Acute Fatty Liver of Pregnancy

The exact pathophysiology of AFLP is unknown. AFLP is unique to pregnancy.[2] There does not appear to be a predilection for any geographical area or race. It appears to occur more commonly in primiparous women than multiparous women.

Women who develop AFLP are more likely to have a heterozygous long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency. LCHAD is found on the mitochondrial membrane and is involved in the beta oxidation of long-chain fatty acids. This gene mutation is recessive; therefore, outside of pregnancy under normal physiological conditions, women have normal fatty acid oxidation. However, if the fetus is homozygous for this mutation, it will be unable to oxidize fatty acids.[3] These acids are passed to the mother, who, because of diminished enzyme function, cannot metabolize the additional fatty acids. This results in hepatic strain leading to the development of AFLP, which can be relieved by delivery of the infant.[4, 5]

United States statistics

AFLP affects 1 in 7000 to 1 in 16,000 deliveries. There is a predilection for nulliparous women and women with multiple gestations. A male fetus is also a risk factor.[6]

Race-, sex-, and age-related demographics

No ethnic or regional variability is apparent.

This condition is unique to pregnancy and therefore only affects women.

This condition can affect any woman of child-bearing age.

The prognosis for women who develop AFLP is excellent, assuming they survive the acute event. However, a case of chronic pancreatitis has been described, occurring about 3 months after recovery and discharge from the hospital.[7]

Morbidity/mortality

Due to advances in diagnostic strategies and supportive care, maternal mortality and perinatal morbidity of AFLP has declined. In the 1980s, Kaplan reported a mortality rate for both mother and fetus of about 85%.[8]  Maternal mortality is now estimated to be 12.5-18%, with a neonatal mortality rate of 7-66%.[9, 10]

While laboratory abnormalities may persist after delivery, in rare cases patients may progress to hepatic failure with the need for liver transplantation.[11]

Morbidity of the infant includes increased risk of cardiomyopathy, neuropathy, myopathy, nonketotic hypoglycemia, hepatic failure, and death associated with fatty acid oxidation defects in newborns.

Complications

Life-threatening complications of AFLP include the following[6] :

• Acute liver failure
• Disseminated intravascular coagulation
• Postpartum hemorrhage
• Acute renal failure
• Gastrointestinal bleeding
• Hepatic rupture
• Hepatic infarction

A study by Joueidi et al identified prognostic factors in AFLP. Prolonged prothrombin time was found to be a risk factor for maternal complications, and gestational age at delivery was associated with an increased risk of fetal and neonatal complications.[12]

Clinical presentation of acute fatty liver of pregnancy (AFLP) is nonspecific, and the patient can present with the following complaints:

• Malaise

• Nausea and vomiting (70%); this may present for the first time in the third trimester

• Right upper-quadrant and epigastric pain (50-80%)[13]

• Upper gastrointestinal hemorrhage

• Acute renal failure

• Infection

• Pancreatitis

• Hypoglycemia

• Fulminant liver failure with hepatic encephalopathy

Women with hepatic and gastrointestinal disease in pregnancy may have atypical symptoms, which can pose a challenge to make the diagnosis and treat the patient.[14] Other diagnostic and treatment challenges include the woman's concerns about the potential use of invasive procedures and pharmacologic teratogenicity.[14]

On physical examination, the patient may present with the following:

• Hypertension

• Bleeding

• Confusion and altered mental status

• Jaundice: Hyperbilirubinemia resulting in jaundice is rarely encountered in patients with severe preeclampsia. When jaundice is present in pregnancy, AFLP should be high on the differential.

The following laboratory studies can be evaluated to help make the diagnosis of acute fatty liver of pregnancy (AFLP).

• Aspartate transaminase (AST) and alanine transaminase (ALT) are not elevated in normal pregnancies. These can become elevated in many different conditions during pregnancy. Some are unique to pregnancy, such as preeclampsia/eclampsia, HELLP, and AFLP. High levels of ALT can be seen in patients with viral hepatitis; however, the highest levels are seen in patients with acute toxic liver injury, as can be seen in acetaminophen overdose.[15] Both AST and ALT can be elevated due to the hepatic injury.

• Hepatic injury results in decreased gluconeogenesis and, therefore, decreased blood glucose levels.

• Liver detoxification is also affected, resulting in elevated levels of blood ammonia, especially late in the disease course.

• In addition, laboratory findings may be consistent with disseminated intravascular coagulation (DIC), specifically, prolongation of prothrombin time, low fibrinogen, and low antithrombin levels. This results in a clinical picture similar to DIC; however, in AFLP, the values are abnormal, not due to consumption of the clotting factors but rather to decreased production by the damaged liver.[16]

• Bilirubin levels are elevated. This elevation is primarily the conjugated form, with levels exceeding 5 mg/dL. This can result in jaundice, which is rarely seen in patients with other forms of pregnancy-related hepatic injury, including preeclampsia.

• Some patients may develop pancreatitis, which can result in elevated amylase, lipase, and increased blood sugars.

• As the maternal kidneys become affected, blood creatine and uric acid can become elevated, leading to metabolic acidosis.

• A study by Meng et al that looked to identify prenatal predictors of AFLP in 43 patients reported that prenatal serum bilirubin, prothrombin time, plasma fibrinogen levels and platelet counts are all predictors of postpartum recovery.[17]

Imaging studies have a low sensitivity for diagnosing AFLP and should not be used to exclude the diagnosis. Liver ultrasonographic examination may reveal increased echogenicity in severe cases. A computed tomography (CT) scan may show decreased or diffuse attenuation in the liver.[18]

Although the criterion standard for diagnosis of AFLP is liver biopsy, this is rarely performed in clinical practice due to the risk of hemorrhage. In addition, AFLP can easily be differentiated from viral or drug-induced hepatitis by obtaining viral serologies and measuring acetaminophen levels in serum.

If a biopsy is performed, the histological findings demonstrate pericentral microvesicular fat infiltration with minimal inflammation or necrosis.[15]

Delivery of the fetus, regardless of gestational age, is the only treatment for acute fatty liver of pregnancy (AFLP) once the diagnosis has been made. Ending the pregnancy by delivery of the infant invariably results in resolution of the hepatic dysfunction and accompanying complications that occur in AFLP.

Mode of delivery is dependent on the following several factors:

• Fetal status: Many fetuses demonstrate evidence of asphyxia and hypoxia; therefore, close monitoring of fetal status is necessary, along with the ability to expedite delivery should fetal compromise be evident.[19]

• Maternal coagulation status: Due to coagulation abnormalities that can accompany AFLP, patients may need to have replacement of their coagulation factors should cesarean delivery be necessary.

• Likelihood of success with induction of labor: If delivery cannot be safely accomplished within 24 hours from the time of diagnosis, then cesarean delivery may be optimal.

Management of the severe hypoglycemia that may occur is necessary to avoid coma and death. Patients require at least a 5% Dextrose solution to maintain blood glucose levels. Blood glucose should be monitored closely until hepatic function returns and the patient tolerates a regular diet.

Renal function can also be affected by several factors, including maternal hemorrhage, which can lead to acute tubular necrosis and hepatorenal syndrome. Fluid balance should be closely monitored, as patients may develop pulmonary edema due to low plasma oncotic pressures.

Martin et al reported on using postpartum plasma exchange to treat severe cases of AFLP in the postpartum period. Patients with severe encephalopathy, on ventilator support, or with severe liver or renal insufficiency who failed to respond to conventional management, underwent plasma exchange. All patients showed improved signs and laboratory values.[20] Jin et al reported success with plasma exchange in 39 patients.[21] Chu et al achieved success in combining plasma exchange with continuous hemodiafiltration for patients with multiple organ dysfunction.[22]

More recent case reports have reported similar success with plasmapheresis[23] or plasmapheresis with continuous renal replacement therapy[24] for women with AFLP during pregnancy.

No specific surgical treatment exists for AFLP. Because of coagulation problems, careful evaluation of the genital tract for lacerations after vaginal delivery or maintaining good hemostasis during cesarean delivery should be practiced.[25]

Not all types of anesthesia can be used in patients with AFLP as some are hepatotoxic with decreased hepatic blood flow. Regional anesthesia may be obtained if a coagulopathy is not evident. However, if a coagulopathy is present, it should be corrected prior to regional anesthesia as bleeding at the puncture site is a concern. With general anesthesia, the anesthesiologist should be careful not to use agents that have potential hepatotoxicity, such as halothane. Isoflurane has no hepatotoxicity and may improve hepatic blood flow.