The adverse influence of pregnancy upon sulphation: a clue to the pathogenesis of intrahepatic cholestasis of pregnancy?
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Sulphation of oestrogens and monohydroxy bile acids is important in attenuating their cholestatic potential. Thus, impairment of sulphation could lead to retention of cholestatic compounds and precipitate intrahepatic cholestasis in susceptible individuals. We tested the hypothesis that such a mechanism may be involved in the pathogenesis of intrahepatic cholestasis of pregnancy. In vivo and in vitro assessment of sulphation capacity was performed in patients with cholestasis of pregnancy, compared with control females on and off the oestrogen-containing oral contraceptive pill and control individuals during normal pregnancy and post partum, to assess the influence of high oestrogen states upon this metabolic pathway. During in vivo studies utilising paracetamol as a metabolic probe, the proportion of paracetamol sulphate and sulphate: glucuronide ratio were decreased in those with elevated oestrogens, whether the rise in oestrogens was endogenous, in pregnancy (paracetamol sulphate p < 0.05; paracetamol sulphate:glucuronide ratio p < 0.01), or exogenous, with the contraceptive pill (paracetamol sulphate p = 0.2; paracetamol sulphate:glucuronide ratio p < 0.001). In vitro, platelet sulphotransferase activity was measured, utilising phenol as substrate. Sulphotransferase activity decreased during pregnancy compared with repeat measurements post partum (p < 0.005) and compared with non-pregnant individuals (p < 0.05). In conclusion, we have shown that elevated oestrogens are associated with significant impairment in sulphation capacity. An imbalance of sulphation with glucuronidation provoked by high circulating oestrogen levels may be contributory in the pathogenesis of cholestasis of pregnancy.