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Obstetric cholestasis (synonymintrahepatic cholestasis of pregnancy) is rapidly emerging from the realms of clinical impressions into a scientific framework. Obstetricians, not least in Britain, have maintained a generally sceptical attitude towards attempts to recognise it as a significant clinical entity. Nevertheless, a consensus is emerging which acknowledges that obstetric cholestasis has major clinical implications for mother and baby.1 The pregnant woman may be driven to distraction by severe pruritus, most severely felt on hands and feet, which leads to regular cold baths and other ineffectual palliation during stressful sleepless nights. The brush off that “itching is of no consequence” and that “everyone itches in pregnancy” merely adds insult to injury. Mothers with a history of obstetric cholestasis have a higher incidence of gallstones. Babies are at increased risk of premature labour with fetal distress and there is a significantly increased risk of stillbirth. Traditional treatments for the pruritus of cholestasis are not very effective, and sequestrants such as cholestyramine exacerbate the tendency to vitamin K deficiency with its attendant risk of perinatal and post-partum haemorrhage.
Several recent reports have emerged of the efficacy of ursodeoxycholic acid (URSO), taken orally, in relieving both the pruritus and biochemical derangements associated with obstetric cholestasis.2 3 4 URSO is the dominant bile acid in the bear but a minority species in humans. It is more hydrophilic than the other primary and secondary human bile acids and protects against the membrane damaging toxicity of its more hydrophobic partners by displacing them from the hepatocyte and partially replacing them in the bile acid pool. Itching remits partially or entirely and serum biochemistry including aminotransferases and serum bile acids improve in the majority of patients during treatment with URSO.5The pivotal double blind controlled clinical trial mounted in Chile, where the incidence of obstetric cholestasis is the highest in the world, was terminated prematurely when only 15 patients had been randomised and a baby was stillborn to a mother who proved to have taken placebo.6 Despite the small numbers involved the data showed significant benefit of URSO over placebo with respect to measures of aminotransferases and serum bile acids. Treatment with URSO tended to normalise the cholate:chenodeoxycholate ratio of serum bile acids, but failed to restore normal concentrations of 7α-hydroxy-4-cholesten-3-one, a measure of de novo bile acid synthesis; this did, however, return to normal in the one placebo treated patient who spontaneously remitted, suggesting that URSO is reversing many of the consequences of obstetric cholestasis without necessarily correcting the underlying defect. Analysis of progesterone metabolites in serum and urine of patients with obstetric cholestasis showed that disulphates with a 3α-hydroxy-5α (H) configuration were notably increased but glucuronide conjugates were not.7 8An increased ratio of 3α:3β hydroxysteroids was closely related to obstetric cholestasis—it was present in all patients with obstetric cholestasis and a reduction in the 3α:3β hydroxysteroid ratio was observed in all seven “responders” to URSO and the one patient in the placebo group who went into spontaneous remission but not in the non-responder among the eight treated with URSO. The easiest way to understand this would be to postulate that URSO was facilitating the secretion into bile of metabolites, particularly progesterone metabolites, which were being retained as a consequence of the cholestasis. Sulphation of these metabolises by the liver is a protective action in that it attenuates their toxicity and promotes their solubility in water and excretion from the urine. The availability of sulphate for conjugation is likely to be limiting under those circumstances.9 Several transporters have recently been characterised which are specifically located to the canalicular membrane and which actively transport bile acids (BSEP), organic anions (MRP2), and phospholipid (MDR3) into bile, allied with genetic defects which impair their function and account for several syndromes of familial intrahepatic cholestasis.10 Jacqueminet al recently described a family in which a child was born with severe neonatal cholestasis due to homozygous mutations in the human multidrug resistance 3 (MDR3) gene.11 The child’s mother and several maternal and paternal aunts were found to have suffered from obstetric cholestasis and to be heterozygous for the MDR3 mutation. We can surmise therefore that similar genetic defects in canalicular bile transporters may account for obstetric cholestasis in other predisposed individuals. URSO could alleviate this problem by modulating nuclear transcription of transporter genes, delivering more transporters to the canalicular membrane or increasing the efficiency of transporter function within the membrane. An effect of URSO on stereospecific progesterone metabolism is not excluded. Given this increasingly compelling evidence regarding both clinical efficacy and underlying scientific rationale for use of URSO in the treatment of obstetric cholestasis, the paper by Rodrigues et al in this issue (see page 446) is important as it suggests that use of URSO in pregnancy is safe. Concentrations of cholic acid and URSO in meconium correlated with maternal serum concentrations although the proportion of URSO barely doubled in meconium compared with an increase from relatively trace amounts to 18% in maternal serum. Despite the increased proportion of URSO in meconium of infants whose mothers were treated with it, there was no increase in its potentially toxic metabolite lithocholic acid. However, although the same group has also previously shown in vitro that URSO restores placental bile acid transport towards normal in placental vesicles from pregnancies complicated by obstetric cholestasis,12 in the study published here there was no diminution of cholic acid in meconium in response to URSO, suggesting that the fetus lacks the means of excreting these bile acids once they have accumulated. The authors contend on this basis, reasonably in my view, that early treatment with URSO is indicated to prevent this accumulation in the fetus of cholate derived from maternal serum, which it is apparently unable to excrete during the remainder of pregnancy. The lack of any reports of adverse fetal reaction to URSO when used to treat obstetric cholestasis is further supported.
See article on page 446
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