Acute Fatty Liver of Pregnancy

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Acute fatty liver of pregnancy (AFLP) was first described in 1934 and is a rare, idiopathic, potentially fatal disease presenting in the third trimester of pregnancy. Incidence ranges from 1 of 7,000 to 1 of 16,000 deliveries and it constitutions 16 to 43% of severe liver disease seen during pregnancy. In its most severe form, it is manifest by fulminant hepatic failure. Seen worldwide, there appears to be no ethnic or geographic variation.

The average maternal age at onset is 26 years (range, 16 to 39 years) with gestational age of onset at about 36 weeks (range, 22 to 40 weeks). AFLP can rarely occur earlier in pregnancy or shortly postpartum. Primagravidas with male gestations comprise most cases (see Table 120-2). Recurrence with subsequent pregnancies, once thought to be uncommon, is increasingly being reported.

AFLP has little or no association with the hormonal changes of pregnancy. Its etiology is unknown, but may stem from decreases in fetal mitochondrial fatty acid p-oxidation by the enzyme long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD). Cholestatic liver disease with microvesicular steatosis is often seen in patients with LCHAD deficiency and an association between LCHAD and AFLP has been described. In many cases, the defect appears to reside in the a-subunit of a trifunctional protein gene, which includes LCHAD activity. This may lead to poor fetal processing of triglycerides and free fatty acids, which are toxic to the maternal hepatocytes. Testing for the genetic variants of the LCHAD enzyme is available. When the deficiency is present, recurrent disease can be seen in subsequent pregnancies. Not all investigations have confirmed this specific association and other genetic variants, such as a defect in short-chain acyl-coenzyme A dehydro-genase, have been associated with AFLP.

Asymptomatic elevations in liver tests may be the only abnormality, but the majority of severe cases present with malaise, fatigue, anorexia, headache, nausea, and vomiting (see Table 120-2). Right upper quadrant or epigastric pain may mimic acute cholecystitis or reflux esophagitis. Within 1 to 2 weeks of onset of symptoms, and within days following clinical jaundice, the disease may rapidly worsen, leading to acute liver failure, with hepatic encephalopathy, ascites, edema, and renal insufficiency. Hallmarks of preeclampsia (hypertension, proteinuria) are seen in over 50% of cases.

Serum aminotransferases are generally less than 1,000 IU/L and do not reflect severity of liver dysfunction. Hyperbilirubinemia averages 10 to 15 mg/dL, but levels up to 30 to 40 mg/dL have been reported. In the setting of eclampsia and preeclampsia, hyperbilirubinemia is predominantly unconjugated and hemolysis is present. Increases in alkaline phosphatase are difficult to interpret because they overlap the normal values seen late in pregnancy. A left-shifted leukocytosis and some degree of thrombocytopenia are nearly universal.

Clinical and laboratory findings suggest the diagnosis of AFLP. The differential diagnosis includes acute viral hepatitis, acute toxic or drug-induced hepatitis, preeclampsia-related liver disease (including hemolysis, elevated liver enzymes, and low platelets syndrome [HELLP]), and biliary tract disorders. Imaging studies are useful in assessing the biliary tree. Virologic markers and history can help to rule out viral and toxic hepatitis.

Liver biopsy provides the diagnostic gold standard, but it is problematic if coagulopathy is present, and is rarely needed (Figure 120-1). Fatty changes in pancreatic acinar cells and renal tubular epithelia have also been described and likely account for the findings of renal failure and pancreatitis in these patients.

Upper gastrointestinal hemorrhage (in 30 to 40% of cases) occurs from a variety of causes. Renal dysfunction is generally mild to moderate, but 25% of patients develop severe renal failure and may require dialysis. Coagulopathy (elevated PT), decreased antithrombin III levels, and thrombocytopenia) probably represents both hepatic synthetic dysfunction and peripheral consumption. Frank disseminated intravascular coagulation (DIC) is common (up to 70%). Pancreatitis develops in up to 30% of patients. Severe hypoglycemia may be seen in 25 to 50% of patients and can occur at any stage in the disease.

AFLP is a medical and obstetrical emergency. It is often difficult to distinguish from toxic or viral hepatitis. Patients may progress to fulminant liver failure and death or require liver transplantation. No specific therapy is available. Patients should promptly be admitted to an experienced liver failure unit, since it is impossible to predict which patients will progress to liver failure. The patient should be medically stabilized and delivery attempted as soon as reasonably possible; ALFP never resolves before delivery. Aggressive maternal supportive care is required and fresh frozen plasma or cryoprecipitate may be necessary prior to delivery. Blood glucose levels should be followed frequently. Likewise, PT must frequently be checked as this helps to assess the severity of disease. With early diagnosis and management, severity of disease and need for liver transplantation can be minimized.

Maternal mortality has been reported as high as 70%, but can be improved to 10 to 20% with early delivery and intensive clinical support. Fetal death occurs in 42 to 90%

FIGURE 120-1. Acute fatty liver of pregnancy. The zone 3 cen-trilobular hepatocytes are swollen with microvesicular fat globules. Sinusoidal compression can be seen but signs of hepatic necrosis and inflammation are often subtle. Hepatic necrosis is a minor feature. Courtesy of Carolyn A Riely, MD.

of cases with only minimal improvement with early delivery (36%). After delivery, affected women improve slowly; full recovery often takes up to a month. There are no hepatic sequelae. Infants who survive should be tested for LCHAD deficiency and other fatty acid transport and mito-chondrial oxidation disorders.

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