HPB P06 Availability of healthy human liver segments for ethical pre-clinical research: a tertiary centre experience

Abstract

Background There is a well-documented scarcity of the availability of healthy human livers for transplantation. The majority of discarded donor livers are used for organ preservation studies in the context of liver transplantation. Hemi-hepatectomies are a common procedure performed in tertiary hepatobiliary units. The specimen, also consisting of healthy liver, is eventually discarded despite the presence of healthy human liver tissue which would be invaluable for research. In 1959, Russel and Burch described the “3Rs” of animal research as replacement, reduction, and refinement (Flecknell, 2002). Optimising the use of hemi-hepatectomy human liver tissue for research would reduce the need for live animals and provide a more economical and physiological model to study invasive hepatic disease. Ex vivo perfusion of human hepatic segments has enormous potential and we are currently investigating this tool to be used as a translational model for invasive disease, including macrophage response to the earliest phases of infection, as demonstrated in porcine organs by Wanford et al (2021). Methods This retrospective service evaluation project was registered locally with audit registration numbers 11852 and 11852a. All liver resections booked electronically over a six month period, between 1/10/20 and 31/3/21, were assessed. Patient records, including intra-operative notes, were reviewed to identify which patients had a partial hepatectomy (left hemi-hepatectomy, right hemi-hepatectomy, or left lateral segmentectomy). The data was then compared against histology reports to identify which segments from the specimen were pathological and which segments were disease-free. A prospective Research Ethics Committee-approved clinical trial was registered by the name of “Tissue Models for Liver Disease” or TIMOLD (ClinicalTrials.gov Identifier: NCT05255042; 8/9/2021). Patients recruited were those aged eighteen or over undergoing elective liver resections. Exclusion criteria included those with acute invasive infection, children and vulnerable groups. A re-audit was performed following implementation of the TIMOLD study for the same time period the following year, between 1/10/21 and 31/3/22. Data analysis was performed using GraphPad Prism. Results Between 1/10/20 and 31/3/21, 43 liver resections were listed. Intra-operatively, 3/43 patients had inoperable disease and 2/43 did not require a resection. Of the 38 liver resections performed, 30 (79%) were for colorectal liver metastases (CRLM), 4/38 (11%) were for hepatocellular carcinoma (HCC), and the remainder for cholangiocarcinoma, neuroendocrine tumours and adenomas. 19/38 (50%) liver resections were a hemi-hepatectomy or left lateral segmentectomy. Histology review found that 11/19 (58%) specimens contained at least one healthy liver segment which was eventually discarded. Between 1/10/21 and 31/3/22, following implementation of the TIMOLD study, 57 liver resections were listed. 6/57 patients were found to have inoperative disease and 1/57 did not require a resection. Of 50 liver resections, 32/50 (64%) were for CRLM, 9/50 (18%) were for HCC and the remainder for cholangiocarcinoma, neuroendocrine tumours, IPMN and benign disease. 27/50 (54%) had a hemi-hepatectomy or left lateral segmentectomy. 17/27 (63%) partial hepatectomies were found to contain at least one healthy liver segment with potential for research use. As part of the TIMOLD trial, 8/17 healthy liver segments were retrieved and used for research during a six-month period, in comparison to none the previous year (p<0.05; Chi-Squared). Conclusions We demonstrate that at least 50% of patients undergoing liver resection at a tertiary HPB unit require a hemi-hepatectomy or left lateral segmentectomy over 12 months. Furthermore, at least half of these partial resections involve healthy anatomical liver segments as part of the specimen. Over six months, eight disease-free human liver segments, which would otherwise have been discarded, were perfused ex vivo in an attempt to develop a model representing human hepatic physiology at the organ level. Expanding this research model to other hepatobiliary units provides scientists an invaluable model for pre-clinical research, negating the need for live animal experimentation.