Presentation: Patient with unexplained intrahepatic cholestasis

A 30-year-old female presents with itching. She had a cholecystectomy for gall stones at the age of 24. She has a persistent cholestatic pattern of elevated liver enzymes: alkaline phosphatase (ALP) 350IU/L (normal range 30–130IU/L), alanine transaminase (ALT) 56IU/L (normal range 0–40IU/L) , gamma-glutamyltransferase (GGT) 222IU/L (normal range 1–78IU/L) and bilirubin 23µmol/L (normal range 0–21µmol/L). Non-invasive tests for other parenchymal liver diseases were negative. A magnetic resonance cholangiopancreatography (MRCP) reported a dilated common bile duct but no intrahepatic duct dilatation and no ductal stones. Her two younger sisters have previously presented with the same manifestations.

• Inherited cholestatic syndromes are rare and can clinically present in early childhood, adolescence or adulthood. Examples include:
  • progressive familial intrahepatic cholestasis (PFIC), which has an estimated prevalence of between 1 in 50,000 and 1 in 100,000;
  • benign recurrent intrahepatic cholestasis (BRIC);
  • intrahepatic cholestasis of pregnancy (ICP); and
  • persistent hepatocellular secretory failure (PHSF).
• Inherited cholestatic syndromes should be considered when serological tests and imaging, with or without a liver biopsy, have not identified another aetiology.
• Eligibility for genomic testing via the National Genomic Test Directory is as follows:
  • neonatal conjugated hyperbilirubinaemia where multifactorial and infective causes have been excluded;
  • unexplained cholestasis developing below the age of 18 (though it may occasionally be appropriate to test individuals presenting over 18 years of age under this indication following expert review);
  • persistence of unexplained cholestasis beyond three months, or recurrence of otherwise unexplained cholestasis, including those with a suspected precipitating drug aetiology; or
  • cholestasis of pregnancy onset in the second trimester or serum bile acids greater than 42μmol/mL in the third trimester.
• Testing may occasionally be appropriate outside these criteria following discussion at the national gastrohepatology genomics multidisciplinary team meeting.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our Knowledge Hub resource ‘Genomic testing in the devolved nations’.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• For investigation of unexplained intrahepatic cholestasis the appropriate panel to choose is:
  • R171 Cholestasis: This is a gene panel test covering a small number of genes that are known to be associated with cholestasis.
• For tests such as R171, which do not include whole genome sequencing, you can use your local Genomic Laboratory Hub test order and consent (record of discussion) forms.
• The majority of tests are DNA-based, and an EDTA sample (typically a purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (typically a green-topped tube).
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• NHS England: National Genomic Test Directory

References:

• Girling J, Knight CL, Chappell L and others. ‘Intrahepatic cholestasis of pregnancy‘. BJOG: An International Journal of Obstetrics & Gynaecology 2022: volume 129, issue 13, pages 95–114. DOI: 10.1111/1471-0528.17206
• European Association for the Study of the Liver. ‘EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis‘. Journal of Hepatology 2017: volume 67, issue 1, pages 145–172. DOI: 10.1016/j.jhep.2017.03.022

For patients

• British Liver Trust
• ICP support