Genetic defects of fatty acid oxidation (FAO) are being increasingly recognized as an important group of potentially rapidly fatal, autosomal recessive diseases which may present with recurrent hypoketotic hypoglycemic encephalopathy or Reye-like syndrome leading to cerebral injury and seizures, hepatopathy, progressive lipid storage myopathy, recurrent myoglobinuria, progressive dilatative/hypertrophic cardiomyopathy, arrhythmias, and sudden unexpected infant deaths (1). Evidence is emerging that certain FAO defects in the fetus may predispose to significant maternal complications of pregnancy. The paper in this issue by Innes et al. (2) puts forth a new etiology, namely carnitine palmitoyltransferase (CPT) I deficiency, in the differential diagnosis of underlying defects in which a heterozygous mother carrying an affected fetus is predisposed to acute fatty liver of pregnancy (AFLP) and possibly hyperemesis gravidarum. Except in the case of a mother carrying a fetus with long-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) who is homozygous or a compound heterozygote for the common Glu474Gln mutation, maternal liver disease of pregnancy has not, to our knowledge, been previously reported in association with other disorders of fatty acid oxidation. In this paper, the enzyme assays are convincing regarding CPT I deficiency in the fetus, although mutational analysis in the affected child and parents would have increased the molecular characterization. Furthermore, although the mother's clinical picture including elevated liver function tests, prolonged PT and “possible” fatty liver on ultrasound are compatible with AFLP, no liver biopsy was performed to definitively differentiate AFLP from the more common HELLP (hemolysis, elevated liver tests and low platelets) syndrome. For these reasons and because this is the first single case report, it may be prudent to be cautious, for the present time, regarding the conclusion that maternal liver disease is caused by CPT I deficiency in the fetus. Nonetheless, it is important to note that both LCHAD deficiency, previously reported in a number of cases AFLP, and CPT I deficiency are both defects of long-chain FAO. This association raises provocative questions regarding the role of impaired long-chain FAO in the pathogenesis of this disorder.
The incidence of LCHADD among the fetuses of women with AFLP is unknown; however, it appears to constitute an increasingly important subgroup in the etiology of AFLP. Treem et al. (3) reported on 12 women with previously diagnosed AFLP, eight of whom were heterozygous for LCHADD. There was a high incidence of AFLP in LCHAD heterozygous mothers carrying affected fetuses, suggesting an important role for toxic metabolites generated by the metabolically impaired feto-placental unit in the pathogenesis of AFLP. The eight heterozygotes had nine pregnancies complicated by AFLP. In seven of these nine pregnancies, the women developed severe preeclampsia and HELLP syndrome. Of the nine offspring delivered from these pregnancies, four were confirmed to be affected with LCHADD and three deceased infants had postmortem findings consistent with LCHADD. The remaining two offspring were apparently heterozygotes, however, these two pregnancies were further complicated by HELLP syndrome. It should be noted that the conclusions of this study were based upon enzyme assays with some potential for overlap between heterozygotes and affected patients and that, as stated by the authors, no DNA analysis had been done to confirm the heterozygote status of these children. The LCHAD heterozygous mothers had seven other normal pregnancies with non-LCHADD fetuses, five of which were found to be heterozygous. None of these pregnancies was complicated by HELLP syndrome. Treem et al. (3) documented a 4-fold increased risk of AFLP in LCHAD heterozygotes whose pregnancies are complicated by severe preeclampsia/HELLP syndrome, suggesting that severe preeclampsia may be an additional metabolic stress that facilitates the development of AFLP in susceptible hosts. Similarly, Wilcken et al. (4) have reported on 11 pregnancies in five heterozygous mothers. Six infants had LCHADD and each of the pregnancies was complicated by either AFLP, HELLP syndrome, or very severe hyperemesis. In contrast, three of the mothers also gave birth to unaffected infants and these pregnancies were uncomplicated. Tyni et al. (5) have reviewed 63 pregnancies in 18 mothers who carried 28 LCHADD fetuses. AFLP was diagnosed only in cases in which hepatic steatosis was proven by ultrasonography or biopsy. Preeclampsia, HELLP syndrome, and AFLP occurred in 31% and intrahepatic cholestasis in 10% of pregnancies with an LCHADD fetus, but in none of the pregnancies with a healthy fetus; of note, 40% of affected neonates were born prematurely and 47% had growth restriction, whereas none of the healthy neonates were premature and growth restriction occurred in only 17%. They also found that the frequency of preeclampsia-related complications in pregnancies with LCHADD fetuses greatly exceeded the incidence in the normal population.
The majority of children with trifunctional protein (TFP) or LCHAD deficiency, which is a component of the α-subunit of the hetero-octameric TFP (6), have infantile-onset with devastating episodes of hypoketotic hypoglycemia with hepatic dysfunction, cardiomyopathy, retinopathy or SIDS and high infant mortality rate with >60% dead by 3 y of age (7, 8). In a series of 13 patients, homozygous for the common G1528C mutation, only one patient, who had had dietary therapy for 9 y, was alive at 14 y, whereas all others had died before 2 y of age (8). In contrast, in a more recent series of 24 children with LCHAD deficiency, 16 children being treated with dietary therapy were alive at follow-up, eight of whom were older than 5 y of age (9). Early recognition and intervention are thus critical. There are three major phenotypes with variable overlap; a hepatic form with Reye-like syndrome that is associated with AFLP, a neonatal cardiomyopathic form, and a less common myoneuropathic form. These phenotypes appear to correlate with specific genotypes (10–13). In further work, Ibdah et al. (9) have studied the relation between mutations in the TFP in 24 infants and acute liver disease during pregnancy in their mothers. Nineteen children had a deficiency only of LCHAD and presented with hypoketotic hypoglycemia and fatty liver. Eight of these children were homozygous for the Glu474Gln mutation and 11 other children were compound heterozygotes, with this mutation in one allele of the α-subunit gene and a different mutation in the other allele. While carrying fetuses with the Glu474Gln mutation, 79% of the heterozygous mothers had AFLP or HELLP syndrome. Five other children, who presented with neonatal cardiomyopathy or progressive myoneuropathy, had complete deficiency of the TFP. None had the Glu474Gln mutation, and none of their mothers had liver disease during pregnancy. Of the 15 women who had liver disease during pregnancies with the affected children, only 10 had the Glu474Gln mutation; the other mothers had mutations causing premature termination codons or an unknown mutation. Thus, the maternal genotype did not correlate with the development of AFLP or HELLP syndrome. It was therefore concluded that women with acute liver disease during pregnancy may have a Glu474Gln mutation in LCHAD and that their infants would be at risk for hypoketotic hypoglycemia and fatty liver. Moreover, it was concluded that a woman, whose affected fetus has the Glu474Gln mutation on one or both alleles of the α-subunit of the TFP, was likely to have AFLP or the HELLP syndrome.
Preeclampsia is a common, very important complication of pregnancy, occurring in about 10% of cases. About 10% of preeclamptics develop HELLP syndrome, which is associated with serious morbidity (14). AFLP is an uncommon but deadly complication of pregnancy in which many believe that preeclampsia is present in most cases (15), although AFLP appears to be a clinically and histologically distinct entity (16). AFLP spans a broad clinical spectrum ranging from acute hepatic failure to subclinical liver disease (17). AFLP has been difficult to predict. Its incidence ranges from 1 in 5,000 to 13,000 deliveries (15, 18). With prompt delivery and aggressive supportive care, mortality has decreased from 85% to ∼18% maternal and 28% fetal mortality (19). It occurs in the latter half of pregnancy, close to term (20). In severe untreated cases, progression is rapid over hours or days to hepatic failure with coma, hypoglycemia, hyperammonemia, renal failure, and severe coagulopathy with hemorrhage from the gastro-intestinal tract or uterus, leading to death of mother and fetus (21). The pathologic signature is one of hepatic microvesicular steatosis and mitochondrial abnormalities similar to Reye's syndrome, valproate toxicity (22), and FAO defects (23).With early intervention, improvement usually occurs within 2–3 d of delivery without hepatic sequelae (17).
To understand the potential role of impaired FAO in the development of AFLP, it is important to consider the changes in the metabolic pathways controlling FAO and ketone body production in the latter stages of normal pregnancy that may increase the vulnerability of a heterozygous mother to a partial defect in FAO. There is a dramatic increase in serum concentrations of triglycerides and FFA, which is most marked at term (24). Lipoprotein lipase inhibition occurs (25). This may be attributable to estrogenic compounds that may also accelerate hepatic triglyceride biosynthesis and produce variable degrees of cholestasis (16). Furthermore, mitochondrial FAO and the use of acetyl-CoA in the TCA cycle have been shown to be reduced by 40% and 26%, respectively, in pregnant mice (26, 27). In preeclampsia there is an added increase of FAO substrates above already elevated levels in normotensive pregnant women (28) placing the heterozygous mother at heightened risk for metabolic decompensation. In preeclamptic sera, lipid peroxidation products are increased and vitamin E, an endogenous antioxidant in LDL, is reduced (29, 30). Preeclamptic sera also reduce endothelin and causes lipid accumulation within cultured endothelial cells (31, 32). Microvesicular steatosis has been found in some patients with preeclampsia (33), although the distribution of hepatic necrosis and vacuolization and decreased amount of fat usually distinguish preeclampsia from AFLP (34).
In consideration of the roles of LCHAD and CPT I deficiency in the pathogenesis of AFLP, both are defects in long-chain FAO (LC-FAO). Both may present with hypoketotic hypoglycemic encephalopathy and liver dysfunction in the affected child. Furthermore, CPT I is one of the key regulatory steps of LC-FAO, determining the entry of long-chain fatty acids into mitochondria (35). The pregnant heterozygote could be at increased risk for AFLP due to a multifactorial combination of 1) the 50% decrease in LC-FAO associated with the genetic defect in the mother, 2) the stress on maternal FAO given the constant substrate demands of the fetus, 3) the normal physiologic inhibition of FAO in the latter stages of pregnancy, 4) the exaggerated liberation of fatty acids associated with severe preeclampsia, 5) the transfer of toxic long-chain fatty acid metabolites from the affected fetus to the mother by an impaired feto-placental unit, leading to maternal liver damage. In LCHADD there would be an accumulation of long-chain L-3–0H-acylcarnitines, -CoAs and -dicarboxylic acids, which may be cytotoxic in excessive amounts and are known to inhibit mitochondrial enzymes including β-oxidation and to uncouple oxidative phosphorylation, impairing ATP production, and to produce ultrastructural changes in isolated mitochondria (36–38). Long-chain acylcarnitines have detergent properties on isolated canine myocytic sarcolemmal membranes and potentiate free-radical-induced lipid membrane peroxidative injury in ischemia (39). These long-chain fatty acids and their metabolites have been linked to liver damage in AFLP (40). In CPT I deficiency, there would be no formation of long-chain acylcarnitines due to the enzymatic block; however, there would still be an accumulation of palmitoyl-CoA, long-chain FFA and triglycerides, suggesting that these may be the key hepatotoxic metabolites.
In AFLP, early identification of heterozygous mothers and homozygous or compound heterozygous infants for LCHAD or CPT I deficiency is critical because:1) The recurrence risk of AFLP in mothers in subsequent pregnancies would be 25% while carrying homozygous mutant or compound heterozygous fetuses. 2) Early diagnosis and institution of standard preventative measures and directed therapies (41) in affected newborns and siblings at risk may prevent or minimize the acute manifestations of the disease and significantly decrease long-term morbidity and mortality. In conclusion, the precise role in AFLP of impaired long-chain FAO and the accumulation of long fatty acid metabolites seen both in CPT I and LCHAD deficiency, provides an “experiment of nature” that may provide key insight into the fetomaternal pathophysiology of AFLP. Severe preeclampsia and HELLP syndrome, which share features with AFLP but seem to be distinct entities, may serve as added risk factors for the development of AFLP in susceptible heterozygotes carrying heterozygote fetuses. There is insufficient data in the literature to determine whether there is a direct relationship between FAO defects and the development of HELLP syndrome or severe preeclampsia, and even less evidence for a link between FAO defects and hyperemesis gravidarum; however, this may represent only the “tip of the iceberg” and as such would be compelling questions worthy of future investigation.
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Tein, I. Metabolic Disease in the Fetus Predisposes to Maternal Hepatic Complications of Pregnancy. Pediatr Res 47, 6 (2000). https://doi.org/10.1203/00006450-200001000-00005
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DOI: https://doi.org/10.1203/00006450-200001000-00005
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