title: Frequency and Pathophysiology of Acute Liver Failure in Ornithine Transcarbamylase Deficiency (OTCD).
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  RESULTS
  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%.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Metabolism and Children`s Research Center (CRC), University Children`s Hospital, Zurich, Switzerland.|radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Zurich, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Laemmle
authors.affiliation: Department of Pediatrics, Medical Genetics, University of California San Francisco, San Francisco, United States of America.
authors.forename: Renata C
authors.initials: RC
authors.lastname: Gallagher
authors.affiliation: Department of Clinical Research and Clinic for Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Keogh
authors.affiliation: Division of Metabolism and Children`s Research Center (CRC), University Children`s Hospital, Zurich, Switzerland.
authors.forename: Tamar
authors.initials: T
authors.lastname: Stricker
authors.affiliation: Department of Pediatrics, University Children's Hospital, Bern, Switzerland.|University Institute of Clinical Chemistry, University of Bern, Bern, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gautschi
authors.affiliation: Department of Pediatrics, University Children's Hospital, Bern, Switzerland.|University Institute of Clinical Chemistry, University of Bern, Bern, Switzerland.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Nuoffer
authors.affiliation: Division of Metabolism and Children`s Research Center (CRC), University Children`s Hospital, Zurich, Switzerland.|radiz-Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Baumgartner
authors.affiliation: Division of Metabolism and Children`s Research Center (CRC), University Children`s Hospital, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Häberle
mesh_terms: D000293:Adolescent; D000328:Adult; D000641:Ammonia / Q000097:blood; D002648:Child; D005260:Female; D006801:Humans; D022124:Hyperammonemia / Q000097:blood / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000473:pathology; D017114:Liver Failure, Acute / Q000097:blood / Q000453:epidemiology* / Q000209:etiology / Q000473:pathology*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020163:Ornithine Carbamoyltransferase Deficiency Disease / Q000097:blood / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D055815:Young Adult
chemical_list: D000641:Ammonia