REVIEW: Intrahepatic cholestasis. A puzzling disorder of pregnancy

Abstract

Intrahepatic cholestasis of pregnancy is characterized by skin pruritus and a biochemical cholestasis of mild to moderate severity appearing during pregnancy (mainly in the third trimester) and disappearing after delivery. It recurs in 40-60% of future pregnancies. The intensity of pruritus and the laboratory alterations (increased serum bile salts and transaminases in almost all patients, hyperbilirubinaemia in 20% of patients) fluctuate during one pregnancy and also vary in subsequent affected pregnancies. This disease has no meaningful consequences for the mother; in contrast, it is associated with an increased risk of foetal distress, causing premature deliveries and stillbirths. Cholestasis of pregnancy has been recognized in most countries and ethnic groups but its prevalence is higher in Chile (14% of deliveries in 1975 and approximately 4% in 1995) and in Sweden than in other countries. The cause in unknown. Sex hormones, mainly oestrogens and progesterone, appear to be involved in its pathogenesis. An interplay between a genetic metabolic predisposition and some environmental factor(s) is apparently relevant. Clinical and experimental studies suggest that a marginal selenium deficiency could be a dietary pathogenic factor. Some drugs attenuate pruritus and improve maternal cholestasis, but not the foetal prognosis. Ursodeoxycholic acid (UDCA) administration provides a significant improvement in maternal pruritus and in the biochemical abnormalities, with no adverse effects in the mother or child. Recent clinical and experimental studies show that UDCA administration improves maternal disease and foetal prognosis without any detectable adverse effects.

Estrogen Receptor α Mediates 17α-Ethynylestradiol Causing Hepatotoxicity

“…Intrahepatic cholestasis of pregnancy (ICP), 2 the most common hepatic disease during pregnancy, starts with modest itching associated with elevated levels of serum bile acids and can lead to spontaneous premature delivery and intrauterine fetal death (2,3). Experimental intrahepatic cholestasis induced by 17␣-ethynylestradiol (EE2) treatment in rodents is a widely used in vivo model to examine the mechanisms involved in estrogen-induced cholestasis (4).…”

Progesterone metabolites and bile acids in serum of patients with intrahepatic cholestasis of pregnancy: Effect of ursodeoxycholic acid therapy

“…The total concentra-disease and of its clinical consequences is still obscure, altion of conjugated bile acids in the 11 patients was 25 { 6 though a role of female sex hormones and/or their metabommol/L (mean { SEM) and decreased to 6.3 { 3.5 mmol/L lites is suggested by several studies. [5][6][7][8] While estrogens have in the 7 patients responding to treatment with UDCA. The received most attention as potential inducers of ICP, it is of level of 7a-hydroxy-4-cholesten-3-one was significantly lower interest that 10 of the 13 patients studied by Bacq et al 4 had (7.2 { 2.2 ng/mL) in patients with ICP than in healthy preg-been given daily doses of 0.2 to 1 g of progesterone shortly nancy (18 { 4.6 ng/mL) (P õ .05).…”

Cholestasis of pregnancy: in need of a more rapid diagnosis

“…First, they report a prevalence of 5.6% in a predominantly Latina population, in the setting of a prevalence of pruritis of 19.7%. Higher rates of ICP have been described previously among women from South America, particularly Chile, 10 as well as women from Sweden, 4 whereas the rates among non-Hispanic Caucasians in Australia and the Unites States have been reported at 1 to 3 per 1000. 13,14 However, prospective studies of the prevalence of ICP in Latinas in the United States have not previously been conducted.…”

“…ICP has been associated with poor perinatal outcomes including higher rates of meconium-stained amniotic fluid, 1 preterm birth, 2 respiratory distress syndrome 3 and intrauterine fetal demise. 4 Additionally, although mothers do not experience any particular perinatal morbidity, they do have an increased future risk of cholelithiasis and other biliary and hepatic disease. 5,6 Despite the neonatal complications associated with ICP, there are no clear management recommendations regarding pregnant women with this complication from the American College of Obstetricians and Gynecologists.…”