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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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 \u2018lipotic\u2019 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-025-06559-4","type":"journal-article","created":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:09:15Z","timestamp":1760234955000},"page":"157-172","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Generation of a pseudo-timeline describing progressive human exocrine and endocrine pancreatic pathology in cystic fibrosis through novel semi-quantitative scoring and AI-driven quantitative image analysis"],"prefix":"10.1007","volume":"69","author":[{"given":"Yara","family":"Al-Selwi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina","family":"Tiniakos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1160-6062","authenticated-orcid":false,"given":"Sarah J.","family":"Richardson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine S.","family":"Flaxman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia","family":"Russell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rowan","family":"Coulthard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashmi","family":"Maheshwari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4173-1913","authenticated-orcid":false,"given":"Nicola","family":"Dyson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6761-2998","authenticated-orcid":false,"given":"Minna","family":"Honkanen-Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6688-086X","authenticated-orcid":false,"given":"G\u00fcnter","family":"Kl\u00f6ppel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2893-3211","authenticated-orcid":false,"given":"James A. 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Brack and B. Hunter. The authors wish to acknowledge the support of M. Palmer (University of Exeter) for his support developing the SRFG analysis pipeline. We are especially thankful to all donors and their families. The graphical abstract was created in BioRender. Kattner, N. (2025)\n                      \n                      .","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"Data are available from the corresponding author upon reasonable request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"This project was supported by the Cystic Fibrosis Trust SRC 019 and the MRC (Quality and Safety in Organ Donation Tissue Bank \u2013 Expansion to include Pancreas\/Islets, Heart and Lungs) (MR\/R014132\/1). This project was further supported by a PhD studentship provided by Newcastle University (YAS). This study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre (SJR, CSF, LR). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This study was supported by the Ray Wilson Memorial Fund (NK).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"JAMS, NK and YAS designed the research studies and wrote the original manuscript. YAS, DT, GK, CSF, SJR, LR, RC, RM and NK performed experiments and\/or acquired\/analysed data. JAMS, SJR, CSF and NK supervised projects. ND and MHS performed tissue sampling for QUOD-PANC. All authors have reviewed and edited the manuscript and approved the final version. JAMS is the guarantor of this work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}