Correspondence
Liver Disease in Pregnancy
N Engl J Med 1997; 336:377-379January 30, 1997
- Article
To the Editor:
We were surprised to find that the review of liver disease in pregnancy (Aug. 22 issue)1 did not mention the recognized association between acute fatty liver of pregnancy and long-chain-3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency,2-5 a disorder of mitochondrial fatty-acid oxidation. This association opens a new chapter in our understanding of the pathogenesis of diseases of pregnancy related to metabolic disorders. For example, the accumulation of phenylalanine in a mother with phenylketonuria can have a teratogenic effect on an unaffected fetus.
A woman who is heterozygous for LCHAD deficiency and whose fetus has the disorder can have unexpected and life-threatening acute fatty liver of pregnancy. The mechanism of the hepatocellular damage is still unclear but is likely to involve abnormal fatty-acid metabolites produced by the fetus that enter the maternal circulation and overwhelm the mitochondrial-oxidation machinery of the heterozygous mother, who is already under stress from the increased demand for fatty-acid oxidation in the latter stages of pregnancy. The result is microvesicular fatty infiltration and liver failure. There is an apparent segregation of acute fatty liver of pregnancy with only certain mutant LCHAD alleles.4,5
The clinical implications arising from the fact that an inborn error of fatty-acid metabolism may underlie acute fatty liver of pregnancy are important to recognize. First, the risk of recurrent acute fatty liver of pregnancy in LCHAD-related cases is 25 percent or even greater, and a recent report documents the disease in pregnancies in which the fetus was only heterozygous for the disorder but the mother had the additional stress of preeclampsia.6 Second, the newborn who survives a pregnancy complicated by acute fatty liver of pregnancy should undergo immediate metabolic testing to prevent or minimize the risk of the acute manifestations of LCHAD deficiency, which include cardiac failure, fulminant liver disease, and sudden death. Finally, fluids and tissues from infants who are stillborn or who die soon after birth can be collected at autopsy and sent for the appropriate biochemical, enzymatic, and molecular studies to rule out a diagnosis of LCHAD deficiency.
6 ReferencesPiero Rinaldo, M.D.
Yale University School of Medicine, New Haven, CT 06520William R. Treem, M.D.
Duke University Medical Center, Durham, NC 27710Caroline A. Riely, M.D.
University of Tennessee School of Medicine, Memphis, TN 381051
Knox TA ,Olans LB . Liver disease in pregnancy. N Engl J Med 1996;335:569-576
Full Text | Web of Science | Medline2
Wilcken B ,Leung K-C ,Hammond J ,Kamath R ,Leonard JV . Pregnancy and fetal long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency. Lancet 1993;341:407-408
CrossRef | Web of Science | Medline3
Treem WR ,Rinaldo P ,Hale DE , et al. Acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Hepatology 1994;19:339-345
CrossRef | Web of Science | Medline4
Sims HF ,Brackett JC ,Powell CK , et al. The molecular basis of pediatric long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy. Proc Natl Acad Sci U S A 1995;92:841-845
CrossRef | Web of Science | Medline5
Isaacs JD Jr ,Sims HF ,Powell CK , et al. Maternal acute fatty liver of pregnancy associated with fetal trifunctional protein deficiency: molecular characterization of a novel maternal mutant allele. Pediatr Res 1996;40:393-398
CrossRef | Web of Science | Medline6
Treem WR ,Shoup ME ,Hale DE , et al. Acute fatty liver of pregnancy, HELLP syndrome, and long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency. Am J Gastroenterol 1996;91:2293-2300
Web of Science | Medline
To the Editor:
Knox and Olans provide an excellent discussion of liver disease in pregnancy but make a serious omission with respect to acute fatty liver of pregnancy, as illustrated by the following case report.
A 30-year-old woman with two previous pregnancies that had ended in abortion presented at 32 weeks of gestation (estimated) with right-upper-quadrant pain and uterine contractions. Her blood pressure was 128/92 mm Hg. Laboratory studies showed a decreased platelet count (82,000 per cubic millimeter), an aspartate aminotransferase concentration of 213 IU per liter, and a uric acid concentration of 6.3 mg per deciliter. Ultrasonography showed changes consistent with fatty liver of pregnancy. Cesarean section was performed, and a 1980-g female infant was delivered. The baby initially did well but required intubation on day 3. She was extubated four days later, but shallow respirations and severe acidosis developed on day 9. She died three hours later despite intensive resuscitative efforts. Cultures were negative. An autopsy showed extensive fatty deposition in the liver and muscle, suggesting a defect in fatty-acid oxidation. Biopsies of skin samples from both parents confirmed that LCHAD activity was 50 percent of normal, indicating that a deficiency of this enzyme caused the baby's death.
It is now recognized that a woman who is carrying a child with LCHAD deficiency is at risk for acute fatty liver of pregnancy,1,2 and recurrent disease has been reported.1 The mechanism seems to relate to fetal factors (production of toxic metabolites such as omega fatty acids) or secondary maternal carnitine deficiency, rather than decreased maternal enzyme activity, since all cases of recurrent acute fatty liver of pregnancy have occurred in women whose fetuses had LCHAD deficiency.2 Recognition of this condition in infants is critical, since dietary modification can prevent acute life-threatening episodes resembling Reye's syndrome. The recent recognition3 that there is a common mutation (G1528C) suggests that the disease can be diagnosed from a blood spot by the polymerase chain reaction and that it can be diagnosed prenatally.
3 ReferencesMarc S. Williams, M.D.
Gundersen–Lutheran Medical Center, La Crosse, WI 546011
Schoeman MN ,Batey RG ,Wilcken B . Recurrent acute fatty liver of pregnancy associated with a fatty-acid oxidation defect in the offspring. Gastroenterology 1991;100:544-548
Web of Science | Medline2
Wilcken B ,Leung K-C ,Hammond J ,Kamath R ,Leonard JV . Pregnancy and fetal long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Lancet 1993;341:407-408
CrossRef | Web of Science | Medline3
Ding J, Yang B, Nada MA, Roe CR. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: the major disease-causing mutation and diagnosis. Presented to the Society for Pediatric Research, Washington, D.C., 1996. abstract.
To the Editor:
Knox and Olans suggest that recurrent fatty liver of pregnancy has been reported in only two women. They refer to a 1993 report, but there have subsequently been at least two more reports of this association.1,2
The increasing awareness of recurrent acute fatty liver of pregnancy has helped in our understanding of the pathogenesis of this condition. It may well be that fatty liver of pregnancy reflects a genetic abnormality in the expression of LCHAD that places women at risk for liver injury during pregnancy if the fetus is heterozygous for LCHAD deficiency. Physicians should be aware of the possibility of this diagnosis.3,4
4 ReferencesRobert G. Batey, M.D.
John Hunter Hospital, New Lambton Heights, NSW 2305, Australia1
Meicler P ,Bernuau J ,Darai E ,Morice P ,Mansour F ,Colau JC . Stéatose aiguë hépatique gravidique récidivante. Rev Fr Gynecol Obstet 1994;89:44-48
Medline2
MacLean MA ,Cameron AD ,Cumming GP ,Murphy K ,Mills P ,Hilan KJ . Recurrence of acute fatty liver of pregnancy. Br J Obstet Gynaecol 1994;101:453-454
CrossRef | Medline3
Treem WR ,Shoup ME ,Hale DE , et al. Acute fatty liver of pregnancy, HELLP syndrome and long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency. Am J Gastroenterol 1996;91:2293-2300
Web of Science | Medline4
Batey RG. Acute fatty liver of pregnancy: is it genetically predetermined. Am J Gastroenterol (in press).
Author/Editor Response
The authors reply:
To the Editor: We appreciate Dr. Batey's updating of our data. There are now at least four reported cases of recurrent acute fatty liver of pregnancy.1-4 This small number underscores the point that recurrent disease is rare.
We are aware of the proposed association between acute fatty liver of pregnancy and LCHAD deficiency. Space limitations precluded a discussion of all proposed mechanisms.
4 ReferencesTamsin A. Knox, M.D., M.P.H.
Lori B. Olans, M.D., M.P.H.
New England Medical Center, Boston, MA 021111
Barton JR ,Sibai BM ,Mabie WC ,Shanklin DR . Recurrent acute fatty liver of pregnancy. Am J Obstet Gynecol 1990;163:534-538
Web of Science | Medline2
MacLean MA ,Cameron AD ,Cumming GP ,Murphy K ,Mills P ,Hilan KJ . Recurrence of acute fatty liver of pregnancy. Br J Obstet Gynaecol 1994;101:453-454
CrossRef | Medline3
Reyes H ,Sandoval L ,Wainstein A , et al. Acute fatty liver of pregnancy: a clinical study of 12 episodes in 11 patients. Gut 1994;35:101-106
CrossRef | Web of Science | Medline4
Meicler P ,Bernuau J ,Darai E ,Morice P ,Mansour F ,Colau JC . Stéatose aiguë hépatique gravidique récidivante. Rev Fr Gynecol Obstet 1994;89:44-48
Medline
- Citing Articles (2)
Citing Articles
1
T GREGORY, S HUGHES, M COLEMAN, A DESILVA. (2007) Acute fatty liver of pregnancy; three cases and discussion of analgesia and anaesthesia. International Journal of Obstetric Anesthesia 16:2, 175-179
CrossRef2
Tracey Glanville, James Walker. (2003) HELLP syndrome. The Obstetrician & Gynaecologist 5:3, 149-154
CrossRef
