Absence of the G1528C (E474Q) Mutation in the α-Subunit of the Mitochondrial Trifunctional Protein in Women with Acute Fatty Liver of Pregnancy

Abstract

Acute fatty liver of pregnancy (AFLP) is a rare and dreaded complication of pregnancy, almost exclusively seen in the third trimester. The histopathologic features of AFLP closely resemble those seen in metabolic disorders characterized by deficiency of fatty acid oxidative enzymes. Several reports have established a strong association between AFLP in the mother and fetal deficiency of the enzyme long-chain L-3-hydroxyacyl-CoA dehydrogenase (LCHAD). However, these studies have an inevitable selection bias resulting from ascertainment through an affected infant, rather than an unselected population of patients with AFLP. We retrospectively examined a series of 10 women with pregnancies complicated by AFLP to determine the prevalence of the common LCHAD mutation (G1528C) in this population. The existing LCHAD primers, which produce a 640-bp amplicon (IJlst L, Ruiter JP, Hoovers JM, Jakobs ME, Wanders RJ: J Clin Invest 98: 1028 -1033, 1996), were modified to make them amenable to analysis of fragmented DNA obtained from microdissected formalin-fixed material. None of the patients were found to harbor the common G1528C mutation. It is likely that AFLP arising in the context of fetal LCHAD deficiency represents only one of the possible etiologies for this uncommon disorder, and the metabolic basis of AFLP is more heterogeneous than previously believed. A spectrum of maternal liver disorders can occur during pregnancy. Many, such as hepatitis or drug-induced hepatotoxicity, can also be seen in nonpregnant individuals, whereas others, including preeclampsia and intrahepatic cholestasis of pregnancy, are unique to the gravid state (1). AFLP is an uncommon but clinically severe form of hepatopathy that is seen almost exclusively in the third trimester of pregnancy. AFLP manifests with jaundice, which can rapidly progress to severe coagulopathy, fulminant hepatic failure, and death of both mother and fetus. Approximately 50% of affected patients have preeclampsia with high blood pressure, proteinuria, and peripheral edema, and up to 20% may have AFLP coexisting with the HELLP syndrome (1). AFLP derives its name from the presence of marked microvesicular steatosis in the liver, often with involvement of the heart, kidneys, and pancreas. Recent studies have reported a maternal mortality rate of 10 -20% with AFLP, underscoring the need for early diagnosis and intervention. The cornerstone of therapy is delivery of the fetus, and the clinical condition dramatically ameliorates in the postpartum period.In recent years, investigators have speculated that AFLP/ HELLP syndrome and certain inherited fatty acid oxidation disorders, specifically LCHAD deficiency, may share a common pathogenic mechanism, based on striking similarities in hepatic pathology. This empirical association was strengthened by reports of AFLP or HELLP syndrome occurring during the third trimester in mothers bearing children with LCHAD deficiency. For example, Wilcken et al. (2) were the first to report the occurrence of AFLP and HELLP syndrome in six of six...

Pregnancy-Related Liver Disorders

“…24 Presence of FAO defects in the fetus is estimated to increase by 18 fold the risk of AFLP and other pregnancy related disorders in the mother. 25 However, not all mothers with AFLP have these described mutations, 26,27 and not all mothers carrying fetus homozygous for these defects develop AFLP. 25 Thus, the pathogenetic mechanism of AFLP is heterogenous.…”

Cribado neonatal ampliado en la Región de Murcia. Experiencia de tres años

“…Finalmente, para detectar reordenamientos se utilizó el kit MLPA SALSA P091 CFTR (MRC_Holland, Amsterdam, Holanda). El aná lisis de las mutaciones en los genes causantes de MCADD y 3-hidroxi-acil-CoA deshidrogenasa de cadena larga (LCHAD) se realizó mediante secuenciació n 12,13 . La bú squeda de mutaciones en el gen GCDH de la aciduria glutá rica tipo I (AG I) y en el de la biotinidasa se realizó en el Institut de Bioquímica Clínica de Barcelona y el Centro de Diagnó stico de Enfermedades Moleculares de Madrid, respectivamente.…”

Liver injury in acute fatty liver of pregnancy: Possible link to placental mitochondrial dysfunction and oxidative stress

“…Although the majority of primary mitochondrial hepatopathies present in childhood, AFLP presents in a previously asymptomatic woman in late pregnancy. The disease is associated with defects in β‐oxidation of fatty acids in mitochondria4 especially the mitochondrial long‐chain acyl coenzyme A dehydrogenase (LCHAD)5, 6 in the fetus, but it is now recognized that AFLP can occur without a mutation in LCHAD 7, 8. This suggests that the metabolic basis of AFLP is more heterogeneous than believed earlier, but the mechanism by which a fetal defect in lipid metabolism causes maternal liver damage is not well understood.…”