Abnormal concentrations of esterified carnitine in bile

Abstract

The etiology of acute liver failure in children is unknown in a large number of cases. Defects in fatty acid oxidation have been shown to lead to severe liver injury. This retrospective analysis examined the bile acylcarnitine profiles of 27 children with acute liver failure who underwent liver transplantation or died. Results were compared with 758 postmortem samples from individuals without acute liver failure. Cumulative amounts of free carnitine, medium-or long-chain species in excess of the 95th percentile of the control group were considered abnormal. Fourteen samples had normal profiles. Three had markedly elevated concentrations of free carnitine, whereas ten showed elevations in medium-or long-chain species. The relative risk of death was 2.86 (95% confidence interval, 1.08-7.54, P ‫؍‬ .01) in the 10 children with elevated concentrations of medium-or long-chain species compared with those with normal analyses. Overall, medium-and long-chain acylcarnitines were increased in those patients who died compared with survivors, (dead vs. alive; medium-chain, 187 ؎ 74 vs. 32 ؎ 12 mol/L, P ‫؍‬ .008; long-chain, 146 ؎ 74 vs. 15 ؎ 8 mol/L, mean ؎ standard error of the mean, P ‫؍‬ .018). These studies describe biliary free and esterified carnitine profiles in children with acute liver failure. In conclusion, the findings raise the hypothesis that abnormalities in fatty acid oxidation may predispose to a worse outcome in acute liver failure. A cute liver failure (ALF) in children is a clinical syndrome consisting of biochemical evidence of severe hepatic synthetic dysfunction with or without encephalopathy. 1 In most circumstances, the etiology cannot be discerned. Well-characterized causes of ALF in children include acetaminophen toxicity, hepatitis A, hepatitis B, drug toxicity, autoimmune hepatitis, Wilson disease, and a range of rare metabolic diseases. Abnormalities in fatty acid metabolism have been associated with ALF in children.Fatty acid oxidation (FAO) plays a major role in energy production during periods of fasting. More than 25 enzymes and transporters are involved in this pathway. 2 Inherited FAO disorders represent a new and rapidly expanding class of metabolic diseases. 3,4 More than 20 FAO disorders have been described to date and present with a variety of clinical manifestations, including metabolic decompensation during fasting, hypoketotic hypoglycemia, abnormal function of fatty acid-dependent tissues, particularly liver and heart, and sudden and unexpected death. Several FAO disorders are described that present with Reye-like episodes or severe liver disease as the predominant clinical feature. Carnitine palmitoyltransferase I deficiency and medium-chain acyl-coenzyme A dehydrogenase deficiency may present with hepatomegaly, abnormal aminotransferases, steatosis, and encephalopathy. The clinical picture is not typically one of acute liver failure, although the encephalopathy is reminiscent of Reye's syndrome.

Acylcarnitine Profiles in HIV-Exposed, Uninfected Neonates in the United States

“…FAO dysfunction can lead to both hepatocytic and cardiomyocytic injury in children with inherited FAO disorders. 43 Hypoglycemia and elevated CPK levels, seen in severe FAO disorders, were not more common in our HEU newborns with abnormal ACP, again suggesting that in the first week of life FAO dysfunction is subclinical and mild. Furthermore, lactate, which is a clinical biomarker of OXPHOS dysfunction, was not significantly increased in those newborns with abnormal ACP.…”

Acute Liver Failure following Cleft Palate Repair: A Case of Therapeutic Acetaminophen Toxicity

“…Finally, acute liver failure in a young infant may be a dramatic presentation of an inborn error of metabolism unmasked by a metabolically stressful event such as surgery. In our patient, detection of aberrant organic acids and carnitine species suggested a disorder of fatty acid oxidation (Shneider et al, 2005). However, detection of these substances at the time of acute hepatic necrosis associated with extreme oxidant stress would not be surprising.…”

Pattern of Diagnostic Evaluation for the Causes of Pediatric Acute Liver Failure: An Opportunity for Quality Improvement

“…Previous work from the PALF group suggested that there were underlying abnormalities in FAO even in patients with another diagnosis 7. Because many of the metabolic diseases affect the newborn, some centers may rely on the newborn screening for young infants.…”