Diagnosis and Therapy of Intrahepatic Cholestasis of Pregnancy

Abstract

Intrahepatic cholestasis of pregnancy (ICP) is characterized by the occurrence of pruritus mostly in the third trimenon. Diagnosis is based on the presence of pruritus and elevated levels of serum bile acids in the absence of pruritic skin diseases. There is strong evidence of a genetic predisposition for ICP. Numerous studies have investigated the association of known cholestasis genes such as ABCB4 (also designated MDR3), ABCB11 ( BSEP) and ATP8B1 ( FIC1) with ICP. The results of these studies implicate a heterogeneous etiology of this syndrome. ICP increases the risk of preterm delivery and fetal loss. Furthermore, intense pruritus may necessitate premature induction of labor with its known higher frequency of complications for mother and child. Therefore, ICP pregnancies should be managed as high-risk pregnancies. Pharmaceuticals to alleviate pruritus or improve cholestasis like antihistamines, phenobarbital, anion exchange resins, dexamethasone or S-adenosylmethionine are not widely accepted because of questionable efficacy or side effects. Recent randomized studies have shown beneficial effects of ursodeoxycholic acid (UDCA) on laboratory data and pruritus in patients with ICP. Improved knowledge about the diagnostic classification of different types and pathophysiological mechanisms of ICP may allow for a more targeted treatment of this disease in future.

Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein)

“…Serum bile salt levels are increased [60,61]. Increased incidence of fetal distress, premature birth, and even stillbirth in association with ICP has been reported (for a review, see [62]). It is generally accepted that women who have suffered from ICP are also susceptible to the development of cholestasis upon the use of oral contraceptives.…”

First description of ABCB4 gene deletions in familial low phospholipid-associated cholelithiasis and oral contraceptives-induced cholestasis

“…UDCA is the treatment of choice for ICP and produces relief from pruritus with improvement in liver tests, with no adverse maternal or fetal effects. 27,32,33 It is generally accepted that women who have suffered from ICP are also susceptible to the development of cholestasis on the use of oral contraceptives (oral contraceptives-induced cholestasis (CIC)). 34,35 Evidences of ABCB4 heterozygous mutations have also been found in patients with druginduced cholestasis or liver injury.…”

Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy

“…However, vehement itching, jaundice and fat malabsorption may impair the mother's quality of life. On the other hand, an increased perinatal fetal risk with possible lethal outcome has been described 2, 6–11…”