17.4.1 ACUTE FATTY LIVER OF PREGNANCY

Acute fatty liver of pregnancy is characterized by fatty infiltration of the liver. It may rapidly progress to hepatic failure and death. Acute fatty liver may be uncommon (1 in 13,328 deliveries), but is important, having a maternal mortality of 18% and fetal mortality of 23%. The etiology is unknown, but the microvesicular fat that accumulates in hepatocytes probably represents disordered intermediary fat metabolism, perhaps related to mitochondrial injury.

Acute fatty liver of pregnancy almost invariably presents in the third trimester, with a peak frequency around 36-37 weeks gestation. Occasionally, it will become apparent only after delivery. There is an association with nulliparity, twin gestations, male fetus and pre-eclampsia or eclampsia. Presentation can vary from nonspecific symptoms to fulminant hepatic failure. Nausea and vomiting with or without abdominal pain are common. Examination may reveal a tender liver. Pruritus is uncommon and would suggest the possibility of a different liver problem such as intrahepatic cholestasis of pregnancy. Progressive hepatic failure then rapidly supervenes, with the development of jaundice, generalized bleeding from coagulopathy, hypoglycemia, hepatic encephalopathy and renal failure. Such severe cases have an inexorable downhill course unless the fetus is delivered; even then, deterioration may continue for a further 48 to 72 hours.

Laboratory features include a moderately elevated aminotransferase, which is usually around 300 IU/L but may range from normal to 1,000 IU/L. Alkaline phosphatase and serum bilirubin are elevated. Liver biopsy reveals tiny droplets of fat (microvesicular fat) inside hepatocytes.

Diagnosis requires a high degree of suspicion, as the presentation is often nonspecific. Acute fatty liver of pregnancy should be considered whenever marked nausea and vomiting develop in the third trimester of pregnancy. Suspicion increases with a twin pregnancy, nulliparity or signs of toxemia. Ultrasound or CT scans may detect the increased fat in the liver and help exclude complications such as a subcapsular hematoma or another entity such as choledocholithiasis. Liver biopsy is diagnostic. Biopsy even via the transvenous route (necessary when a coagulopathy makes percutaneous liver biopsy hazardous) should be done if the results will alter management. For example, differentiation of acute viral hepatitis from acute fatty liver is important to determine whether rapid delivery is indicated. Delivery can be life-saving in acute fatty liver.

Management involves aggressive supportive care. The only definitive treatment for the condition is prompt delivery. The risk of acute fatty liver of pregnancy is not increased in subsequent pregnancies.

17.4.2 INTRHEPATIC CHOLESTASIS OF PREGNANCY

Intrahepatic cholestasis of pregnancy accounts for 20-25% of cases of jaundice during pregnancy. The etiology is unknown. There is a clear genetic predisposition, likely autosomal dominant, with an increased frequency in women of Scandinavian or Chilean descent. The cholestasis (failure of bile formation) represents an exaggerated response of the liver to the normal increase in endogenous estrogens during pregnancy.

Presentation typically is in the third trimester with the insidious onset of pruritus. In half of these patients, jaundice follows. Other cholestatic features include dark urine and, occasionally, pale stool. Otherwise women generally feel well, without nausea, vomiting or abdominal pain. Serum alkaline phosphatase and cholesterol rise, but aminotransferases are only modestly elevated. Ultrasound and cholangiography are normal. The evaluation of the pregnant woman with cholestasis involves excluding other causes of jaundice and pruritus including viral hepatitis, primary biliary cirrhosis and biliary tract disease by the appropriate laboratory and ultrasound investigations. Liver biopsy, which shows only cholestasis without inflammation, may be necessary in some atypical cases.

Although a benign condition for the mother (other than the inexorable pruritus), intrahepatic cholestasis may decrease fetal survival and increase the risk of prematurity. Treatment is supportive with bile salt-binding agents such as cholestyramine. Ursodeoxycholic acid therapy improves bile formation, perhaps washing out "toxic" bile acids and pruritogenic agents. S-adenosylmethionine, which alters membrane fluidity, and rifampin, which increases the excretion of pruritogenic agents, also work. Treatment for cholestasis and pruritus, however, generally is unsatisfactory. Delivery should occur as soon as fetal lung maturity is documented, to prevent the increased risk of stillbirth. Parenteral vitamin K may be needed to correct a prothrombin deficiency.

Symptoms usually abate within two weeks of delivery. There is a significant risk of recurrence with subsequent pregnancies and with the use of oral contraceptives or other estrogens.

17.4.3 PREGNANCY TOXEMIAS AND THE HELLP SYNDROME

In severe pre-eclampsia or eclampsia, liver involvement is evident by abdominal tenderness and abnormal liver biochemistry. Hepatocellular necrosis can occur from endothelial damage and platelet and fibrin deposition in the sinusoids. Subcapsular hematoma and hepatic rupture rarely develop.