Transplanted liver pathology in the late post-transplant period: analysis of real clinical practice

Background. Late post-transplant diseases can be latent or present as late graft dysfunction.

The objective was to assess the nature of pathological changes in liver transplant recipients in the long-term based on the severity of graft dysfunction.

Material and methods. The results of a histological examination of the liver performed no earlier than one year after transplantation in 168 recipients were studied. The median follow-up was 57.8 (26.3; 94.9) months. Graft dysfunction was defined as overt if alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) increased to more than 1.5 times the upper limit of normal (n=73). Borderline dysfunction was defined as an increase in at least one of these parameters to more than 1 but less than 1.5 times the upper limit of normal, or an increase in gamma-glutamyl transferase (GGT) to more than 1.5 times the upper limit of normal (n=37). Graft dysfunction was absent in 58 recipients.

Results. In the subgroup of recipients without graft dysfunction, a slight increase in body mass index (BMI) (+1.1 kg/ m²) was noted compared to BMI at transplantation. Recipients with the borderline graft dysfunction had a lower BMI (25.4 kg/m²), and those with the overt dysfunction had an even lower BMI (23.7 kg/m²), than the subgroup without graft dysfunction (26.8 kg/m²; p=0.015). Clinical signs of the graft dysfunction were absent in 34.5% of recipients at the time of examination; however, only 22.4% of these recipients showed no significant abnormalities on histological examination. Among the remaining recipients with normal liver tests, there was evidence of chronic hepatitis (19%), fatty liver disease (31%), or intralobular fibrosis (25.9%), and in one case, graft cirrhosis. Graft fibrosis was observed in 60.3% of recipients without graft dysfunction. Marked fibrosis (classified by the Liver Allograft Fibrosis (LAF) scoring system as LAF > 2) was detected in 31%, and significant portal tract fibrosis (assessed as the meta-analysis of histological data in viral hepatitis (METAVIR) score >2) was found in 20.7% of recipients without signs of graft dysfunction. In the subgroup of recipients with overt graft dysfunction, ductopenia was the only pathological finding in 11.1% of recipients. More than two-thirds of cases of fatty liver disease and intrahepatic fibrosis do not manifest with clinically significant abnormalities in functional liver tests. Histological examination allowed for the clarification of the cause of overt graft dysfunction in 69.4% of cases.

Conclusion. Protocol biopsies in long-term liver transplant recipients enable the detection of pathological changes of varying severity, as well as the assessment of hepatitis activity, fibrosis stage, and the cause of graft dysfunction, and the identification of autoimmune disease recurrence.

1. Adam R, Karam V, Cailliez V, O'Grady J, Mirza D, Cherqui D, et al. 2018 Annual Report of the European Liver Transplant Registry (ELTR) - 50-year evolution of liver transplantation. Transpl Int. 2018;31(12):1293–1317. PMID: 30259574 https://doi.org/10.1111/tri.13358

2. Kwong AJ, Ebel NH, Kim WR, Lake JR, Smith JM, Schladt DP, et al. OPTN/SRTR 2020 Annual Data Report: liver. Am J Transplant. 2022;22 Suppl 2:204–309. PMID: 35266621 https://doi.org/10.1111/ajt.16978

3. Aberg F, Gissler M, Karlsen TH, Ericzon BG, Foss A, Rasmussen A, et al. Differences in long-term survival among liver transplant recipients and the general population: a population-based Nordic study. Hepatology. 2015;61(2):668677. PMID: 25266201 https://doi.org/10.1002/hep.27538

4. Bellamy COC, O'leary JG, Adeyi O, Demetris AJ, El-Monayeri M, Fontana RJ, et al. Banff 2022 Liver Group Meeting report: monitoring long-term allograft health. Am J Transplant. 2024;24(6):905–917. PMID: 38461883 https://doi.org/10.1016/j.ajt.2024.03.008

5. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349(9055):825–832. PMID: 9121257 https://doi.org/10.1016/S01406736(96)07642-8

6. Venturi C, Sempoux C, Bueno J, Ferreres Pinas JC, Bourdeaux C, Hoyos SP, et al. Novel histologic scoring system for long-term allograft fibrosis after liver transplantation in children. Am J Transplant. 2012;12(11):2986–2996. PMID: 22882699 https://doi.org/10.1111/j.1600-6143.2012.04210.x

7. Demetris AJ, Batts KP, Dhillon AP, Ferrell L, Fung J, Geller SA, et al. Banff schema for grading liver allograft rejection: an international consensus document. ё1997;25(3):658-663. PMID: 9049215 https://doi.org/10.1002/hep.510250328

8. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–1321. PMID: 15915461 https://doi.org/10.1002/hep.20701

9. Duseja A, Nanda M, Das A, Das R, Chawla Y. Prevalence of obesity, diabetes mellitus and hyperlipidaemia in patients with cryptogenic liver cirrhosis. Trop Gastroenterol. 2004;25(1):15–17. PMID: 15303464

10. Malinovskaya YuO, Kokina KYu, Sumtsova OV, Afanasev AV, Karalnik VL, Landyshev YuS, et al. Late liver allograft dysfunction: definition, risk factors and outcomes. Transplantologiya. The Russian Journal of Transplantation. 2024;16(2):163–177. (In Russ.). https://doi.org/10.23873/2074-0506-2024-16-2163-177

11. Evans HM, Kelly DA, Mckiernan PJ, Hubscher S. Progressive histological damage in liver allografts following pediatric liver transplantation. Hepatology. 2006;43(5):1109–1117. PMID: 16628633 https://doi.org/10.1002/hep.21152

12. Neuberger J, Wilson P, Adams D. Protocol liver biopsies: the case in favour. Transplant Proc. 1998;30(4):1497-1499. PMID: 9636609 https://doi.org/10.1016/S0041-1345(98)00332-7

13. Sebagh M, Rifai K, Feray C, Yilmaz F, Falissard B, Roche B, et al. All liver recipients benefit from the protocol 10-year liver biopsies. Hepatology. 2003;37(6):1293–1301. PMID: 12774007 https://doi.org/10.1053/jhep.2003.50231

14. Slapak GI, Saxena R, Portmann B, Gane E, Devlin J, Calne R, et al. Graft and systemic disease in long-term survivors of liver transplantation. Hepatology. 1997;25(1):195–202. PMID: 8985290 https://doi.org/10.1002/hep.510250136

15. Duclos-Vallee JC, Sebagh M, Rifai K, Johanet C, Ballot E, Guettier C, et al. A 10 year follow up study of patients transplanted for autoimmune hepatitis: histological recurrence precedes clinical and biochemical recurrence. Gut. 2003;52(6):893–897. PMID: 12740348 https://doi.org/10.1136/gut.52.6.893

16. Berenguer M, Rayon JM, Prieto M, Aguilera V, Nicolás D, Ortiz V, et al. Are posttransplantation protocol liver biopsies useful in the long term? Liver Transpl. 2001;7(9):790–796. PMID: 11552213 https://doi.org/10.1053/jlts.2001.23794

17. Abraham SC, Poterucha JJ, Rosen CB, Demetris AJ, Krasinskas AM. Histologic abnormalities are common in protocol liver allograft biopsies from patients with normal liver function tests. Am J Surg Pathol. 2008;32(7):965–973. PMID: 18460980 https://doi.org/10.1097/PAS.0b013e3181622490

18. Syn WK, Nightingale P, Gunson B, Hubscher SG, Mirza DF. Natural history of unexplained chronic hepatitis after liver transplantation. Liver Transpl. 2007;13(7):984–989. PMID: 17520743 https://doi.org/10.1002/lt.21108

19. Mohamed R, Hubscher SG, Mirza DF, Gunson BK, Mutimer DJ. Posttransplantation chronic hepatitis in fulminant hepatic failure. Hepatology. 1997;25(4):1003-1007. PMID: 9096611 https://doi.org/10.1002/hep.510250435

20. Mells G, Mann C, Hubscher S, Neuberger J. Late protocol liver biopsies in the liver allograft: a neglected investigation? Liver Transpl. 2009;15(8):931– 938. PMID: 19642126 https://doi.org/10.1002/lt.21781