title: Reduced mitochondrial DNA content and heterozygous nuclear gene mutations in patients with acute liver failure.
abstract: OBJECTIVE
  Historically, mitochondrial disorders have been associated with predominantly multisystem or neurological symptoms. If present, hepatic complications were thought to be a late feature. Recently, mutations in at least 4 nuclear genes have been identified in infants presenting with rapidly progressive hepatic failure, which may be precipitated by infection or drugs. We aimed to determine whether hepatic mitochondrial DNA (mtDNA) depletion is associated with apparently isolated hepatic failure in individuals with acute liver failure (ALF) of known or unknown etiologies undergoing liver transplant (LT). In addition, we wished to establish whether there was an excess of mutations in gene known to cause hepatic mtDNA depletion.
  
  
  METHODS
  Using previously established methods, we demonstrated that end-stage liver disease from known causes did not lead to hepatic mtDNA depletion.
  
  
  RESULTS
  Using thresholds derived from receiver-operator curve analysis, 66% of cases with ALF had probable or definite mtDNA depletion, including 34% with definite mtDNA depletion. There was a small but significant increase in the proportion of patients undergoing LT for ALF with heterozygous mutations known to lead to mtDNA depletion and hepatic failure compared with controls (P = 0.001).
  
  
  CONCLUSIONS
  Liver disease severe enough to require LT does not cause secondary mtDNA depletion; however, the majority of patients undergoing LT for ALF had reduced mtDNA content, which fell within the range seen in patients with classic mtDNA depletion. A subset of patients with ALF has mutations in genes known to lead to mtDNA depletion and hepatic failure. Together, these results suggest defective mtDNA maintenance is associated with ALF.
authors.affiliation: *Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI †Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
authors.forename: Daniel
authors.initials: D
authors.lastname: Helbling
authors.forename: Adam
authors.initials: A
authors.lastname: Buchaklian
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Lee-Jun
authors.initials: LJ
authors.lastname: Wong
authors.forename: David
authors.initials: D
authors.lastname: Dimmock
mesh_terms: D002467:Cell Nucleus / Q000235:genetics*; D004272:DNA, Mitochondrial; D006579:Heterozygote; D006801:Humans; D008099:Liver / Q000601:surgery; D017114:Liver Failure, Acute / Q000235:genetics* / Q000601:surgery; D016031:Liver Transplantation; D008928:Mitochondria / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics*; D009154:Mutation; D012372:ROC Curve
chemical_list: D004272:DNA, Mitochondrial