Acute fatty liver of pregnancy (AFLP) is an uncommon but potentially fatal complication of pregnancy, which results in microvesicular fat deposition in the liver, resulting in severe liver dysfunction. Hallmarks of the disease include jaundice, coagulopathy, and encephalopathy. Although most commonly a disorder of the late third trimester, very rare cases have been reported as early as 23 weeks. The incidence of AFLP appears to have increased over the past 30 years (from 1:15,900 to 1:6692 deliveries), possibly as more widespread recognition of the disease and identification of milder cases occurs. Prior to the 1970s, maternal and fetal mortality rates were reported to be as high as 75% and 85%, respectively. However, recent reports suggest markedly improved maternal mortality, ranging from 0% to 10% and fetal mortality from 8% to 25%. Deaths have been attributed to bleeding complications, aspiration, renal failure, and sepsis. Survivors of AFLP generally recover without sequelae. Early diagnosis is critical and AFLP should be considered in all pregnant women presenting in the third trimester of pregnancy with nausea, vomiting, or epigastric pain.

The precise etiology of AFLP remains unknown, but dysfunction of fatty acid metabolism is a predominant characteristic of this condition. Women with multiple gestations are at higher risk for developing AFLP, given the larger amount of fatty acid metabolites produced by more than one fetus. Additionally, women with metabolic disorders such as type 2 diabetes are also at risk for AFLP given the association with nonalcoholic fatty liver disease.

In some cases, an autosomal recessive fetal enzyme deficiency involved in the mitochondrial fatty acid oxidation pathway has been linked to the development of maternal AFLP. The largest study to date of 27 women affected by AFLP found that 19% of the offspring of these pregnancies had long-chain 3-hydroxyacyl coenzyme dehydrogenase (LCHAD) deficiency. In contrast, no newborns had LCHAD deficiency when 81 maternal hemolysis, elevated liver transaminases, low platelets syndrome (HELLP syndrome) cases were evaluated. It is postulated that toxic metabolites, such as free fatty acids from an impaired fetoplacental unit, result in maternal illness in these cases of AFLP. Recently, placentas of women who had AFLP were shown to have impaired mitochondrial function, resulting in free radical production and fatty acid accumulation, generating oxidative stress. Importantly, LCHAD deficient infants are at subsequent risk for hepatic steatosis, hypoglycemia, coagulopathy, coma, and death, all of which can be prevented with the use of a special diet and frequent regular feedings. It has been recommended that newborns of all women with AFLP should undergo molecular analysis for LCHAD gene mutations. Nationally, all states have now implemented LCHAD and other fatty acid enzyme disorder testing as part of routine newborn screening via tandem mass spectrometry. Abnormal LCHAD function may represent only one of a variety of fatty acid metabolic disorders resulting in the clinical phenotype of AFLP.

The pathway of impaired mitochondrial oxidation has been implicated in other microvesicular liver disorders in nonpregnant individuals that are remarkably similar to AFLP. Exogenous impairment of mitochondrial oxidation can occur with ingestion of aspirin, valproic acid, and tetracycline, and would, in susceptible individuals with latent oxidative enzyme deficiencies, result in liver dysfunction, such as is seen in Reyes disease, tetracycline toxicity, and valproic acid injury. Common histopathologic findings include the presence of fine fat droplets in swollen hepatocytes, due to the accumulation of triglycerides and, particularly in AFLP, free fatty acids. Fat deposits are most prominent in pericentral and mid zones and spare the periportal cells. Microvesicular fat deposition can be missed if the tissue is fixed before examination, and Oil Red O or Sudan stains should be used on frozen tissue sections. Electron microscopy of the liver shows mitochondrial abnormalities. Intrahepatic cholestasis is usual and, unlike in preeclampsia, cellular infiltration with lymphocytes is minimal. Although the diagnosis of AFLP can be made by liver biopsy, today the diagnosis is usually made clinically (Tables 15-1 and 15-2).

Noninvasive radiologic techniques have been used in order to avoid liver biopsy and support a clinical diagnosis. Unfortunately, the reported sensitivities are low. Abnormalities in the imaging studies of 19 patients with AFLP were reported in 25% of ultrasounds, 50% of computerized tomography (CT) scans, and none of the magnetic resonance imaging (MRI) studies. A larger series of ultrasounds from 45 women with AFLP reported abnormalities in just 27%. Imaging studies can be used to exclude biliary obstruction as a cause of jaundice, however (Table 15-3).

Table 15-4 reviews the results of common liver assays in normal pregnancy, and Table 15-5 presents the laboratory abnormalities encountered in AFLP. The laboratory hallmark of AFLP is hyperbilirubinemia, with values typically elevated to 3 to 10 mg/dL, with a reported range of 3 to 40 mg/dL. Alkaline phosphatase, normally elevated up to 2-fold in pregnancy, is commonly elevated up to 10-fold in AFLP. Due to decreased ammonia utilization by the urea cycle enzymes of the hepatocytes, serum ammonia is elevated, and associated with hepatic encephalopathy. Transaminase elevation is mild to moderate, usually less than 250 to 500 U/mL, but can be greater than 1000 U/mL. Transaminase elevation is less than typically seen in acute hepatitis. Typically serum glutamic oxaloacetic transaminase (SGOT) levels (aspartate) are greater than serum glutamic pyruvic transaminase (SGPT) levels (alanine). Severe liver dysfunction also leads to coagulopathy. Production of vitamin K-dependent clotting factors by the liver is depressed, resulting in another hallmark of AFLP, an elevated prothrombin time. With worsening liver failure, the partial thromboplastin time becomes elevated. Decreased fibrinogen production results from further liver dysfunction. A profound depression of antithrombin III (ATIII) activity is also reported in AFLP, to a far greater degree than in preeclampsia or HELLP syndrome. ATIII activity is not significantly affected by normal pregnancy, or pregnancy with chronic hypertension alone. The low levels in AFLP are probably due to derangement in liver production, but may also be associated with accelerated consumption and disseminated intravascular coagulation (DIC). Despite the marked decrease in ATIII, which is a natural inhibitor of coagulation, clinical large vessel thrombosis does not occur, perhaps due to proportional impairment of clotting activators.