Presentation: Patient at risk of drug-induced liver injury

A 60-year-old woman presents with erythema, oedema and warmth in her left lower leg after an insect bite. She is diagnosed with cellulitis and given a one-week prescription of flucloxacillin. She presents jaundiced four weeks later. Her laboratory tests are: bilirubin 229µmol/L (normal range 0–21µmol/L), alanine transaminase (ALT) 548 international units/litre (IU/L) (normal range 0–45IU/L), and ALP 644 IU/L (normal range 40–130IU/L) with a cholestatic pattern of liver injury. An abdominal ultrasound scan is normal.

• The National Genomic Test Directory eligibility criteria for genomic testing is:
  • persistence of unexplained cholestasis beyond three months or recurrence of otherwise unexplained cholestasis, including those with a suspected precipitating drug.
• Testing may occasionally be appropriate outside these criteria following discussion at the national gastro-hepatology genomics multidisciplinary team meeting.
• Histogenetic testing might be helpful in the following clinical scenarios:
  • HLA-B*5701 allele increases the risk of drug-induced liver injury (DILI) following exposure to flucloxacillin 80-fold. Most (85%) of those who develop flucloxacillin-induced DILI have HLA-B*5701 (compared with 6% of the general population). In clinical practice, this can be used to support diagnosis as well as to rule out flucloxacillin-induced DILI, with a negative predictive value over 95% in challenging cases where DILI is one of the differential diagnoses.
  • HLA-DRB1*0301 or HLA-DRB1*0401 could be an adjunct in the differential diagnosis of DILI versus autoimmune hepatitis (AIH); international AIH diagnostic criteria attributes additional scores for carriage of one of these alleles.
  • Individuals with HLA-B*15:02 or HLA-A*31:01 alleles are associated with an increased risk of severe cutaneous adverse reactions (such as Stevens-Johnson syndrome) as well as DILI in patients treated with carbamazepine.
• If your patient does not meet these criteria but you have a strong suspicion that genomic testing would be useful, discuss with your local Genomics Laboratory Hub.

• 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 dedicated Knowledge Hub resource.
• 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 possible DILI, 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 DILI.
• For tests such as R171, which do not include whole genome sequencing, you can use your local Genomics 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

• European Association for the Study of the Liver: Clinical Practice Guidelines: Drug-induced liver injury (PDF, 40 pages)
• Pro-Euro-DILI network

References:

• Swen JJ, van der Wouden CH, Manson LEN and others. ‘A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study‘. The Lancet 2023: volume 401, issue 10,374, pages 347–356. DOI: 10.1016/s0140-6736(22)01841-4
• Fontana RJ, Liou I, Reuben A and others. ‘AASLD practice guidance on drug, herbal, and dietary supplement–induced liver injury‘. Hepatology 2023: volume 77, issue 3, pages 1,036–1,065. DOI: 10.1002/hep.32689

For patients

• British Liver Trust: Drug induced liver injury (DILI)