Intrahepatic cholestasis of pregnancy: from bedside to bench to bedside

Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder that usually manifests during late pregnancy and disappears spontaneously after delivery. ICP complicates less than 1% of pregnancies in Western Europe. A prospective study conducted in west Sweden between February 1, 1999 and January 31, 2002, including 45 485 pregnant women, reveals that ICP (defined as otherwise unexplained pruritus of pregnancy in combination with fasting serum bile acid levels higher than 10mM) was diagnosed in 505 of them, i.e., on average 1.1 of 100 pregnancies (1). The highest incidence is found in Chile where it occurs in up to six of 100 pregnancies. ICP increases the risk of preterm delivery and fetal loss. In up to 3.5% of cases, the fetus dies suddenly for unknown reasons. While there is no vital risk for the mother, pruritus may cause considerable discomfort. Pruritus linked to ICP should be differentiated from specific dermatoses of pregnancy, especially pruritic urticarial papules and plaques, which manifest during the third trimester of pregnancy. These dermatoses not associated with abnormal liver function tests may represent up to one-third of the cases of pruritus occurring in late pregnancy (2). The main biochemical features of ICP are increased serum alanine–aminotransferase activities and serum bile acids levels. Serum bilirubin levels are elevated in the most severe forms. Serum gglutamyl transpeptidase (GGT) activity is increased in about 10–15% of the reported cases. The prevalence of cholelithiasis is higher in ICP patients than in the normal population. Signs or symptoms of cholelithiasis are found in up to 22% of the patients presenting with severe forms of ICP (1, 3). The cause of ICP is unknown. Hormonal and genetic factors are likely to be involved. Familial cases clustering as well as the high incidence in the Araucanos Indians of Chile stress the importance of genetic susceptibility (4). Steroids (estrogens, progesterone and corticosteroids) reach at term concentrations up to 1000-fold higher than those in non-pregnant individuals. All these steroids are metabolized by the liver and have a major influence on nuclear hormone receptors governing the activity of their own biliary transporters as well as of bile acids and other cholephilic anion transporters. For this reason, recent studies have focused mainly on genetic variants and polymorphisms of canalicular transporters (3, 5–9). Data obtained in the last 3 years support an involvement of MDR3 (ABCB4) genetic variation in the pathogenesis of ICP, especially in patients with cholelithiasis or elevated serum GGT activity. The majority of mutations reported to date are unique, the only exceptions being 959C4T, which has been described in two patients which symptomatic gallstones and ICP from two independent, non-consanguineous families, the 481 G41 (R 150 K) mutation that segregates with ICP in a UK pedigree and the S320F reported in our series of patients with both cholestasis of pregnancy and LPAC syndrome as well as in one of 14 ICP studied in Switzerland and Germany. In total, MDR3 mutation could account for up to 15% of all cases yet explored. Available analysis of BSEP and FICI sequence variation suggests that these genes are probably less important for the development of ICP. Finally, all molecules involved in bile acid metabolism (CYP, biliary transporters, nuclear receptors) could be potential players in the pathogenesis or phenotypic expression of ICP. The clinical heterogeneity of ICP strongly supports this view. In this issue of the journal, Zapata and coworkers report their 12-year experience treating ICP patients with ursodeoxycholic acid (UDCA). Thirty-two patients with ICP and absence of cholelithiasis, treated with UDCA (15mg/kg day) for at least 3 weeks before delivery, were compared with 16 historical controls who did not receive UDCA. The study shows that UDCA clearly improves pruritus and biochemical cholestasis, and significantly increases the proportion of deliveries at term with higher birth weight compared with historical controls. Some Liver International 2005: 25: 467–468 Printed in Denmark. All rights reserved Copyright r Blackwell Munksgaard 2005