{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T18:55:31Z","timestamp":1789844131062,"version":"4.0.1"},"reference-count":83,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2017,2,28]],"date-time":"2017-02-28T00:00:00Z","timestamp":1488240000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>The evolving history of the small intestinal biopsy and its interpretation\u2014and misinterpretations\u2014are described in this paper. Certain interpretative errors in the technical approaches to histological assessment are highlighted\u2014even though we may never be rid of them.  For example, mucosal \u201cflattening\u201d does not reduce individual villi to their cores, as still seems to be widely believed. Neither is the mucosa undergoing an atrophic process\u2014since it can recover structurally. Rather, the intestinal mucosa manifests a vast hypertrophic response resulting in the formation of large plateaus formed from partially reduced villi and their amalgamation with the now increased height and width of the inter\u2010villous ridges: this is associated with considerable increases in crypt volumes. Sections through mosaic plateaus gives an erroneous impression of the presence of stunted, flat\u2010topped villi which continues to encourage both the continued use of irrelevant \u201catrophy\u201d terminologies and a marked failure to perceive what random sections through mosaic plateaus actually look like. While reviewing the extensive 40+ year literature on mucosal analysis, we extracted data on intraepithelial lymphocytes (IEL) counts from 607 biopsies, and applied receiver\u2010operating characteristic (ROC)\u2010curve analysis. From that perspective, it appears that counting IEL\/100 enterocyte nuclei in routine haematoxylin and eosin (H&amp;E) sections provides the most useful discriminator of celiac mucosae at histological level, with an effective cut\u2010off of 27 IEL, and offering a very high sensitivity with few false negatives. ROC\u2010curve analysis also revealed the somewhat lesser accuracies of either CD3+ or \u03b3\u03b4+ IEL counts. Current official guidelines seem to be somewhat inadequate in clearly defining the spectrum of gluten\u2010induced mucosal pathologies and how they could be optimally interpreted, as well as in promoting the ideal manner for physicians and pathologists to interact in interpreting intestinal mucosae submitted for analysis.  Future trends should incorporate 3\u2010D printing and computerised modelling in order to exemplify the subtle micro\u2010anatomical features associated with the crypt\u2010villus interzone. The latter needs precise delineation with use of mRNA in\u2010section assays for brush border enzymes such as alkaline phosphate and esterase. Other additional approaches are needed to facilitate recognition and interpretation of the features of this important inter\u2010zone, such as wells, basins and hypertrophic alterations in the size of inter\u2010villous ridges. The 3\u2010D computerised models could considerably expand our understandings of the microvasculature and its changes\u2014in relation both to crypt hypertrophy, in addition to the partial attrition and  subsequent regrowth of villi from the inter\u2010villous ridges during the flattening and recovery processes, respectively.<\/jats:p>","DOI":"10.3390\/nu9030213","type":"journal-article","created":{"date-parts":[[2017,2,28]],"date-time":"2017-02-28T10:57:52Z","timestamp":1488279472000},"page":"213","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Evolutionary\u00a0Developments\u00a0in\u00a0Interpreting\u00a0the\u00a0 Gluten\u2010Induced\u00a0Mucosal\u00a0Celiac\u00a0Lesion:\u00a0An\u00a0 Archimedian\u00a0Heuristic"],"prefix":"10.3390","volume":"9","author":[{"given":"Michael","family":"Marsh","sequence":"first","affiliation":[{"name":"Luton and Dunstable Hospitals University NHS Trust, and Wolfson College, University of Oxford, Linton Road, Oxford OX2 6UD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calvin","family":"Heal","sequence":"additional","affiliation":[{"name":"Centre for Biostatistics, Faculty of Biology, Academic Health Science Centre, University of Manchester, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,2,28]]},"reference":[{"key":"ref_1","first-page":"17","article-title":"On the Coeliac Affection","volume":"24","author":"Gee","year":"1888","journal-title":"St. Bartholomew\u2019s Hosp. 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