GENETIC EVALUATION OF PATIENTS LISTED FOR LIVER TRANSPLANTATION WITH CRYPTOGENIC CIRRHOSIS

IntroductionIdentifying the underlying cause of liver disease is important, however in 5–30% of patients with cirrhosis no cause can be found, which is referred to as cryptogenic cirrhosis (CC). From registry data 4% of liver transplants are performed for CC. UK Transplant Registry data suggests CC recipients have a lower 1-year and 5-year survival than the national rate. Understanding of the genetics underpinning liver disease has evolved significantly. More recently whole exome sequencing (WES) has been proposed for the evaluation of cryptogenic liver disease. We sought to evaluate the diagnostic work-up of patients listed for transplant in the UK with CC, with a specific focus on the use of genomics.MethodA retrospective search of the UK Transplant Registry was performed for adult elective NHS patients registered for first liver transplant at 6 transplant centres between 1/1/15 and 31/12/20. Patients with CC or genetic liver disease as an indication at registration were included. Clinical information and results of diagnostic tests were collected.ResultsAfter exclusion of 59 patients (42 genetic co-factor, 17 alternate aetiology), 228 patients were included: 120 CC, 4 diagnosed with genetic liver disease during assessment, 104 known genetic liver disease. The patients without previously known genetic liver disease (n=124) had a median age at onset of liver disease of 49 years (IQR, 37–56), 82 (66%) were male, 16 (13%) had a family history of liver disease. Median age at listing was 55 years (IQR, 42–62), UKELD 56 (52–59) and MELD 15 (12–20). Prior diagnostics included: liver biopsy 80 (65%), cross sectional imaging 123 (99%), and cholangiography 26 (21%). A genetic test was performed in 29 (23%) patients: 10 ATP7B, 20 HFE, 9 cholestasis gene panel, and 1 underwent WES. There were 4 new diagnoses of genetic liver disease made during evaluation: 2 MDR3 deficiency, 1 Wilson disease, 1 alpha-1-antitrypsin. In 2 other patients there were ABCB4 variants of uncertain significance and potential MDR3 deficiency.DiscussionGenetic sequencing is performed in selected patients assessed for transplant with CC, and in some cases a new diagnosis of genetic liver disease has been made. With increasing access to genetic testing and the NHS Long Term Plan to offer whole genome sequence as routine care, more widespread use of genetic testing in patients with CC listed for transplant should be considered.