Genetic Determinants of Drug-induced Cholestasis and Intrahepatic Cholestasis of Pregnancy

Christiane Pauli-Magnus, M.D.; Peter J. Meier, M.D.; Bruno Stieger, Ph.D.

Disclosures

Semin Liver Dis. 2010;30(2):147-159. 

In This Article

Incidence and Diagnostic Criteria of Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is an acquired form of cholestasis, which is observed in otherwise healthy pregnant women with a normal medical history. It usually occurs in the second and third trimester of pregnancy, when serum concentrations of estrogens and progesterone reach their peak[50,51] and is characterized by pruritus, elevated concentrations of bile salts, transaminases, and rarely of bilirubin in serum.[52–55] The suggested pathogenic key role of female sex hormones is further supported by the rapid cessation of cholestatic symptoms after delivery,[56] the higher incidence of ICP in twin pregnancies,[50] and the increased susceptibility of affected patients to develop intrahepatic cholestasis under oral contraception.[57]

The incidence of ICP varies widely, originally ranging from 0.05 to >20% between different ethnic groups and geographic locations, with highest incidence rates reported for women with Araucanian Indian descent in Chile.[54] In Caucasian populations of the United States and Europe, incidence rates vary between 0.5 and 1.5%, with highest rates observed in Sweden and the Baltic countries. Since 1980, the incidence of ICP in Chile has declined, which has mainly been attributed to changes in environmental factors. The importance of environmental factors in the pathogenesis of ICP is also supported by the higher disease prevalence during the winter months in Chile, Finland, and Sweden.

Data collected in different geographic locations including Europe, North and South America, and Australia, have reached consensus about the catalog of clinical and laboratory criteria essential to the diagnosis of ICP.[58,59,60] The onset of ICP is typically indicated by the development of pruritus starting in late pregnancy in the absence of a past medical history; physical or ultrasonographic signs of liver disease; or biochemical, virologic, or autoimmune abnormalities that could reveal acute or chronic liver disease. Pruritus may precede laboratory abnormalities and shows a characteristic distribution pattern, starting in the palms and soles before generalizing to other zones of the body surface.

Elevation of fasting serum total bile acid concentrations >10 μmol/L may be the first and only laboratory abnormality in ICP.[61,62] Specifically, serum cholic acid becomes the primary bile acid in ICP women in contrast to normal pregnant women and nonpregnant women, in whom its proportion is almost similar to chenodeoxycholic acid. This results in a marked elevation of the cholic/chenodeoxycholic acid ratio compared with pregnant women without ICP.[63–65] Other laboratory findings reflecting cholestasis include variable elevations in the serum concentrations of alkaline phosphatase, 5' nucleotidase, total and direct bilirubin and transaminases. Elevation of alkaline phosphatase levels is not specific of cholestasis during pregnancy due to the placenta isoenzyme, and the extent of transaminases elevation varies between twofold to 10-fold the upper limit of normal.[58]

Surprisingly, the serum concentrations of gamma-glutamyl transpeptidase (GGT) are normal or only modestly elevated in most patients with ICP and might allow conclusions about the underlying defect in bile acid transport. Specifically, there is an indication that elevated GGT levels indicate an impairment of MDR3 function, whereas GGT is normal in BSEP-related forms of estrogen-associated cholestasis.[66] Therefore, GGT might be useful to clinically distinguish between MDR3 and BSEP-related forms of estrogen-related cholestasis, as it is has already done for progressive forms of inherited familial intrahepatic cholestasis.[42,67]

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