Browse by author
Lookup NU author(s): Yara Al-Selwi, Professor Dina Tiniakos, Dr Sarah Richardson, Dr Rashmi Maheshwari, Nicola DysonORCiD, Minna Honkanen-Scott, Professor James ShawORCiD, Dr Nicole KattnerORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025. Aims/hypothesis: Cystic fibrosis (CF) is associated with pancreatic exocrine insufficiency (PEI) early in life and diabetes in at least 50% of adults. Underlying CF-related changes within the pancreas remain incompletely understood due to scarcity of available human tissue, protracted disease course and absence of robust and reproducible analytical approaches. This study aimed to develop and apply a systematic analysis cross-sectionally to CF pancreatic tissue samples to construct a timeline of exocrine and endocrine changes with progressive disease. Methods: Through a pathologist-led iterative approach, a light-microscopy semi-quantitative scoring system and artificial-intelligence-driven quantitative image analysis for individual pancreatic variables were developed. These were applied to human pancreatic tissue from 29 CF and 58 control donors without pancreatic disease. Results: Rapid loss of acinar tissue with virtually complete absence and replacement by adipocytes by the age of 7 years was confirmed. Ductal blockage by thickened secretions was associated with increasing ductal dilatation accompanied by periductal fibrosis, followed by ductal loss with involution of associated fibrosis in parallel with increasing adipocyte proportional area. Remaining ducts were relatively small, surrounded by residual fibrosis. Islets became increasingly clustered, initially surrounded by pancreatic stellate cells and fibrosis, then disorganised by interposing fibrotic tissue between endocrine cell regions and surrounded by residual collagen stranding in a ‘lipotic’ pancreas. Overall islet mass was not reduced but proportional beta cell area was reduced from birth without further loss over the course of progressive disease. Conclusions/interpretation: The natural history of pancreatic CF progresses rapidly from duct blockage and dilatation associated with periductal fibrosis to global fat replacement in keeping with early onset of PEI in the majority of affected individuals. Beta cell proportional area is reduced at birth before clinical evidence of pancreatic endocrine dysfunction without significant further loss of islet/beta cell mass with age. Increasing islet disorganisation and intra-islet collagen deposition in older donors temporo-spatially implicates fibrosis in and around the islet as being aetiologically important in the development of CF-related diabetes.
Author(s): Al-Selwi Y, Tiniakos D, Richardson SJ, Flaxman CS, Russell L, Coulthard R, Maheshwari R, Dyson N, Honkanen-Scott M, Kloppel G, Shaw JAM, Kattner N
Publication type: Article
Publication status: Published
Journal: Diabetologia
Year: 2025
Pages: Epub ahead of print
Online publication date: 12/10/2025
Acceptance date: 11/07/2025
Date deposited: 27/10/2025
ISSN (print): 0012-186X
ISSN (electronic): 1432-0428
Publisher: Springer Nature
URL: https://doi.org/10.1007/s00125-025-06559-4
DOI: 10.1007/s00125-025-06559-4
Data Access Statement: Data are available from the corresponding author upon reasonable request.
PubMed id: 41076452
Altmetrics provided by Altmetric
