Intrahepatic Cholestasis of Pregnancy (ICP)

Background

People Panel D_2x4_Rare DiseasesIntrahepatic cholestasis of pregnancy (ICP) is defined as gestational pruritus in association with abnormal liver function tests and raised maternal serum bile acids. Severe ICP, defined by onset ≤32 weeks’ gestation with bile acids ≥40µmol/L affects ~ 1:5000 pregnancies in the UK. In addition to intense pruritus experienced by the mother, it is associated with adverse pregnancy outcomes, including spontaneous preterm labour, fetal asphyxia and intrauterine death. These complications occur more commonly in pregnancies with higher maternal serum bile acid concentrations. Affected women are at increased risk of biliary disease in later life, and their 16 year old children have higher rates of obesity and dyslipidaemia. ICP has a complex aetiology with a 12-fold increase in susceptibility in first-degree female relatives. There is evidence that severe disease may have a larger genetic component. However, systematic studies of the inheritance in families have been hindered as this is a disease of pregnancy and although some women show related phenotypes outside of pregnancy (e.g. contraception-induced cholestasis), no male phenotype has been identified.

Severe ICP has been demonstrated, at least in part, to be driven by rare variants of large effect. Pathogenic heterozygous mutations of ABCB4 (a phosphatidyl choline floppase) and ABCB11 (the bile salt export pump) have been identified in a subset of cases. However, it is clear from our studies and those of others working in paediatric cholestatic liver disease (where recessive homozygous mutations of these genes cause severe early-onset liver disease) that not all cases of hereditary cholestasis have protein coding mutations at these loci, or other known cholestatic loci. We expect ~15% of cases will harbour pathogenic (coding and potentially non coding) mutations of ABCB4 (up to 10% of cases) and ABCB11 (up to 5%). Beyond these two known genes, our analysis will focus upon genes implicated in other forms of cholestatic disease that have not been evaluated in ICP and identification of new loci.

In addition to our established cohort who will be re-consented for this study, we will recruit new cases through our networks across the UK, in parallel with the NIHR-funded PITCHES drug trial and through the patient support organisation with whom we have close links.

The identification of the range of genetic mutations underlying severe ICP will greatly enhance our understanding of the disease and link specific mutations to higher-risk pregnancies, treatment response and subsequent maternal disease.

Recruitment Criteria

Inclusion Criteria
Confirmed diagnosis of ICP at ≤32 weeks’ gestation with serum bile acids ≥40 µmol/L.

Exclusion Criteria
Diagnosis of another hepatic disorder (e.g viral or autoimmune hepatitis) or extrahepatic biliary obstruction

Centres at which ICP is currently recruiting:

Birmingham Women’s Hospital
Chelsea & Westminster Hospitals NHS Trust
Epsom & St Helier University Hospitals NHS Trust
Frimley Park Hospital NHS Foundation Trust
Guy’s & St Thomas’ NHS Foundation Trust, London
Heart of England NHS Foundation Trust,
Birmingham
Imperial College Healthcare NHS Trust, London
Ipswich Hospitals NHS Trust
Lancashire Teaching Hospitals NHS Trust
Newcastle upon Tyne Hospitals NHS Foundation Trust
Oxford University NHS Trust
St. George’s Healthcare NHS Trust
Warrington & Halton Hospital NHS Trust

Leads:
Dr Catherine Williamson
Dr Peter Dixon