric patients without liver disease aged between three and 18 yr were screened for anti‐HEV IgG. HEV seroprevalence was 2.4% in renal Tx (2/83), 4.9% in liver Tx patients (2/41), and 3.2% overall (4/124). Three of these four patients were HEV RNA‐negative. In one renal transplant patient, HEV genotype 3 RNA excretion persisted and liver enzymes were elevated, indicating chronic hepatitis. In the control group, eight patients (7.4%) were HEV IgG‐positive without biochemical evidence of hepatitis. The prevalence of HEV infection in pediatric renal or liver transplant recipients is not higher compared with immunocompetent children. Chronic HEV infection with long‐term carriage of the virus may develop in pediatric transplant recipients. Autochthonous HEV infection needs to be considered in uncertain cases of hepatitis in immunosuppressed as well as immunocompetent children

Congenital Diarrhea and Cholestatic Liver Disease: Phenotypic Spectrum Associated with MYO5B Mutations

Myosin Vb (MYO5B) is a motor protein that facilitates protein trafficking and recycling in polarized cells by RAB11- and RAB8-dependent mechanisms. Biallelic MYO5B mutations are identified in the majority of patients with microvillus inclusion disease (MVID). MVID is an intractable diarrhea of infantile onset with characteristic histopathologic findings that requires life-long parenteral nutrition or intestinal transplantation. A large number of such patients eventually develop cholestatic liver disease. Bi-allelic MYO5B mutations are also identified in a subset of patients with predominant early-onset cholestatic liver disease. We present here the compilation of 114 patients with disease-causing MYO5B genotypes, including 44 novel patients as well as 35 novel MYO5B mutations, and an analysis of MYO5B mutations with regard to functional consequences. Our data support the concept that (1) a complete lack of MYO5B protein or early MYO5B truncation causes predominant intestinal disease (MYO5B-MVID), (2) the expression of full-length mutant MYO5B proteins with residual function causes predominant cholestatic liver disease (MYO5B-PFIC), and (3) the expression of mutant MYO5B proteins without residual function causes both intestinal and hepatic disease (MYO5B-MIXED). Genotype-phenotype data are deposited in the existing open MYO5B database in order to improve disease diagnosis, prognosis, and genetic counseling