Chapter 15: Acute Fatty Liver of Pregnancy

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 1:15,900-1:6692 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. However, 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 HELLP 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 in fact, 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 feeding. 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. The 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 CT scans, and none of the 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 DIC. Despite the marked decrease in ATIII, which is a natural inhibitor of coagulation, clinical large vessel thrombosis does not occur, perhaps due to the proportional impairment of clotting activators.

Hypoglycemia is often present and is presumed to be due to impairment of glycogenolysis within the liver, resulting from depression of glucose-6-phosphatase activity. Approximately 15% of patients with AFLP will have severe hypoglycemia and over half will require glucose supplementation with 10% dextrose to maintain adequate blood glucose.

Laboratory evaluation also reveals dysfunction of other organ systems. Renal insufficiency appears to be universal in AFLP, but infrequently requires dialysis. An elevated serum creatinine has been documented in some patients before the development of liver failure, and renal insufficiency may not be due to hepatorenal syndrome as has been postulated. Instead, it may be due to inhibition of beta oxidation of fat in the kidneys, as in the liver, and thus might be a direct effect of the underlying mitochondrial dysfunction on the kidneys. Autopsy findings in patients with AFLP have shown microvesicular deposition of fat in the renal tubules. In addition, diabetes insipidus has been noted in up to 10% of patients with AFLP, resulting in polyuria and hypernatremia. The etiology is not yet clear. Pancreatitis, associated with microvesicular fat deposition in the pancreas, results in elevated amylase and lipase in some patients. Because pancreatitis may not develop until after the onset of liver failure and because it may be a poor prognostic sign, serial screening with a daily lipase has been recommended in those with AFLP. Although hypoglycemia due to liver impairment is common in AFLP, hyperglycemia may be present if there is pancreatitis.

Table 15-6 outlines a comparison of liver diseases in pregnancy which must be distinguished from AFLP, a task which is sometimes difficult. Atypical preeclampsia and HELLP syndrome (hemolytic anemia, elevated liver function test, and low platelets) are probably the most common conditions the obstetrician will consider as alternate diagnoses to AFLP. Features in common to these entities include elevated transaminases, thrombocytopenia, and frequently, an elevated serum creatinine. In addition, proteinuria and even hypertension are frequent in patients with AFLP, as is always seen in preeclampsia, and usually in HELLP syndrome. Importantly, in both AFLP and preeclampsia/HELLP, delivery is ultimately curative. Clinical jaundice, apparent when the bilirubin rises above 2 to 3 mg/dL, is a hallmark in AFLP, but uncommon in preeclampsia/HELLP syndrome. While an elevated prothrombin time is a hallmark of AFLP, the prothrombin time and fibrinogen levels are usually normal in preeclampsia/HELLP, unless placental abruption or fetal death has occurred with associated DIC. Hypoglycemia, common in AFLP, is not expected in preeclampsia/HELLP. Cholestasis of pregnancy is the most common liver disease in pregnant women. This entity can be associated with elevated transaminases and bilirubin, but usually to a lesser degree than in AFLP. Importantly, unlike in AFLP, cholestasis is associated with pruritus.

The clinical presentation may be similar in both AFLP and viral hepatitis, including malaise, nausea, emesis, and a tender right upper quadrant. Fulminant acute viral hepatitis is typically associated with much higher transaminase values than AFLP, usually >1000 U/L. In addition, unlike many patients with AFLP, hypertension and proteinuria are not present. Risk factors may be identified for hepatitis, including drug exposure or known hepatitis exposure. Finally, hepatitis does not have a predilection for the third trimester.

Both hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) share some features with AFLP, including thrombocytopenia, renal insufficiency, microangiopathic anemia, and alterations in mental status. However, the coagulopathy which is a hallmark of AFLP is not found in TTP or HUS cases, in which the prothrombin time and fibrinogen levels will be normal. In addition, ATIII activity is normal in TTP and HUS.

The most critical component of caring for a woman with AFLP is delivery of her fetus. There is no clear benefit to immediate cesarean delivery versus induction of labor and vaginal delivery with meticulous supportive care. In fact, in one report of 28 patients with AFLP, almost all of the maternal hemorrhagic complications occurred in association with surgical trauma. However, factors such as known fetal growth restriction and uteroplacental insufficiency, nonreassuring fetal status by fetal heart rate monitoring, and early gestational age with a markedly unfavorable cervix may appropriately influence a decision to choose cesarean section over vaginal delivery. Coagulation parameters should be corrected prior to surgical delivery, and consideration given to a vertical midline incision, avoiding the dissection associated with a Pfannenstiel incision. The use of an intraperitoneal, closed suction drain, as well as a similar subcutaneous drain (or delayed secondary closure) can also be considered. If vaginal delivery can be accomplished, avoidance of episiotomy in the presence of a coagulopathy is suggested. Anesthesia should be carefully planned, and regional anesthesia considered if coagulation abnormalities can be corrected. If not, and general anesthesia is chosen, inhalation agents with the potential for hepatotoxicity (such as halothane) should be avoided. The use of isoflurane has been described. In addition, the dose of narcotics, which are metabolized by the liver, should be adjusted.

Additional supportive care for AFLP includes monitoring for hypoglycemia, treatment of coagulopathy with transfusion when clinically indicated, optimizing nutrition, and surveillance for infection. Although transfusion with ATIII has been suggested in light of its severe depression in patients with AFLP, this approach is not known to be of clinical benefit. Worsening of liver and renal function can be seen for up to 2 to 3 days after delivery, as well as the development of pancreatitis. Additional therapies which have been reported empirically in very small numbers of patients with uncertain benefit have included plasma exchange and albumin dialysis. Plasma exchange was used for 6 patients in one small series who continued to worsen from 2 to 9 days after delivery. Albumin dialysis (molecular adsorbent recirculating system or MARS) has been utilized in nonpregnant patients with hepatic encephalopathy and reported in 2 AFLP patients on days 3 and 9 after delivery. Another small case series from China described combined plasma exchange with hemofiltration in 11 patients with AFLP, with 9% mortality, similar to that reported overall in the literature. Although there are several reported cases of liver transplantation for patients with ongoing liver failure in the immediate postpartum period, it has been argued that with ongoing supportive care, all patients with AFLP will ultimately experience complete resolution of the liver failure. Importantly, AFLP has been recognized to recur in subsequent pregnancy, in a small number of cases. At least one such case was associated with LCHAD heterozygosity in the patient. Table 15-7 presents the cornerstones of supportive care for patients with AFLP.