Effect of oral and transdermal hormone therapy on hyaluronic acid in women with and without a history of intrahepatic cholestasis of pregnancy.

OBJECTIVE: Intrahepatic cholestasis of pregnancy predisposes women to liver disorders years after affected pregnancy. We compared the basal levels and responses of hyaluronic acid, a marker of liver fibrosis, and liver transaminases to postmenopausal hormone therapy in women with (n = 20) and without (n = 20) a history of intrahepatic cholestasis of pregnancy. STUDY DESIGN: This was a randomized, double-blind, placebo-controlled, crossover trial. RESULTS: Basal levels of hyaluronic acid were similar in both groups. Two weeks of oral estradiol 2.0 mg/day led to significant but similar (10.9% to 15.4%) rises in hyaluronic acid in both groups. Increasing the dose of oral estradiol to 4.0 mg/day resulted in normalization of the levels, whereas the addition of medroxyprogesterone acetate led to falls (11.0% to 10.7 %) in hyaluronic acid. Transdermal estradiol 50 microg led to a rise (3.2 %) in hyaluronic acid only in the control group. Other liver markers were normal at baseline and during hormone therapy. CONCLUSION: Normal basal levels and/or normal responses of hyaluronic acid and other liver markers to hormone therapy in women with previous intrahepatic cholestasis suggest that this therapy does not predispose these women to liver diseases.

Intrahepatic cholestasis of pregnancy as an indicator of liver and biliary diseases: a population-based study.

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder, thought to be specific for pregnancy and to spontaneously resolve after delivery. Increased rates of gallstone formation and hepatitis C have previously been associated with ICP. However, there are no longitudinal studies to determine its significance as an indicator of subsequent liver or biliary diseases. In this retrospective cohort study with cases and controls we assessed the risk of liver and biliary diseases in 21,008 women, 10,504 with a history of ICP during the years 1972-2000 (cases) and 10,504 with a normal pregnancy (controls). Cases and controls were matched for age, time of delivery, and place of delivery. The diagnoses of liver and biliary disease were traced from the Finnish Hospital Discharge Register with an almost 100% coverage. Several liver and biliary diseases were found to have a significantly higher incidence in patients with ICP than in controls. The rate ratio for hepatitis C was 3.5 (CI 1.6-7.6; P < .001), for nonalcoholic liver cirrhosis 8.2 (CI 1.9-35.5; P < .05), for gallstones and cholecystitis 3.7 (CI 3.2-4.2; P < .001) and for nonalcoholic pancreatitis 3.2 (CI 1.7-5.7; P < .001). In conclusion, there is an association of ICP with several liver and biliary diseases. Some patients with ICP are at risk of the subsequent development of cirrhosis and other severe chronic diseases. Contrary to what has been previously thought, follow-up may need to be considered for these patients.

Sequence variation in the ATP8B1 gene and intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic condition that may affect women during the third trimester of pregnancy. Symptoms experienced by these women generally resolve spontaneously following delivery, but prior to delivery the fetus is at increased risk of intrauterine distress and sudden intrauterine death. The genetic etiology of most cases of ICP is unknown, although heterozygous carriers of mutations causing progressive familial intrahepatic cholestasis (PFIC) diseases may experience ICP. When examining linkage to known cholestasis genes, affected members of four Finnish ICP families shared haplotypes around ATP8B1, the gene responsible for PFIC1. This gene was subsequently screened in 176 familial and sporadic ICP patients. A total of 17 sequence changes were detected, five exonic and 12 intronic. No intronic change was associated with ICP in sporadic cases. Four intronic changes segregated with ICP in three families, a different change in each of two families and three changes in another family, although the significance of this is currently unknown. Three exonic changes were nonsynonymous, one (in exon 23) is probably a polymorphism while two predict novel amino-acid replacements (N45T and K203R). These changes, in exons 2 and 7, were detected in one individual each, and may have predisposed these individuals to ICP. In conclusion, although the exon 2 and 7 changes may have functioned as risk alleles, ATP8B1 is probably not a major gene contributing to the occurrence of ICP.

Postmenopausal estrogen therapy and serum estradiol fatty acid esters in women with and without previous intrahepatic cholestasis of pregnancy.

BACKGROUND: Fatty acid esters of 17beta-estradiol (E2) are estrogen metabolites associated with lipoproteins in blood. AIM: To study the effects of estrogen therapy on concentrations of serum E2 fatty acid esters in postmenopausal women with a history of an estrogen-related liver disorder, intrahepatic cholestasis of pregnancy (ICP), and in healthy women in a double-blind, crossover fashion. METHOD: ICP (n = 10) and control women (n = 10) received increasing doses of E2 valerate orally 2-4 mg/day, or transdermal E2 50-100 microg/day for 6 weeks. After a 4-week wash-out period, the subjects crossed over to the alternate E2 treatment. Concentrations of serum E2 fatty acid esters were quantified after saponification by fluoroimmunoassay. RESULTS: Oral E2 administration increased median serum E2 fatty acid ester concentrations from 57 to 73 pmol/L in the ICP and from 56 to 74 pmol/L in the control group, in association with elevations in serum E2, estrone and sex hormone-binding globulin levels. Transdermal E2 treatment did not increase serum E2 ester levels. CONCLUSIONS: The increase in serum E2 fatty acid esters during oral E2 administration may be attributed, at least partly, to the higher estrogen dose during oral compared with transdermal therapy. A history of ICP did not affect esterification of E2 during estrogen therapy.