Introduction

Intrahepatic cholestasis of pregnancy (ICP; synonymous: obstetric cholestasis) represents a rare form of genetically linked, hormone-dependent reversible cholestasis ¹. It typically presents in the second half of pregnancy and resolves rapidly after delivery. Clinically, it is characterized by severe pruritus in the absence of primary skin lesions. Secondary skin changes, due to scratching, follow with disease progression and include excoriations and prurigo lesions. Biochemically, elevation of total serum bile acid levels is diagnostic. ICP is particularly prevalent in South America (Chile, Bolivia) and Scandinavia, whereas incidence rates of 0.1–1.5% have been described for Central Europe and Northern America. There is a positive family history in up to 50% of cases. In contrast to the other dermatoses of pregnancy, ICP is associated with significant fetal risk (Table 7.1)¹.

Table 7.1 Fetal Risks Associated with Intrahepatic Cholestasis of Pregnancy

Fetal Risks	Prevalence¹
Premature births	19–60%
Intrapartal fetal distress Abnormal intrapartum heart rate Meconium staining of amniotic fluid	22–33%
Stillbirths	1–2%

Historical background

Although ICP had been addressed as an important differential diagnostic consideration in most comprehensive studies of pregnancy-related disorders, it was usually omitted from the classification of specific dermatoses of pregnancy as it is not a primary dermatosis but associated with only secondary skin lesions due to scratching. Shornick ², in 1998, was the first to include it in the category of specific dermatoses of pregnancy, along with pemphigoid gestationis, polymorphic eruption of pregnancy, and prurigo of pregnancy. He postulated that failure to appreciate ICP in a pregnant woman with pruritus and excoriated papules, in retrospect, had certainly accounted for some of the confusion in terminology. The importance of considering ICP within a classification of pregnancy dermatoses has also been supported by Roger et al.³, who in their series observed a high incidence of ICP associated with significant fetal risk and impaired pregnancy outcome. Also the most recent classification of pregnancy dermatoses⁴, based on the results of a large retrospective study on more than 500 pregnant women with pruritus, includes ICP within this category.

Etiology

The etiology of ICP appears to be multifactorial. Potential contributing factors include a genetic predisposition interacting with the effects of estrogen and progesterone metabolites on bile secretory mechanisms ⁵. The central role of hormonal factors is supported by the higher incidence of cholestasis in twin pregnancies and the fact that predisposed women often suffered from pruritus when taking oral contraceptives. Historically, ICP has been associated with the cholestatic effect of estradiol metabolites, in particular 17ß-estradiol glucuronide. Progesterone metabolites, however, play an even more important role in its pathogenesis. Their profile in serum and urine from patients with ICP differs significantly from that seen in normal pregnancy and may be related to malfunction of biliary canalicular transporters normally responsible for their secretion from hepatocytes into bile.

Several of these transporters have recently been characterized. Mutations in the ABCB4 gene, encoding a member of the ATP-binding cassette (ABC) family of membrane transporters, and variants in the ATP8B1 gene have been identified in a small number of patients with ICP ⁶. Thus, it has been suggested that genetically linked mild malfunction of canalicular transporters, which causes no problem outside pregnancy, may lead to clinical symptoms of cholestasis when the transporters’ capacity to secrete substrates is exceeded – as occurs with the high levels of sex hormones produced in pregnancy⁷. Besides hormonal and genetic factors, environmental factors may also contribute to the pathogenesis of ICP. This is based on the observation of a seasonal variability of incidence, an incomplete recurrence at subsequent pregnancies, as well as a decrease in the prevalence of ICP in Sweden and Chile in association with improved nutritional (i.e., selenium) supply over the past decades^8,⁹. Only very recently, an increased intestinal permeability (“leaky gut”), which has been demonstrated in several liver diseases, was also detected in ICP patients¹⁰. Reyes and co-workers¹⁰ postulate that a leaky gut may participate in the pathogenesis of ICP by enhancing the absorption of bacterial endotoxin and the enterohepatic circulation of cholestatic metabolites of sex hormones and bile salts. The exact pathophysiologic relevance of these findings, however, has yet to be determined.