General Considerations

Various hepatic conditions may occur in pregnancy, and the interpretation of common liver biochemical tests in women who are pregnant can sometimes be challenging. Among the specific conditions unique to pregnancy that may manifest with altered liver tests are HG, ICP, AFLP, preeclampsia/eclampsia, and HELLP syndrome. Other common hepatic conditions, such as viral hepatitis and cirrhosis, are not unique to but can manifest during pregnancy.

The pregnant state is accompanied by a 30–50% increase in blood volume. As a result, several biochemical values are reduced during pregnancy. These include serum albumin, total protein, and bilirubin (Table 8–1).

The most significant change is noted during the second trimester. The serum alkaline phosphatase level is elevated because of the presence of placental-derived alkaline phosphatase. The biliary-derived alkaline phosphatase remains within the normal range as illustrated by normal levels of γ-glutamyl transpeptidase (GGT) and 5′-nucleotidase (5′ NT). Serum cholesterol also increases to approximately twice its prepregnancy level. Lastly, the hepatic markers of inflammation, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are unchanged.

Pathologic conditions that result in abnormal biochemical tests during pregnancy tend to be divided into three broad categories: (1) those that lead to a mild increase in transaminases, (2) those that lead to marked increase in transaminases, and (3) those that result in predominantly cholestatic biochemical abnormalities. Conditions that lead to mild increase in transaminases include preeclampsia, eclampsia, HELLP syndrome, Budd-Chiari syndrome, ICP, drug-induced hepatitis, and chronic liver diseases. Those that result in marked increase in ALT and AST also include preeclampsia and eclampsia, especially in the setting of hepatic infarct, AFLP, Budd-Chiari syndrome with portal vein thrombosis, hepatic rupture, acute viral or autoimmune hepatitis (AIH), drug-induced hepatitis, and ischemic hepatopathy (“shock liver”). Lastly, conditions that result predominantly in cholestasis include ICP, choledocholithiasis, or drug-induced cholestasis.

Hyperemesis Gravidarum

HG occurs in 0.3–2% of pregnancies, usually within the first trimester, and is defined as excessive and intractable nausea and vomiting. Severe forms are associated with metabolic derangements such as carbohydrate depletion, dehydration, or electrolyte disturbance. Risk factors for HG include multiple gestations, molar pregnancies, and fetal anomalies such as hydrops fetalis and trisomy 21. Liver biochemical abnormalities, specifically elevations in aminotransferases are seen in more than 50% of patients hospitalized as a result of HG. The level of aminotransferase elevation is on average two to three times the upper limit of normal, but can be elevated up to 20 times of that. It appears that the severity of nausea and vomiting correlates well with the degree of liver enzyme elevations. Fulminant liver failure has not been reported. Jaundice is rare (Table 8–2).

The cause of hepatic dysfunction in HG is unclear. Current investigations underscore the potential roles of starvation injury, release of inflammatory cytokines by the placenta, and impairment of fatty acid oxidation in the pathogenesis of the liver disease in HG.

Treatment is symptom management-based with intravenous hydration, intravenous antiemetics, and bowel rest. In the most severe cases, parenteral feeding may be necessary. Liver function abnormalities usually return to normal levels within a few days of volume expansion and the cessation of vomiting and no long-term sequelae of liver dysfunction have been described.

Intrahepatic Cholestasis of Pregnancy

ICP is characterized by pruritus and increased serum bile acids and/or transaminases and usually occurs in the second and third trimester of pregnancy and resolves with delivery. Incidence varies considerably with country and ethnicity, the highest rates reported in Chile and Bolivia in the 1970s. The incidence ranges from 0.3% to 5.6% (in a predominantly Latina population in Los Angeles) in the United States and 0.5–1.5% in Europe. Risk factors for ICP include multiparity, advanced maternal age, family history, and previous cholestasis while on oral contraceptives.

Mutations of genes encoding several proteins involved in hepatobiliary transport have been associated with ICP. Heterozygous mutations in the ABCB4 (adenosine triphosphate–binding cassette, subfamily B, member 4) gene which encodes the hepatic phospholipid transporter MDR3 (multidrug resistance 3) have been found in patients with ICP. Mutations in genes encoding the bile salt export pump (BSEP), farnesoid X receptor (FXR), and familial intrahepatic cholestasis 1 protein (FIC1) have less frequently been found in patients with ICP.