Both acute fatty liver, a devastating illness, and the more common hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome are disorders of late pregnancy whose clinical and biochemical features overlap. Some fetuses of affected women are later found to have a deficiency of an enzyme found in the mitochondrial trifunctional protein, long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase. This protein also contains the active site of long-chain 2,3-enoyl-CoA hydratase and long-chain 3-ketoacyl-CoA thiolase. This study examined the relationship between mutations in the trifunctional protein in infants with defective fatty acid oxidation and acute liver disease during pregnancy. The study included 24 families in which one child had clinical features suggesting defective fatty acid oxidation as well as an isolated deficiency of 3hydroxyacyl-CoA dehydrogenase (or complete deficiency of the trifunctional protein).
Nineteen of the 24 children had an isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase and presented with acute liver dysfunction. All but one had hypoketotic hypoglycemia, hepatic encephalopathy, and an enlarged liver. They also were hypotonic and had high serum aminotransferase levels. Five of these children became comatose and died, and the autopsies of two revealed massive hepatic steatosis. Two of the 19 children also had severe cardiomyopathy, and one had chronic myopathy. Eight of the 19 children had a homozygous mutation with glutamine rather than glutamic acid at residue 474 (Glu474Gln). The other 11 children were compound heterozygotes with a different mutation in the other allele. The incidence of fatty liver or HELLP syndrome in mothers who carried these fetuses was 79 percent. The remaining five children, who presented in the neonatal period with dilated cardiomyopathy or progressive neuromyopathy, had complete deficiency of the trifunctional protein with loss of activity of all three constituent enzymes. None of them had the Glu474Gln mutation, and none of their mothers had liver disease while pregnant.
These findings strongly indicate that pregnant women whose fetus has an isolated deficiency of long-chain 3hydroxyacyl-CoA dehydrogenase are at risk of lifethreatening liver disease. Testing for the Glu474Gln mutation is indicated for all women who develop acute fatty liver of pregnancy or the HELLP syndrome, as well as their partners and children.
N Engl J Med 1999;340:1723-1731