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Reduced Mitochondrial DNA Content and Heterozygous Nuclear Gene Mutations in Patients With Acute Liver Failure

Helbling, Daniel*; Buchaklian, Adam*; Wang, Jing; Wong, Lee-Jun; Dimmock, David*

Journal of Pediatric Gastroenterology and Nutrition: October 2013 - Volume 57 - Issue 4 - p 438–443
doi: 10.1097/MPG.0b013e31829ef4b4
Original Articles: Hepatology and Nutrition

Objectives: 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.

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*Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.

Address correspondence and reprint requests to Dr David Dimmock, Department of Pediatrics and Human Molecular Genetics Center, 8701 Watertown Plank Road, Milwaukee, WI 53221 (e-mail:

Received 1 March, 2013

Accepted 30 May, 2013

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Normal and pathologic human liver were obtained through the Liver Tissue Cell Distribution System, Minneapolis, Minnesota; Pittsburgh, Pennsylvania, and Richmond, Virginia, which was funded by NIH Contract #N01-DK-7–0004/HHSN267200700004C.

The authors report no conflicts of interest.

© 2013 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,