Frequency and Pathophysiology of Acute Liver Failure in Ornithine Transcarbamylase Deficiency (OTCD)

Acute liver failure (ALF) has been reported in ornithine transcarbamylase deficiency (OTCD) and other urea cycle disorders (UCD). The frequency of ALF in OTCD is not well-defined and the pathogenesis is not known. To evaluate the prevalence of ALF in OTCD, we analyzed the Swiss patient cohort. Labor...

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Bibliographic Details
Published in:PloS one 2016-04, Vol.11 (4), p.e0153358-e0153358
Main Authors: Laemmle, Alexander, Gallagher, Renata C, Keogh, Adrian, Stricker, Tamar, Gautschi, Matthias, Nuoffer, Jean-Marc, Baumgartner, Matthias R, Häberle, Johannes
Format: Article
Language:English
Subjects:
Adolescent
Adult
Ammonia
Ammonia - blood
Ammonium
Ammonium chloride
Analysis
Biology and Life Sciences
Brain damage
Cell culture
Child
Children & youth
Chlorides
Coagulation
Complications and side effects
Defects
Diagnosis
Family medical history
Female
Females
Hepatocytes
Hospitals
Humans
Hyperammonemia
Hyperammonemia - blood
Hyperammonemia - metabolism
Hyperammonemia - pathology
Laboratories
Liver
Liver - pathology
Liver diseases
Liver failure
Liver Failure, Acute - blood
Liver Failure, Acute - epidemiology
Liver Failure, Acute - etiology
Liver Failure, Acute - pathology
Liver transplants
Longitudinal Studies
Male
Males
Medicine and Health Sciences
Metabolic disorders
Middle Aged
Mortality
Mutation
Nervous system diseases
Ornithine
Ornithine Carbamoyltransferase Deficiency Disease - blood
Ornithine Carbamoyltransferase Deficiency Disease - complications
Ornithine Carbamoyltransferase Deficiency Disease - metabolism
Ornithine Carbamoyltransferase Deficiency Disease - pathology
Pathogenesis
Patients
Pediatrics
Physical Sciences
Physiology
Protein biosynthesis
Protein synthesis
Risk factors
Secretion
Transaminases
Urea
Urea cycle
Vitamin K
Young Adult
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Summary:Acute liver failure (ALF) has been reported in ornithine transcarbamylase deficiency (OTCD) and other urea cycle disorders (UCD). The frequency of ALF in OTCD is not well-defined and the pathogenesis is not known. To evaluate the prevalence of ALF in OTCD, we analyzed the Swiss patient cohort. Laboratory data from 37 individuals, 27 females and 10 males, diagnosed between 12/1991 and 03/2015, were reviewed for evidence of ALF. In parallel, we performed cell culture studies using human primary hepatocytes from a single patient treated with ammonium chloride in order to investigate the inhibitory potential of ammonia on hepatic protein synthesis. More than 50% of Swiss patients with OTCD had liver involvement with ALF at least once in the course of disease. Elevated levels of ammonia often correlated with (laboratory) coagulopathy as reflected by increased values for international normalized ratio (INR) and low levels of hepatic coagulation factors which did not respond to vitamin K. In contrast, liver transaminases remained normal in several cases despite massive hyperammonemia and liver involvement as assessed by pathological INR values. In our in vitro studies, treatment of human primary hepatocytes with ammonium chloride for 48 hours resulted in a reduction of albumin synthesis and secretion by approximately 40%. In conclusion, ALF is a common complication of OTCD, which may not always lead to severe symptoms and may therefore be underdiagnosed. Cell culture experiments suggest an ammonia-induced inhibition of hepatic protein synthesis, thus providing a possible pathophysiological explanation for hyperammonemia-associated ALF.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0153358