The Metabolic Profile in Intrahepatic Cholestasis of Pregnancy and Diabetes Mellitus
Condition: Intrahepatic Cholestasis of Pregnancy; Gestational Diabetes Mellitus
MeSH terms: Cholestasis; Cholestasis, Intrahepatic; Diabetes, Gestational; Pregnancy Complications; Diabetes Mellitus
Study type: Observational

Summary: 
      ICP is known to cause abnormal bile acid homeostasis and to be associated with an increased
      risk of diseases of the biliary system in later life. There have been small studies (Dann et
      al. 2006; Wójcicka-Jagodzińska et al. 1989) suggesting that it causes dyslipidaemia (raised
      lipids) and impaired glucose tolerance in pregnancy. However the underlying mechanisms of
      these abnormalities is not known. Similarly the influence of cholestasis on fetal metabolism
      is not known, and nor is the role of the placenta. It is also not known whether women with
      ICP have a predisposition to abnormal lipid and glucose homeostasis when they are not
      pregnant.

      GDM is characterized by raised plasma glucose levels in pregnant women (in the absence of
      pre-pregnancy diabetes mellitus). This condition is associated with large-for-gestational age
      babies and obstructed labour. Women with GDM have increased risk of subsequent type 2
      diabetes mellitus, and if they have this condition in a subsequent pregnancy there is an
      increased risk of stillbirth. This work is important to understand the causes of the
      metabolic abnormalities associated with ICP and GDM. If we demonstrate abnormal lipid and
      glucose profiles, these may be of relevance to the fetal complications of both disorders. It
      will also be of relevance to the future health of affected women and their children.
    

Detailed description: 
      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).

      THE ROLE OF BILE ACIDS IN LIPID AND GLUCOSE METABOLISM:

      There is accumulating evidence that FXR, the nuclear hormone receptor responsible for
      regulation of bile acid homeostasis, also plays a role in the regulation of lipid and glucose
      metabolism. FXR null mice have been shown to have abnormal blood lipid profiles including
      elevated plasma cholesterol, low density lipoprotein, high density lipoprotein and
      triglyceride levels (Ma, 2006). They also exhibit glucose intolerance and reduced insulin
      sensitivity (Zhang, 2006). Furthermore, ICP patients have raised levels of cholesterol and
      other lipid parameters (Dann et al. 2006). Specifically, the serum concentrations of
      low-density lipoprotein (LDL), apolipoprotein B-100, cholesterol and total cholesterol were
      markedly increased in women with ICP. They have also been shown to have impaired glucose
      tolerance (Wójcicka-Jagodzińska et al. 1989). Recent data from our group (Martineau et al.
      2014, 2015) and others (Marschall et al. 2014) have shown that women with ICP have increased
      rates of GDM, and implicate raised serum bile acids in susceptibility to diabetes mellitus.
      Therefore this study will also include women with ICP and superimposed GDM in addition to
      women with GDM in the absence of ICP. This will enable us to evaluate the impact of
      cholestasis on the onset of diabetes mellitus in pregnant women.

      In cholestasis bile acids accumulate in the liver, and this results in the induction of
      pathways that enhance bile acid excretion. This may also cause abnormal cholesterol and
      triglyceride levels. Bile acids also signal via FXR in the gut. Bile acids are stored in the
      gallbladder in the fasting state and released following ingestion of a meal. Once bile acids
      are in the intestine they are transported into enterocytes (gut cells) where they activate
      FXR which causes production and release of the hormone FGF19. FGF19 binds the FGF4 receptor
      on hepatocytes, and signals (via the jnk kinase pathway) to suppress cholesterol 7
      alpha-hydroxylase (CYP7A1), a critical rate-limiting enzyme in synthesis of bile acids from
      cholesterol. There have been no studies of the gut-liver axis in pregnancy, but we
      hypothesise that abnormal bile acid signalling causes raised cholesterol in addition to
      increased serum bile acids.

      Bile acids also bind the G-protein-coupled receptor (TGR5). In the gut this results in
      release of glucagon-like peptide-1 (GLP-1)(Thomas et al. 2009). GLP-1 is an anti-diabetic
      hormone that increases glucose-dependent insulin production and decreases glucagon production
      by the pancreas. To date, there have been no studies of the relationship between cholestasis
      and GDM and the levels of other fasting gut hormones that may influence glucose and lipid
      metabolism in pregnancy.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Pregnant and non pregnant women who have had intrahepatic cholestasis of pregnancy and/or
        gestational diabetes mellitus matched with parous women who have had uncomplicated
        pregnancies
      
Biospecimen description: 
      Serum, whole blood, plasma.
    
Keywords: ICP, GDM