26 research outputs found
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
Organogenesis: Making Pancreas from Liver
AbstractMaking endocrine pancreas cells at will is one of the major goals of cellular based therapies for diabetes. The experimentally induced conversion of hepatocytes into pancreatic cells, using a modified version of the transcription factor Pdx-1, may provide an alternative to stem cell approaches
Differences in CNS metabolism between pups and adults in an animal model of biliary cirrhosis: longitudinal, non-invasive in vivo study
Complement C3 is necessary for early patterning of neural crest, foregut and blood in Xenopus laevis
Hippocampal and Cerebellar Astrocytes Morphological Alterations in a Rat Model of Chronic Hepatic Encephalopathy
Juvenile autoimmune hepatitis: A comprehensive review
Autoimmune hepatitis (AIH) is a rare, chronic disease that affects both adults and children, including infants.
The disease is probably triggered by environmental factors in genetically predisposed individuals. The clinical
presentation ranges from asymptomatic patients or patients with non-specific symptoms, such as fatigue, to
fulminant liver failure, many children presenting with symptoms indistinguishable from those of acute hepatitis.
Raised transaminase and immunoglobulin G (IgG) levels, in association with circulating autoantibodies, guide
towards the diagnosis. The histological hallmark is interface hepatitis, which however is non-specific and may be
absent. There are no bile duct changes on cholangiography. Presence of anti-nuclear antibody (ANA) and/or
anti-smooth muscle antibody (SMA) is characteristic for type 1 AIH, whereas presence of anti-liver kidney microsomal
type 1 (LKM1) antibody and/or anti-liver cytosol type 1 (LC1) antibody defines type 2 AIH. The latter
accounts for about one third of the juvenile AIH cases, presents more acutely than type 1 AIH and is very rare in
adults. Immunosuppressive therapy, based on steroids and azathioprine, is required, and in the vast majority of
patients leads to clinical and biochemical remission, defined as absence of symptoms, normal transaminase and
IgG levels, and negative or low-titer autoantibodies. In patients intolerant or non-responder to standard therapy,
a number of second line drugs have been employed with variable results. For the rare cases who progress to endstage
liver disease, liver transplantation is life-saving, but recurrence of the disease is possible. A better understanding
of the underlying pathogenic mechanisms will help to develop new, more effective and less toxic
therapies, and to tailor treatment regimens to the individual patient