Acute fatty liver of pregnancy and neonatal long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency
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- Gutiérrez Junquera, C., Balmaseda, E., Gil, E. et al. Eur J Pediatr (2009) 168: 103. doi:10.1007/s00431-008-0696-z
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Here we report a 7-month-old girl with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency with hypoketotic hypoglycemia; the mother had a history of acute fatty liver in a previous pregnancy leading to fetal death at 34 weeks of gestation. The misense mutation 1528G > C was detected in both alleles in the proband and in one allele in both parents. We emphasize that screening for fatty acid oxidation disorders and specifically LCHAD deficiency should be performed in newborns from mothers with hepatic complications during pregnancy such as acute fatty liver of pregnancy or severe or recurrent HELLP syndrome.
KeywordsAcute fatty liver of pregnancyHELLP syndromeFatty acid oxidation disordersLCHAD deficiency
- HELLP syndrome
Hemolysis, elevated liver enzymes, and low platelet count syndrome
Acute fatty liver of pregnancy
Long-chain 3-hydroxiacyl-coenzyme A dehydrogenase
Mitochondrial trifunctional protein
Activated partial thromboplastin time
Fetal-maternal interactions are critical determinants of maternal health during pregnancy and of perinatal outcome. Liver diseases uniquely related to pregnancy may develop, including acute fatty liver of pregnancy (AFLP) and the syndrome of hemolysis, elevated liver enzymes and low platelet counts (HELLP syndrome). These complications occur mainly in the third trimester of pregnancy and are associated with high maternal and fetal morbidity and mortality.
Although the pathogenesis of these entities has not been completely elucidated, they have been associated with fetal fatty oxidation disorders, as a condition in which fetal disease has a detrimental effect on maternal health. Single case reports have linked maternal hepatic complications with fetal carnitine palmitoyltransferase I deficiency, short-chain acyl-coenzyme A dehydrogenase deficiency and medium-chain acyl-CoA dehydrogenase deficiency, but the most strong association observed has been with fetal defects of long-chain fatty oxidation .
We report an infant with hypoketotic hypoglycemia in which the maternal history of AFLP in a previous pregnancy led to the diagnosis of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency due to the mutation 1528G > C. We review the present knowledge of this association and the recommendations for screening and prevention.
A 7-month-old girl was admitted to the pediatric intensive care unit with hypotonia and decreased level of consciousness. She is the first child of nonconsanguineous parents. The mother had a previous pregnancy 4 years before complicated with AFLP leading to fetal death at 34 weeks of gestation. The present pregnancy was unremarkable although delivery was initiated at 36 + 2 weeks of gestational age and terminated by caesarean section. The mother stated that the baby had anorexia since birth and occasional vomiting. Three days before admission she had more frequent vomiting and she refused feedings, without an infectious illness. On physical exam she was comatose with poor perfusion, and hepatomegaly was detected.
The metabolic crisis was treated with intravenous glucose (rate of 10 mg kg−1 min−1) and bicarbonate. Clinical and neurological situation improved progressively. Hypoglycemia, hyperammonemia, and lactic acidosis resolved. Liver function tests showed deterioration in the first 24 h of admission (GOT 967 U/l, GPT 432 U/l, GGT 195 U/l, albumin 2.8 g/dl) but improved progressively in the following days. Three days after admission, feeding was initiated with a formula containing protein, carbohydrates, vitamins, and minerals. After obtaining the metabolic work-up, a diet containing 10% of calories from long-chain triglycerides (LCT) and 20% of calories from medium-chain triglycerides (MCT) was started with a 3-h period of fasting during the day and nocturnal drip by nasogastric tube. A percutaneous endoscopic gastrostomy tube was placed 1 month after admission. After 10 months of follow-up, she is doing well with no metabolic crisis and normal growth and psychomotor development. Follow-up echocardiography was unremarkable, and she has not presented arrhythmias.
Maternal history regarding previous pregnancy 4 years ago was reviewed. She noticed decreased fetal movements at 34 weeks gestational age and was admitted with an initial diagnosis of fetal death and HELLP syndrome (hemoglobin 12.4 g/dl, LDH 1253 IU/l, AST 70 IU/l, platelet count 63,000/μl). She received blood cells and platelets transfusion, and an emergency caesarean section was performed. She was admitted to the intensive care unit with a clinical course complicated with hemolytic anemia, jaundice (maximum direct bilirubin 23 mg/dl), hypoglycemia, renal failure (plasma creatinin level 3 mg/dl), and disseminated intravascular coagulation. This clinical picture prompted the diagnosis of AFLP. She recovered completely with supportive treatment.
Hepatic maternal complications during pregnancy have been associated with fetal defects in fatty acid oxidation. Single case reports have linked HELLP syndrome or AFLP to three fatty acid oxidation disorders, but AFLP has been more frequently reported in association with fetal LCHAD deficiency. In a case control study of 50 children with fatty acid oxidation disorders, Browning et al. found that maternal liver disease (AFLP or HELLP) occurred in 16% of them, compared with 0.88% in the general population. Long-chain defects were 50 times and short-chain defects 12 times more likely than controls to develop those complications .
LCHAD deficiency is caused by a genetic defect of mitochondrial trifunctional protein (MTP). MTP is a hetero-octamer of four α- and four β- subunits and catalyzes the last three reactions of the fatty acid β-oxidation spiral with longer chain substrates. The α-subunit N-terminal domain contains the long-chain 3-enoyl-coA hydratase activity, while LCHAD activity resides in the C-terminal domain. The β-subunit has the long-chain 3-ketoacyl-CoA thiolase activity. The genes encoding both subunits are located on chromosome 2. Defects in the MTP complex may cause isolated LCHAD deficiency with normal or partially reduced thiolase activity or complete deficiency with marked reduction in activity of the three enzymes.
Ibdah et al. reported the α-subunit molecular defects and phenotypes in 24 patients with isolated LCHAD deficiency or complete MTP deficiency . Patients with the more common isolated LCHAD deficiency, as the case we report, predominantly had a Reye-like syndrome and carried a prevalent missense mutation on one or both alleles. In this prevalent mutation, there is a G-to-C nucleotide change at position 1528 (1528G > C) of the coding region, which causes a glutamate-to-glutamine change at position 474 (E474Q) in the mature TFP α-subunit. Patients with complete MTP deficiency predominantly have cardiomyopathy or neuromyopathy and carry mutations other than the prevalent E474Q mutation.
Several studies have reported the association of HELLP syndrome and AFLP and defects in the activity of MTP. In 1991, Schoerman et al. first reported the association of recurrent maternal acute fatty acid oxidation disorder in two siblings who died at the age of 6 months . In 1993 and 1994, as the biochemical diagnosis of LCHAD became feasible, Wilcken et al.  and Treem et al.  reported on six families with children who had LCHAD deficiency and who had been born to mothers in whom AFLP or HELLP syndrome developed while carrying the affected fetuses.
Other investigators have analyzed the prevalence of HELLP syndrome and AFLP in families with known LCHAD deficiency or complete MTP deficiency. Tyni et al. analyzed the pregnancy outcome in 18 families with LCHAD deficiency and reported maternal complications (including preeclampsia, HELLP syndrome, AFLP) in 31% of the pregnancies of affected fetuses . Yang et al. investigated pregnancy history and offspring genotypes in 35 families with heterogeneous mutations . Forty-nine percent of the women who carried affected fetuses had acute fatty liver of pregnancy, and 11% of those women had HELLP syndrome. All the women who had maternal illness carried fetuses with isolated LCHAD deficiency with the prevalent 1528G > C mutation on one or both alleles. Although less frequently, association of maternal liver disease and complete MTP deficiency may occur, as it has been reported in four cases in England .
Other studies have investigated prospectively the incidence of LCHAD deficiency in pregnancies that were complicated by maternal AFLP or HELLP syndrome. In one report, 113 Dutch women with a history of HELLP syndrome were screened for the common mutation and only one was heterozygous for it . Holub et al. performed acylcarnitine profiles and LCHAD common mutation screening in 88 newborns from mothers who suffered HELLP syndrome in Austria, not detecting any fatty acid oxidation disorder in the offspring . More recently Mutze et al. investigated the frequency of the 1528G > C mutation in 103 mothers with HELLP syndrome, in 82 children of affected pregnancies, and in 21 fathers in families where fetal DNA was not available . The mutation was not detected in the study population indicating that neither maternal nor fetal heterozygosity for the 1528G > C mutation is a relevant factor of HELLP syndrome. In contrast, Zi Yang et al. found common mutation in 5 of 27 (19%) families with maternal history of AFLP, but only 1 woman with HELLP syndrome (of 81 women) was heterozygous for the common mutation; no mutation was found in the newborn .
These studies indicate the significant association between LCHAD deficiency and AFLP, but fetal fatty acid oxidation disorders do not seem to be a relevant factor for the development of HELLP syndrome. Nevertheless some issues need to be considered. First, the studies include a small number of cases, due to the low prevalence rate of hepatic maternal complications. Second, differential diagnosis between both illnesses may be difficult in the clinical setting due to overlapping symptoms and signs, as pointed out in our clinical observation. HELLP syndrome is more frequent (1/1,000 pregnancies) and diagnosis criteria include the presence of preeclampsia and microangiopathic hemolytic anemia, platelet count ≤100,000 cells/μl, serum LDH ≥600 IU/l, or total bilirubin ≥1.2 mg/dl and serum AST ≥70 IU/l. AFLP is a more infrequent complication (incidence 1/7,000 to 1/16,000 pregnancies) and more severe. Jaundice, coagulopathy, low glucose concentration and elevated creatinin concentrations are more common in women with AFLP than HELLP. Liver biopsy shows characteristic microvesicular fatty infiltration in hepatocytes in AFLP but this procedure is not usually performed as it is hazardous for the mother and the treatment in both situations is prompt delivery after maternal stabilization. In the case we report, the diagnosis at admission of the mother was HELLP syndrome, but after delivery she developed jaundice, coagulopathy, and renal insufficiency compatible with AFLP.
The precise mechanisms leading to the development of hepatic complications in mothers carrying fetuses with LCHAD defficiency are not completely understood. Mothers are obligate heterozygous with reduced capacity to oxidize long-chain fatty acids. Pregnancy is a stressful event with increased levels of plasma fatty acids and reduced mitochondrial fatty acid oxidation. Finally 3-hydroxy-fatty acid accumulation in LCHAD deficiency may act as a maternal hepatic toxin.
In conclusion, with the report of this case, we want to emphasize that AFLP and severe or recurrent HELLP syndrome (i.e., associated with fetal death) may indicate the presence of a fatty acid oxidation disorder in the newborn. These complications are more frequent in mothers who carry a fetus with LCHAD deficiency with the c1548G > C mutation in at least one allele, as observed in the case we report. Acylcarnitine profile and molecular screening should be done in this setting, especially if there is not a universal screening program of newborns for fatty acid oxidation disorders. This would prevent the delay in diagnosis until clinical symptoms develop, as occurred in the family we report. Early detection and treatment of LCHAD deficiency are clearly associated with better prognosis for the newborn. In addition, identification of heterozygous mothers with risk of recurrence of maternal complications enables genetic counselling and molecular prenatal diagnosis.