The Association Between Acute Fatty Liver of Pregnancy and Fatty Acid Oxidation Disorders Patricia A. Jamerson PRINCIPLES & PRACTICE.

Transcription

1 PRINCIPLES & PRACTICE The Association Between Acute Fatty Liver of Pregnancy and Fatty Acid Oxidation Disorders Patricia A. Jamerson Acute fatty liver of pregnancy is a relatively rare but potentially fatal liver disorder of late pregnancy. Recent advances in molecular diagnostic procedures provide evidence of a genetic basis for this condition and a link to offspring disorders in fatty acid oxidation. This relationship implies the need for genetic testing and follow-up of at-risk women and their neonates. JOGNN, 34, 87-92; DOI: / Keywords: Acute fatty liver of pregnancy Fatty acid oxidation disorder Genetics Pregnancy Inborn errors of metabolism Accepted: January 2004 Acute fatty liver of pregnancy (AFLP) is a relatively rare liver disorder associated with significant perinatal and neonatal morbidity and mortality. Although prompt diagnosis and supportive care have improved both maternal and fetal survival rates, the actual etiology of AFLP has been evasive. Numerous theories have been proposed, but the development of molecular diagnostic techniques has enabled researchers to better define the etiology of AFLP. In this article, a genetic basis for acute fatty liver and its association with fatty acid oxidation (FAO) defects will be discussed, along with implications for the affected woman and her family. Epidemiology Acute fatty liver of pregnancy affects women of all ages, races, and ethnic backgrounds (Treem, 2002), although nulliparous women and those with multiple pregnancies seem to be at higher risk (Riely, 1987; Snyder & Hankins, 1986). The incidence of AFLP is reported to range from 1 in 6,692 to 1 in 13,328 pregnancies (Castro, Goodwin, Shaw, Ouzounian, & McGehee, 1996; Pockros, Peters, & Reynolds, 1984; Purdie & Walters, 1988; Treem, 2002). However, the incidence is thought to be underestimated. Women with AFLP may be diagnosed with other liver diseases with similar presentations. Also, AFLP may be confused or coexist with pregnancy-induced hypertension (PIH) and HELLP (hemolysis, elevated liver enzymes, and low platelet) syndrome (Ibdah, Yang, & Bennett, 2000; Simpson, Luppi, & O Brien-Abel, 1998; Treem, 2002; Treem et al., 1996). The relationship between AFLP, PIH, and HELLP is not clear, but approximately half of women with AFLP have PIH, and approximately 20% have HELLP (Riely, 1987; Strauss et al., 1999; Treem et al., 1996). Recurrence in subsequent pregnancies is rare, but several cases have been reported (Barton, Sibai, Mabie, & Shanklin, 1990; MacLean et al., 1994; Reyes et al., 1994; Schoeman, Batey, & Acute fatty liver of pregnancy is a highrisk disorder seen late in pregnancy that is associated with both maternal and neonatal morbidity and mortality. January/February 2005 JOGNN 87

2 Wilcken, 1991; Sims et al., 1995; Visconti, Manes, Giannattasio, & Uomo, 1995; Wilcken, Leung, Hammond, Kamath, & Leonard, 1993). Clinical Presentation and Pathophysiology First described in 1934 as acute yellow atrophy of the liver in pregnancy (Standler & Cadden, 1934), AFLP is characterized by mitochondrial disruption and microvesicular fatty infiltrates (steatosis) in the liver (Ibdah et al., 2000). Fatty infiltrates also may occur in the brain, heart, pancreas, kidneys, and bone marrow (Cashion, 1992; Treem et al., 1996). As a result of fatty infiltrates, the liver is unable to maintain normal function, and hepatic failure with hypoglycemia, coagulopathy, and encephalopathy rapidly develops. Metabolic acidosis, renal insufficiency, and death also may occur, but prompt diagnosis and immediate delivery of the infant often reverse the woman s pathology, leading to a complete recovery (Ibdah et al., 2000; Vigil-De Gracia, 2001). AFLP is a 3rd-trimester disorder that usually manifests suddenly around 35 to 36 weeks of gestation (Watson & Seeds, 1990). Women with AFLP present with a variety of symptoms, many of which also are common in other liver diseases seen in pregnancy; yet, there are distinct differences. Symptoms most commonly associated with AFLP are malaise, fatigue, headache, anorexia, nausea with or without vomiting, and right upper quadrant or epigastric abdominal pain. Jaundice is a common sign (Treem, 2002; Treem et al., 1996; Vigil-De Gracia, 2001). Laboratory findings consistent with AFLP are elevated liver enzymes, increased direct bilirubin and ammonia levels, decreased antithrombin III activity, coagulopathy, decreased cholesterol and albumin levels, increased white blood cell counts, anemia, thrombocytopenia, hypoglycemia, proteinuria, and increased uric acid, blood urea nitrogen (BUN), and creatinine (Treem, 2002). The pathology and clinical picture of AFLP have long been recognized to be similar to Reye s syndrome and the inherited derangements in mitochondrial FAO defects, such as muscle carnitine palmitoyltransferase (CPT) deficiency and short- (SCAD), medium- (MCAD), or longchain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiencies (Ibdah et al., 2000; Riely, 1987; Treem, 2002). However, it has only been in the past decade that an association was demonstrated between deficits in FAO and preeclampsia, AFLP, and HELLP syndrome (Ibdah, Dasouki, & Strauss, 1999; Innes et al., 2000; Isaacs et al., 1996; Maitra et al., 2002; Matern et al., 2001; Nelson, Lewis, & Walters, 2000; Schoeman et al., 1991; Sims et al., 1995; Treem, Rinaldo, & Hale, 1994; Treem et al., 1996; Tyni, Ekholm, & Pihko, 1998; Wilcken et al., 1993; Yang, Yamada, Zhao, Strauss, & Ibdah, 2002). Understanding the FAO process and common derangements helps explain the pathology seen in AFLP. Fatty Acid Oxidation Fatty acid oxidation is the predominant source of energy during periods of fasting. Under these conditions, glucagon levels rise, mobilizing fatty acids from adipose tissue. Fatty acids are then transported, bound to albumin, through the circulation to the liver and to cardiac and skeletal muscle where they will be oxidized within the mitochondria. The oxidation of fatty acids is complex and varies depending on the type of fatty acid (saturated, unsaturated) presented to the tissues (see Figure 1). First, fatty acids are transported across the plasma membrane into the cytoplasm and then again into the mitochondria where β-oxidation occurs. This process is mediated by a series of enzymes acyl-coa synthetase, CPT I and II, carnitine acylcarnitine translocase, very-long-chain acyl-coa dehydrogenase, trifunctional protein, long-chain acyl- CoA dehydrogenase, medium-chain acyl-coa dehydrogenase, short-chain acyl-coa dehydrogenase, LCHAD, long-chain enoyl-coa hydratase, long-chain ketothiolase, short-chain enoyl-coa dehydrogenase, and mediumchain ketothiolase. Deficits in any of these enzymes may result in an inability to oxidize fatty acids. Deficits in Fatty Acid Oxidation The first disorders of FAO were described in the early 1970s (Engel & Angelini, 1973). To date, inherited defects in 11 enzymes have been described (Roe & Ding, 2001). Inheritance of FAO disorders occurs in an autosomal recessive pattern, which means affected individuals must be homozygous for the mutated gene. It also means that both parents are heterozygous carriers. Acute fatty liver of pregnancy has been noted to occur in 31% to 79% of pregnancies in which the fetus was found to have a LCHAD deficiency (Ibdah, Bennett, et al., 1999; Tyni et al., 1998). Long-chain 3-hydroxyacyl-CoA dehydrogenase is part of the trifunctional protein complex within the mitochondria. The trifunctional protein is a hetero-octamer of four α and four β subunits. The activity of LCHAD occurs in the α subunit. The α subunit is encoded by the hydroxyacyl-coenzyme A dehydrogenase/3-ketoacyl-coenzyme A thiolase/enoyl-coenzyme A hydratase (HADHA) gene, which has been mapped to region 23 on the short arm of chromosome 2. The HADHA gene is 20 exons long, but only exons 11 to 20 code for LCHAD activity. Currently, 17 different mutations are known (Ibdah, Bennett, et al., 1999). The most common mutation, seen in 65% to 95% of affected individuals, is a single base change from guanine to cytosine at nucleotide position 1528 on exon 15, resulting in a 88 JOGNN Volume 34, Number 1

3 FIGURE 1 Acyl -CoA dehydrogenase H 2 O Acyl-CoA 2,3-Enoyl-CoA Enoyl-CoA hydratase 3-L-Hydroxyacyl-CoA 3-L-Hydroxyacyl -CoA dehydrogenase 3-Ketoacyl-CoA 3-Ketoacyl-CoA thiolase Acetyl-CoA The metabolism of fatty acids through b-oxidation is a repetitive process that occurs in the mitochondrial matrix until all that remains is a two-carbon fatty acid. Each pass through b-oxidation shortens the fatty acid by two carbons. However, transport across the mitochondrial membrane and into the matrix is regulated. Fatty acids must first undergo a series of reactions before entering the matrix. First, fatty acids in the cytoplasm are activated by acyl-coa synthetase to form acyl-coa esters. The acyl-coa esters are then facilitated across the mitochondrial membrane by reacting with carnitine. This process, called the carnitine cycle, is a two-step process. First, acyl-coa is converted to acylcarnitine by carnitine palmitoyltransferase (CPT) I enzyme, located on the outer mitochondrial membrane. Next, acylcarnitine is re-esterified to acyl-coa by CPT II, which is located on the matrix side of the inner mitochondrial membrane and transported into the mitochondria by carnitine-acylcarnitine translocase. Once inside the matrix, the four-step b-oxidation process occurs. First, acyl-coa, in a dehydrogenation process, is catalyzed by size-specific (long, medium, short) acyl-coa dehydrogenase to form 2,3-enoyl-CoA. Next, 2,3- enoyl-coa is hydrated to form 3-L-hydroxyacyl-CoA. This step is catalyzed by enoyl-coa-hydrase and size-specific acyl-coa dehydrogenase enzymes. Then, 3-L-hydroxyacyl-CoA is dehydrogenated in a reaction catalyzed by 3-L-hydroxyacyl-CoA dehydrogenase to form 3-ketoacyl- CoA, which in the final step undergoes cleavage catalyzed by 3-ketoacyl-CoA thiolase to form acetyl-coa. Acetyl-CoA can either enter the Krebs tricarboxylic acid cycle or be used to make ketone bodies. change in the nucleic acid produced from glutamic acid to glutamine (Hagenfeldt, Venizelos, & Dobeln, 1995; Ibdah, Bennett, et al., 1999; Ijlst, Ruiter, Hoovers, Jakobs, & Wanders, 1996; Isaacs et al., 1996; Tyni et al., 1998; Tyni et al., 1997). This mutation is fairly common, with a carrier rate of 1 in 100 to 200 individuals (Sims et al., 1995). The biochemical effect of this mutation is an isolated LCHAD deficiency resulting in accumulation of 3- hydroxy fatty acid metabolites. Clinically, individuals with LCHAD deficiency usually present in the newborn period or after an extended fast. The most common presentation is that of an infant who, at a few months of age, experiences an acute metabolic crisis characterized by nonketotic hypoglycemia and hepatic encephalopathy. Other signs and symptoms of LCHAD deficiency include lethargy, hypotonia, hepatomegaly, liver dysfunction, a Reye-like syndrome, dilated or hypertrophic cardiomyopathy, sensorimotor neuropathy, rhabdomyolysis, pigmentary retinopathy, seizures, and sudden, unexplained death (Ibdah et al., 2000; Roe & Ding, 2001; Sims et al., 1995; Treem et al., 1996). Affected fetuses are reported to have a higher incidence of prematurity, intrauterine growth retardation, asphyxia, and intrauterine death (Tyni et al., 1998).Unfortunately, LCHAD deficiency is not the only disorder of fatty acid metabolism with which AFLP is associated; AFLP is also associated with deficiencies in CPT I (Innes et al., 2000), medium-chain acyl-coa dehydrogenase (Nelson et al., 2000), and short-chain acyl-coa dehydrogenase (Matern et al., 2001). Fetal-Maternal Mechanisms for AFLP It still is not clear why some women who give birth to a child with an FAO defect develop AFLP and others do not. Several mechanisms have been suggested (Ibdah et al., 2000; Rakheja, Bennett, Foster, Domiati-Saad, & Rogers, 2002). First, because mothers are carriers of the gene mutation, they will have a reduced complement of the enzymes necessary to oxidize fatty acids. This reduced capacity for FAO in the presence of steadily increasing levels of plasma fatty acids throughout pregnancy that peak in the 3rd trimester and the normal reductions in FAO seen in the 3rd trimester of pregnancy secondary to Women who are heterozygous carriers of a fatty acid oxidation gene mutation have a higher risk of developing acute fatty liver of pregnancy. estrogen and progesterone may be one explanation for AFLP. Another possible explanation is that as maternal FAO decreases, long-chain fatty acids may accumulate. Fetal and placental metabolites also enter the maternal circulation and may contribute to this load (Rakheja et al., 2002). Fatty acid metabolites are known inhibitors of FAO and also may be a hepatic toxin or cause endothelial damage (Ibdah et al., 2000; Rakheja et al., 2002). January/February 2005 JOGNN 89

4 Implications for Practice The significance of the association between FAO defects and AFLP lies in the implications for practice. Although both AFLP and FAO disorders are associated with high morbidity and mortality, early diagnosis and intervention enhance the potential for long-term survival. The first consideration is the appropriate identification of the at-risk family. In obtaining a prenatal history, the nurse should determine whether the woman has a history of AFLP, has had a child who died unexpectedly or from a Reye-like syndrome in the first 2 years of life, or has a child with an FAO disorder. A woman who is positive for any of these factors should be referred along with her partner to a genetic specialist for screening and counseling regarding carrier status and risk. The woman at risk for AFLP, whether because she has previous history of liver disease during pregnancy, is a known carrier, or has an affected child, should be monitored closely for signs of pregnancy-related liver disease throughout pregnancy, as early detection is paramount. Abnormalities in serum creatinine, uric acid, and antithrombin III as early as the 2nd trimester may be apparent (Treem, 2002). The at-risk woman also should be instructed to maintain a high-carbohydrate, low-fat diet. Fasting should be avoided, and the woman should contact her physician if Genetic counseling should be provided to women with a history of acute fatty liver of pregnancy, and their neonates should be tested for fatty acid oxidation defects. TABLE 1 States That Require long-chain 3-hydroxyacyl- CoA dehydrogenase (LCHAD) Screening in Newborns Delaware Illinois Indiana Minnesota Mississippi North Carolina Oregon Wisconsin Developed from the United States National Screening Status Report- MS/MS, by the National Newborn Screening and Genetics Resource Center [Online]. Available from newborn/msmstests.htm. she experiences anorexia, vomiting, or fever, even if it is minor, because fasting or increased catabolism stimulates the FAO process (Treem, 2002). Women at risk also should be advised to avoid nonsteroidal antiinflammatory drugs (NSAIDS), salicylates, tetracycline, and valproic acid, as they may interfere with FAO (Treem, 2002). Given the seriousness of AFLP, at-risk women and their partners may be extremely anxious about the outcome of the pregnancy. Prenatal testing is available to detect the presence of FAO disorders through direct enzyme assays of cultured amniocytes or chorionic villus samples, but it is not routinely recommended (Rinaldo, Studinski, & Matern, 2001; Roe & Ding, 2001). Instead, the practice is to evaluate the newborn of the woman with AFLP or couples who are known carriers of FAO defects immediately after birth because FAO disorders are treatable if detected early. Few states include routine screening for FAO disorders in their panel of tests for newborns. Table 1 lists the states that require LCHAD deficiency screening. However, blood spot acylcarnitine profiles may be ordered, and positive results may be confirmed by skin fibroblast studies. While awaiting test results, all infants at risk should be treated as if they have an FAO disorder. The infant should be given high-carbohydrate, low-fat formula and not allowed to fast for more than 4 hours at any time. If the infant cannot take anything by mouth, a continuous intravenous infusion should be started. Parenteral lipid solutions and propofol, as well as the use of NSAIDS and valproic acid, should be avoided in these infants. Parents of at-risk or affected infants should be instructed to call the physician whenever the child refuses to eat, is vomiting, or has a fever, no matter how minor the illness. As a relatively new disorder, little is known about the prognosis and long-term outcomes for children diagnosed with an FAO defect. It is known, however, that morbidity and mortality, once reported as high as 75% to 90%, are dramatically decreased with early identification and ongoing diet therapy (Ibdah, Bennett, et al., 1999). It also is known that pigmentary retinopathy occurs despite diet therapy. Implications for Research Given the strong evidence supporting a connection between AFLP and FAO defects and the paucity of nursing research regarding either disorder, the implications for research are broad. First, studies are needed to better explain the relationship between AFLP, PIH, and HELLP. These three disorders seem to represent a spectrum of dis- 90 JOGNN Volume 34, Number 1

5 ease, but what dictates the different presentations manifested? Are there moderator genes that make a difference? Is more than one mutation present? Are there environmental factors that make a distinction? Studies are also needed to better understand why some women who give birth to a child with FAO develop AFLP and others do not, even when they are positive for the identified genetic mutations. This difference in phenotype also would suggest that there is a yet-to-be-identified, moderating variable that affects outcome. Research also is needed to determine whether differences observed in the severity or presentation of AFLP and responsiveness to therapy are based on the type of genetic mutation present. Additional considerations for research include studying the effect of maternal status during labor and delivery (e.g., dehydration, hypoglycemia) on the status of the infant at birth. The association between the maternal disease process and an FAO defect in the offspring also raises questions regarding the effects on maternal-infant bonding. Finally, natural history studies are needed to learn more about the prognosis and outcomes of infants with FAO defects. Summary The association of AFLP with FAO disorders has provided valuable insight into the risk factors and mechanisms underlying the pathophysiology of AFLP. As a result, more women at risk for developing AFLP can be identified, further enhancing early detection and interventions that are essential for a good outcome. More infants with FAO disorders also are more likely to be identified, enhancing their opportunity for early treatment and survival. REFERENCES Barton, J. R., Sibai, B. M., Mabie, W. C., & Shanklin, D. R. (1990). Recurrent acute fatty liver of pregnancy. American Journal of Obstetrics and Gynecology, 163(2), Cashion, K. (1992). Liver disease in pregnancy. NAACOG s Clinical Issues in Perinatal and Women s Health Nursing, 3(3), Castro, M. A., Goodwin, T. M., Shaw, K. J., Ouzounian, J. G., & McGehee, W. G. (1996). Disseminated intravascular coagulation and antithrombin III depression in acute fatty liver of pregnancy. American Journal of Obstetrics and Gynecology, 174, Engel, A. G., & Angelini, C. (1973). Carnitine deficiency of human skeletal muscle with associated lipid storage myopathy: A new syndrome. Science, 179(76), 899. Hagenfeldt, N., Venizelos, N., & Dobeln, U. (1995). Clinical and biochemical presentation of long chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Journal of Inheritable Metabolic Disorders, 18, Ibdah, J. A., Bennett, M. J., Rinaldo, P., Zhao, Y., Gibson, B., Sims, H. F., et al. (1999). A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women. New England Journal of Medicine, 340(22), Ibdah, J. A., Dasouki, M. J., & Strauss, A. W. (1999). Longchain 3-hydroxyacyl-CoA dehydrogenase deficiency: Variable expressivity of maternal illness during pregnancy and unusual presentation with infantile cholestasis and hypocalcaemia. Journal of Inheritable Metabolic Disorders, 22(7), Ibdah, J. A., Yang, Z., & Bennett, M. J. (2000). Liver disease in pregnancy and fetal fatty acid oxidation defects. Molecular Genetics and Metabolism, 71(1-2), Ijlst, L., Ruiter, J. P. N., Hoovers, J. M. N., Jakobs, M. E., & Wanders, R. J. A. (1996). Common missense mutation G1523C in long-chain 3-hydroxyacyl-coA dehydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosome localization of the mitochondrial trifunctional protein alpha subunit gene. Journal of Clinical Investigation, 98(4), Innes, A. M., Seargeant, L. E., Balachandra, K., Roe, C. R., Wanders, R. J. A., Ruiter, J. P. N., et al. (2000). Hepatic carnitine palmitoyltransferase I deficiency presenting as maternal illness in pregnancy. Pediatric Research, 47(1), Isaacs, J. D., Sims, H. F., Powell, C. K., Bennett, M. J., Hale, D. E., Treem, W. R., et al. (1996). Maternal acute fatty liver of pregnancy associated with fetal trifunctional protein deficiency. Molecular characterization of a novel maternal mutant allele. Pediatric Research, 40(3), MacLean, M. A., Cameron, A. D., Cumming, G. P., Murphy, K., Mills, P., & Hilan, K. J. (1994). Recurrence of acute fatty liver of pregnancy. British Journal of Obstetrics and Gynaecology, 101(5), Maitra, A., Domiati-Saad, R., Yost, N., Cunningham, G., Rogers, B. B., & Bennett, M. J. (2002). Absence of the G1528C (E474Q) mutation in the alpha subunit of the mitochondrial trifunctional protein in women with acute fatty liver of pregnancy. Pediatric Research, 51(5), Matern, D., Schehata, B. M., Shekhawa, P., Strauss, A. W., Bennett, M. J., & Rinaldo, P. (2001). Placental floor infarct complicating the pregnancy of a fetus with long chain 3- hydroxyacyl-coa dehydrogenase deficiency. Molecular Genetics and Metabolism, 72(3), Nelson, J., Lewis, B., & Walters, B. N. (2000). The HELLP syndrome associated with fetal medium-chain acyl-coa dehydrogenase deficiency. Journal of Inheritable Metabolic Disorders, 23(5), Pockros, P. J., Peters, R. L., & Reynolds, T. B. (1984). Idiopathic fatty liver of pregnancy findings in ten cases. Medicine, 63(1), Purdie, J. M., & Walters, B. N. (1988). Acute fatty liver of pregnancy. Clinical features and diagnosis. Australia New Zealand Obstetric and Gynecology, 28(1), Rakheja, D., Bennett, M. J., Foster, B. M., Domiati-Saad, R., & Rogers, B. B. (2002). Evidence for fatty acid oxidation in human placenta, and the relationship of fatty acid oxidation enzyme activities with gestational age. Placenta, 23(5), January/February 2005 JOGNN 91

6 Reyes, H., Sandoval, L., Wainstein, A., Ribalta, J., Donoso, S., Smok, G., et al. (1994). Acute fatty liver of pregnancy: A clinical study of 12 episodes in 11 patients. Gut, 35(1), Riely, C. A. (1987). Acute fatty liver of pregnancy. Seminars in Liver Disease, 7(1), Rinaldo, P., Studinski, A. L., & Matern, D. (2001). Prenatal diagnosis of disorders of fatty acid transport and mitochondrial oxidation. Prenatal Diagnosis, 21, Roe, C. R., & Ding, J. (2001). Mitochondrial fatty acid oxidation disorders. In C. R. Scriver, A. L. Beaudet, W. S. Sly, & D. Valle (Eds.), The metabolic and molecular bases of inherited disease (8th ed., Vol. 2, pp ). New York: McGraw Hill. Schoeman, M. N., Batey, R. G., & Wilcken, B. (1991). Recurrent acute fatty liver of pregnancy associated with a fattyacid oxidation defect in the offspring. Gastroenterology, 100(2), Simpson, K. R., Luppi, C. J., & O Brien-Abel, N. (1998). Acute fatty liver of pregnancy. Journal of Perinatal and Neonatal Nursing, 11(4), Sims, H. F., Brackett, J. C., Powell, C. K., Treem, W. R., Hale, D. E., Bennett, M. J., et al. (1995). The molecular basis of pediatric long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy. Proceedings of the National Academy Science, 92(3), Snyder, R. R., & Hankins, G. D. V. (1986). Etiology and management of acute fatty liver of pregnancy. Clinics of Perinatology, 13(4), Standler, H. J., & Cadden, B. S. (1934). Acute yellow atrophy of the liver in pregnancy. American Journal of Obstetrics and Gynecology, 28, Strauss, A. W., Bennett, M. J., Rinaldo, P., Sims, H. F., O Brien, L. K., Zhao, Y., et al. (1999). Inherited long-chain 3- hydroxyacyl-coa dehydrogenase deficiency and a fetalmaternal interaction cause maternal liver disease and other pregnancy complications. Seminars in Perinatology, 23(2), Treem, W. R. (2002). Mitochondrial fatty acid oxidation and acute fatty liver of pregnancy. Seminars in Gastrointestinal Disease, 13(1), Treem, W. R., Rinaldo, P., & Hale, D. E. (1994). Acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-CoA deficiency. Hepatology, 19(2), Treem, W. R., Shoup, M. E., Hale, D. E., Bennett, M. J., Rinaldo, P., Millington, D. S., et al. (1996). Acute fatty liver of pregnancy, hemolysis, elevated liver enzymes, and low platelets syndrome, and long chain 3-hydroxyacyl-coenzyme. A dehydrogenase deficiency. American Journal of Gastroenterology, 91(11), Tyni, T., Ekholm, E., & Pihko, H. (1998). Pregnancy complications are frequent in long-chain 3-hydroxyacyl-coenzyme. A dehydrogenase deficiency. American Journal of Obstetrics and Gynecology, 178, Tyni, T., Palotie, A., Viinikka, L., Valanne, L., Salo, M., von Dobeln, U., et al. (1997). Long-chain 3-hydroxyacylcoenzyme. A dehydrogenase deficiency with the G1528C mutation: Clinical presentation in 13 patients. Journal of Pediatrics, 130(1), Vigil-De Gracia, P. (2001). Acute fatty liver and HELLP syndrome: Two distinct pregnancy disorders. International Journal of Gynecology and Obstetrics, 73, Visconti, M., Manes, G., Giannattasio, F., & Uomo, G. (1995). Recurrence of acute fatty liver of pregnancy. Journal of Clinical Gastroenterology, 21(3), Watson, W. J., & Seeds, J. W. (1990). Acute fatty liver of pregnancy. Obstetrical and Gynecological Survey, 45(9), Wilcken, B., Leung, K. C., Hammond, J., Kamath, R., & Leonard, J. V. (1993). Pregnancy and fetal long chain 3- hydroxyacyl coenzyme. A dehydrogenase deficiency. Lancet, 341(8842), Yang, Z., Yamada, J., Zhao, Y., Strauss, A. W., & Ibdah, J. A. (2002). Prospective screening for pediatric mitochondrial trifunctional protein defects in pregnancies complicated by liver disease. Journal of the American Medical Association, 288(17), Patricia A. Jamerson, PhD, RN, is a nurse scientist researcher at St. Louis Children s Hospital, St. Louis, MO. Address for correspondence: Patricia A. Jamerson, PhD, RN, St. Louis Children s Hospital, 1 Children s Place, St. Louis, MO paj3987@bjc.org. 92 JOGNN Volume 34, Number 1