Acute fatty liver of pregnancy

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Literature review current through: Jul 2016. | This topic last updated: Aug 10, 2015.

INTRODUCTION — Acute fatty liver of pregnancy, characterized by microvesicular fatty infiltration of hepatocytes, is a disorder which is unique to human pregnancy [1]. It was described in 1940 and was initially thought to be universally fatal [2]. However, early diagnosis and prompt delivery have dramatically improved the prognosis, and maternal mortality should now be the exception rather than the rule [1].

The major clinical features of acute fatty liver of pregnancy will be reviewed here. A general approach to the pregnant woman who develops liver disease is presented elsewhere and has also been addressed in a guideline issued by the American College of Gastroenterology (table 1) [3]. (See "Approach to liver disease occurring during pregnancy".)

EPIDEMIOLOGY — Acute fatty liver of pregnancy is rare, with an approximate incidence of 1 in 7000 to 1 in 20,000 deliveries [4-8]. It is more common with multiple gestations and possibly in women who are underweight.

One of the largest population-based studies included 1,132,964 pregnancies at 229 hospitals in the United Kingdom between 2005 and 2006 [8]. There were a total of 57 women diagnosed with acute fatty liver of pregnancy (5 cases per 100,000 pregnancies, 95% CI 3.8-6.5). Of these, 18 percent of women had twin pregnancies and 20 percent were underweight (body mass index <20).

CLINICAL MANIFESTATIONS — Acute fatty liver occurs typically in the third trimester. The disease is always present before delivery, although it is not always diagnosed prior to delivery.

The most frequent initial symptoms are nausea or vomiting (approximately 75 percent of patients), abdominal pain (particularly epigastric, 50 percent), malaise, anorexia, and jaundice. About one-half of patients have signs of preeclampsia at presentation or at some time during the course of illness [9].

Extrahepatic complications can occur. In one series of 32 patients with severe liver dysfunction requiring admission to a liver failure unit, infection occurred in 17 patients and major intra-abdominal bleeding in 10 patients, some of whom required surgery [10]. Transient polyuria and polydipsia due to central diabetes insipidus also can be seen; this is thought to be caused by decreased levels of arginine vasopressin secondary to reduced clearance of vasopressinase by the impaired liver [11]. Rare patients develop pancreatitis, which can be severe. Pancreatitis generally becomes apparent only after development of hepatic and renal dysfunction [12].

Laboratory tests — Women with acute fatty liver of pregnancy have abnormal liver tests, with serum aminotransferase elevations usually ranging from modest values up to 500 int. unit/L. Serum bilirubin levels are also usually elevated. The white blood cell count may be higher than is usually seen in pregnancy, a change that is nonspecific. The platelet count may be decreased with or without other signs of disseminated intravascular coagulation (DIC) which is associated with marked reduction in antithrombin III [13,14]. Severely affected patients also have elevations in serum ammonia, prolongation of prothrombin time, and hypoglycemia caused by hepatic insufficiency. Acute kidney injury and hyperuricemia are often present [15].

PATHOGENESIS — The association of cases of acute fatty liver of pregnancy with one of the inherited defects in mitochondrial beta-oxidation of fatty acids, long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency, suggested that some affected women and their fetuses might have an inherited enzyme deficiency in beta-oxidation that predisposes the mother to this disorder [16-18]. In addition, defects in short- and medium-chain acyl-CoA dehydrogenase (SCAD; MCAD) activity in infants have also been associated with acute fatty liver of pregnancy [19].

The LCHAD catalyzes the third step in the beta-oxidation of fatty acids in mitochondria (the formation of 3-ketoacyl-CoA from 3-hydroxyacyl-CoA). The accumulation of long-chain 3-hydroxyacyl metabolites produced by the fetus or placenta is toxic to the liver and may be the cause of the liver disease.

The role of LCHAD in the pathogenesis of acute fatty liver of pregnancy has been illustrated in a number of studies:

●In a report of 12 women with a previous episode of acute fatty liver of pregnancy, eight had evidence of being heterozygous for LCHAD [20]. These eight women had nine pregnancies complicated by fatty liver; seven of these pregnancies were also associated with preeclampsia and HELLP (presumably stressing the woman's compromised beta-oxidation function) and seven of the nine offspring were proven or presumed to be homozygous deficient (spilling unmetabolized long chain fatty acids into the maternal circulation). The other two offspring had heterozygous LCHAD.

 

●One series focused on three families with children presenting with sudden unexplained death or hypoglycemia and elevated liver enzymes (Reye-like syndrome) [21]. In all families, the mothers had acute fatty liver of pregnancy during the pregnancies with the affected infants. Three children who were studied had mutations in both alleles for LCHAD.

 

●The effects of fetal genotype on maternal and fetal outcomes were evaluated in 35 families with mitochondrial trifunctional protein mutations in the United States [22]. Approximately one-half of women who carried affected fetuses had acute fatty liver of pregnancy, and 11 percent had a HELLP syndrome. All women who had a maternal illness carried fetuses with isolated LCHAD deficiency. No maternal or fetal complications were associated with heterozygous or wild-type fetal genotypes.

 

However, some investigators have not been able to confirm the association with LCHAD [23,24]. One possible explanation is that only specific genetic defects associated with LCHAD lead to an increased risk of acute fatty liver of pregnancy. This hypothesis was evaluated in a study that included 24 children with 3-hydroxyacyl-CoA deficiency in whom nucleotide-sequence analysis was used to identify mutations in the alpha subunit of a trifunctional protein [25], which is associated with the inner mitochondrial membrane and provides the active site for LCHAD activity [26,27]. Nineteen children were either homozygotes for the G1528C mutation in which glutamic acid was replaced with glutamine (E474Q) or compound heterozygotes (with the glutamine mutation plus a different mutation on the other allele). Fifteen mothers of these children (79 percent) developed acute fatty liver of pregnancy, the HELLP syndrome, or both. In contrast, pregnancy-related liver disease was not observed during pregnancies in children who had other mutations or in pregnancies in which the fetus had at least one wild-type allele. Another possible explanation for the absence of detectable LCHAD mutations is that other defects in beta oxidation of fatty acids have been described in association with acute fatty liver of pregnancy [28].

The proportion of children with LCHAD deficiency born to mothers with acute fatty liver of pregnancy was estimated in a cohort study that included 108 consecutive blood samples from women who developed acute fatty liver or HELLP syndrome [29]. Mutations causing LCHAD deficiency were detected in 19 percent of women with a maternal history of fatty liver but only one woman with HELLP syndrome. The most common maternal mutation was the mutation G1528C mutation which alters amino acid 474 from glutamic acid to glutamine on the protein (E474Q). Testing for the known genetic variants of this LCHAD is available and should be considered in affected women, their infants, and fathers [21,27,30]. However, testing only for the G1528C mutation does not rule out LCHAD deficiency, which may be caused by a number of other mutations.

When stressed, infants with LCHAD are at risk to develop fatal nonketotic hypoglycemia, imitating Reye's syndrome or defects in urea cycle function [18]. In addition, some forms of LCHAD deficiency are associated with neonatal dilated cardiomyopathy or progressive neuromyopathy. In one report, these features were observed in five children who had complete deficiency of the mitochondrial trifunctional protein required for 3-hydroxyacyl-CoA dehydrogenase activity [25].

Because the diagnosis of LCHAD-deficiency in the newborn can be life-saving, all women with acute fatty liver of pregnancy and their children should undergo molecular testing for LCHAD, at least for the most common G1528C mutation [31,32]. If this mutation is not detected, consideration should be given towards more extensive testing for other defects in fatty acid oxidation (eg, MCAD, SCAD) [19,28]. Testing should be coordinated with a metabolic or genetic specialist.

DIAGNOSIS — The diagnosis of acute fatty liver of pregnancy is usually made clinically based upon the setting, presentation, and compatible laboratory and imaging results. Laboratory tests that are helpful include serum aminotransferases, serum bilirubin, coagulation studies, electrolytes, serum glucose, uric acid level and creatinine, and a white blood cell count.

The major other condition that must be excluded is the HELLP syndrome, which is characterized by hemolysis, elevated liver enzymes, and a low platelet count. There is a large clinical overlap between acute fatty liver of pregnancy and HELLP syndrome, and it may be difficult, even impossible, to differentiate them. However, evidence of hepatic insufficiency such as hypoglycemia or encephalopathy and abnormalities in coagulation studies is more consistent with acute fatty liver of pregnancy. In one series of 46 women who developed liver disease during pregnancy severe enough to require admission to a liver failure unit, 70 percent had acute fatty liver and 15 percent had HELLP [10]. Most of the remaining patients had liver disease that was unrelated to pregnancy. (See "HELLP syndrome".)

Imaging tests of the liver are primarily used to exclude other diagnoses, such as a hepatic infarct or hematoma [33]. Some authors have reported finding fat on either ultrasonography or computed tomography, but these tests are most useful in retrospect, when comparing the images obtained during the height of the illness with those obtained several months later [34,35].

Liver biopsy — Liver biopsy is diagnostic, showing the characteristic picture which is the microvesicular fatty infiltration of the hepatocytes. The fat droplets surround centrally located nuclei, giving the cytoplasm a foamy appearance. The fatty infiltration is prominent in central and mid zonal parts of the lobule and usually spares a sharply defined rim of cells around the portal tracts [36]. Tissue should be set aside at the time of the procedure for special stains (oil red O on frozen section, or electron microscopy) for confirmation of diagnosis in patients without evident vacuolization (picture 1) [37,38]. Because liver biopsy is invasive, it is not always performed. Liver biopsy should be approached with caution during pregnancy, and reserved for cases in which the diagnosis is in doubt and the appropriate treatment (delivery) is being delayed.

TREATMENT AND COURSE — Treatment of acute fatty liver of pregnancy is a combination of maternal stabilization and prompt delivery of the fetus, regardless of gestational age.

Maternal stabilization requires glucose infusion and reversal of coagulopathy (eg, administration of fresh frozen plasma, cryoprecipitate, packed red blood cells and platelets), as needed. Attention should be paid to the woman's overall fluid status because the low plasmatic oncotic pressure can lead to pulmonary edema. Hypoglycemia is common and all patients should have glucose monitored until normal liver function returns [7]. We typically treat hypoglycemia with a continuous infusion of 10 percent dextrose solution. Some patients with severe hypoglycemia may require multiple supplementary ampules of 50 percent dextrose [7].

The route of delivery is contingent on a combination of factors: fetal status, maternal status, and the probability of successful labor induction. The fetus should be continuously monitored to assess for the presence of any concerning fetal heart rate patterns. Labor induction is a reasonable option if the mother and fetus can be stabilized and vaginal delivery is likely to be accomplished within 24 hours. Cesarean delivery is indicated if accomplishing a successful vaginal birth within 24 hours is unlikely or if there is concern for rapidly progressing maternal/fetal decompensation. In the setting of coagulopathy, delivery should be undertaken with concomitant administration of appropriate blood products. (See "Clinical use of plasma components" and "Clinical and laboratory aspects of platelet transfusion therapy".)

Patients with acute fatty liver of pregnancy are extremely susceptible to developing coagulopathies due to decreased hepatic production of coagulation factors and/or disseminated intravascular coagulation (DIC). As a result, these patients are at high risk for bleeding complications (eg, postpartum hemorrhage). Serial monitoring of the patient's platelet count, international normalized ratio (INR), partial thromboplastin time, and fibrinogen levels should be undertaken to assess for overt or evolving coagulopathy. In the setting of acute fatty liver of pregnancy, the clinician must be aware of the normal references ranges for coagulation parameters in pregnancy (table 2). If a patient demonstrates abnormalities in coagulation parameters outside of normal for pregnancy (eg, third trimester fibrinogen level <300 mg/dL,INR>1.1), especially if it is near the time of delivery, we suggest early administration of appropriate blood products. (See "Clinical use of plasma components" and "Clinical and laboratory aspects of platelet transfusion therapy".)

The liver tests and coagulopathy usually start to normalize shortly after delivery. In one series, most laboratory values normalized within 7 to 10 days after delivery [39]. A transient worsening of liver and renal functions and coagulopathy may be observed during the first few days after delivery followed by a definitive improvement [39]. In most severe cases, mostly when diagnosis has been delayed, there may be many more days of illness requiring maximal supportive management in an intensive care unit, including mechanical ventilation because of coma, dialysis for acute renal failure, parenteral nutrition because of associated pancreatitis, or even surgery to treat bleeding from a preceding cesarean section.

Most severely ill patients recover and have no sequelae of the liver disease itself [7,39]. However, substantial morbidity and mortality can occur. In a population-based study that included 57 patients with acute fatty liver of pregnancy, one woman required a liver transplant and one woman died (case fatality rate of 1.8 percent, 95% CI 0-9 percent) [8]. There were seven deaths among 67 infants (perinatal mortality rate of 104 per 1000 births, 95% CI 32-203). In a second report with 51 women with acute fatty liver of pregnancy, there were two maternal deaths (4 percent), and the stillbirth rate was 120 per 1000 births [39]. Other reports have also described patients who required liver transplantation, but it is unlikely to be needed with early diagnosis and prompt delivery [40,41].

RECURRENCE — Acute fatty liver of pregnancy can recur in subsequent pregnancies, even if the search of long-chain 3-hydroxyacyl CoA dehydrogenase deficiency mutation is negative [6,16,20,24,42-44]. However, the exact risk of recurrence is unknown. Affected women should be warned of this possibility and subsequent pregnancies can be undertaken provided that the woman understands the risks. Such patients should be monitored by an expert in maternal-fetal medicine.

SUMMARY AND RECOMMENDATIONS

●Acute fatty liver of pregnancy, characterized by microvesicular fatty infiltration of hepatocytes, is a disorder which is unique to human pregnancy. It is rare, with an approximate incidence of 1 in 7000 to 1 in 20,000 deliveries. It is more common with multiple gestations and possibly in women who are underweight. (See 'Epidemiology' above.)

 

●Acute fatty liver occurs typically in the third trimester. The disease is always present before delivery, although it is not always diagnosed prior to delivery. The most frequent initial symptoms are nausea or vomiting (approximately 75 percent of patients), abdominal pain (particularly epigastric, 50 percent), anorexia, and jaundice. About one-half of patients have signs of preeclampsia at presentation or at some time during the course of illness. (See 'Clinical manifestations' above.)

 

●The diagnosis of acute fatty liver of pregnancy is usually made clinically based upon the setting, presentation, and compatible laboratory and imaging results. Laboratory tests that are helpful include serum aminotransferases, serum bilirubin, coagulation studies, electrolytes, serum glucose, uric acid level and creatinine, and a white blood cell count. The major other condition that must be excluded is the HELLP syndrome, which is characterized by hemolysis, elevated liver enzymes, and a low platelet count. (See 'Diagnosis' above.)

 

●The primary treatment is prompt delivery of the fetus after maternal stabilization. (See 'Treatment and course' above.)

 

●The association of cases of acute fatty liver of pregnancy with one of the inherited defects in mitochondrial beta-oxidation of fatty acids, long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency, suggested that some affected women and their fetuses might have an inherited enzyme deficiency in beta-oxidation that predisposes the mother to this disorder. We suggest that all women with acute fatty liver of pregnancy and their children undergo molecular testing for LCHAD, at least for the most common G1528C mutation. Additional testing for other defects in fatty acid oxidation can be considered if this mutation is not detected. (Grade 2B). Testing is commercially available and should be coordinated with a metabolic or genetic specialist. (See 'Pathogenesis' above.)

 

●Acute fatty liver can recur in subsequent pregnancies, even if the search of LCHAD mutation is negative. Women with a history of acute fatty liver who are contemplating pregnancy should be monitored by an expert in maternal-fetal medicine. (See 'Recurrence' above.)

 

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