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Reduced mitochondrial DNA content and heterozygous nuclear gene mutations in patients with acute liver failure.

ABSTRACT: 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.

SUBMITTER: Helbling D

PROVIDER: S-EPMC4966813 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Reduced mitochondrial DNA content and heterozygous nuclear gene mutations in patients with acute liver failure.

Helbling Daniel D Buchaklian Adam A Wang Jing J Wong Lee-Jun LJ Dimmock David D

Journal of pediatric gastroenterology and nutrition 20131001 4

<h4>Objectives</h4>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 h ...[more]

PMID: 23783014

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Project description:Pediatric acute-liver-failure due to acetaminophen (APAP) administration at therapeutic dosage is rare, while viral infections and metabolic defects are the prevalent causes. Yet, as acetaminophen is routinely used in febrile illnesses, it may be mistakenly held responsible for the acute liver damage.An 11 month old boy had been on acetaminophen for 10 days (total dose 720 mg = 72 mg/kg) when he developed acute-liver-failure with encephalopathy. As he rapidly improved on N-acetylcysteine (NAC) infusion, it was concluded that chronic acetaminophen administration in an infant had lead to acute-liver-failure even at therapeutic doses, that N-acetylcysteine infusion had been life-saving and should be immediately started in similar circumstances. The child, however, had two further episodes of acute liver damage over a 34-month period, without having been given acetaminophen, as the parents carefully avoided using it. His clinical, laboratory and radiological findings between the acute episodes were unremarkable. His features and skeletal surveys were not suggestive of a syndromic condition. He then went on to suffer another episode of acute-liver-failure with multi-organ failure, necessitating an urgent liver transplant. All efforts to come to a diagnosis for the causes of his recurrent episodes of liver failure had been unsuccessful, until a biallelic mutation in the NBAS gene was reported to be associated with recurrent acute-liver-failure in children. The boy's DNA analysis revealed compound heterozygous pathogenic mutations in the NBAS gene. Liver failure episodes in these patients are triggered and worsened by fever, most likely due to thermal susceptibility of hepatocytes, hence APAP, rather than being a culprit, is part of the supportive treatment.We suggest that, in acute-liver-failure with a history of acetaminophen exposure at therapeutic dosage, clinicians should not be contented with administering NAC, but should consider an alternative etiology, above all if the episodes are recurrent, and actively start supportive and antipyretic treatment while seeking the advice of a specialist unit.

Dataset Information

Reduced mitochondrial DNA content and heterozygous nuclear gene mutations in patients with acute liver failure.

Publications

Reduced mitochondrial DNA content and heterozygous nuclear gene mutations in patients with acute liver failure.

Similar Datasets

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