A Longitudinal Study of Alterations in Metabolic Markers and Gut Hormones in Pregnant and Non-pregnant Patients With Intrahepatic Cholestasis of Pregnancy, Gestational Diabetes Mellitus and Normal Pregnant and Non-pregnant Controls

CLINICAL FEATURES OF INTRAHEPATIC CHOLESTASIS OF PREGNANCY:

Intrahepatic cholestasis of pregnancy (ICP), is a pregnancy-specific liver disorder which typically presents with maternal pruritus (itching) in late pregnancy and affects about 0.7% of women in the UK. Biochemically, it is characterised by liver dysfunction with raised serum bile acids, and clinically by a significantly increased incidence of fetal complications, including spontaneous preterm labour, fetal distress, meconium staining of the amniotic fluid and sudden fetal death (Geenes and Williamson 2009).

The cause of ICP is complex and not fully understood. In addition the pathological mechanisms behind the adverse fetal outcomes have not been elucidated. The maternal disease is likely to be caused by interaction between sex hormone metabolites and bile acids in genetically susceptible women (Abu-Hayyeh et al. 2010). To date, we and others have identified genetic variation in several biliary transporters e.g. ABCB4, ATP8B1, ABCB11 and the main bile acid receptor, FXR, that predispose women to the disease (Dixon et al., 2000; Mullenbach et al., 2005; Pauli-Magnus et al., 2004; Van Mil et al, 2007; Dixon et al. 2009). Due to their inherent toxicity, bile acids are also likely to be responsible for the fetal component of the disease. Consistent with this the incidence of fetal complications has been shown to be increased in pregnancies where the levels exceed 40 uMol /L (Glantz et al., 2004). There are currently several theories about how bile acids may affect fetal wellbeing; with regard to the increased incidence of spontaneous prematurity, they have been shown to cause premature delivery in sheep (Campos et al., 1986), and increased myometrial contractility in response to oxytocin (Germain et al., 2003; Israel et al., 1986). Furthermore, bile acids are also known to cause increased colonic motility in rabbits (Snape et al., 1980) and cardiac dysrhythmias in rats (Williamson et al., 2001), which could explain meconium staining of the amniotic fluid and sudden fetal death respectively. While it is known that bile acids can be transported by proteins in the placenta, the precise role of the placenta in bile, lipid and glucose metabolism is not known. Our group has demonstrated that cholestasis alters lipid pathways in mouse placentas (unpublished data) but this has not been studied in humans.

BILE ACID HOMEOSTASIS:

Bile acids are the end product of hepatic cholesterol metabolism and act as the main route of excretion for cholesterol. In the adult human two primary bile acids are produced by the liver, i.e. cholic acid and chenodeoxycholic acid. There is some evidence that maternal bile acids gradually rise with advancing gestation, but they usually remain within normal limits (< 14 uMol /L) (Fulton et al., 1983; Pascual et al., 2002). This is in contrast to an ICP pregnancy, where maternal bile acids may be raised to 100 times the upper limit of normal (Walker et al.,2002). In OC, elevated levels of bile acids are also found in the fetal circulation (Laatikainen, 1975).