Individuals with particular genetic backgrounds develop immune responses to wheat proteins and become ‘gluten-sensitised’. Mucosal pathology arises through activated mucosal T lymphocytes, resulting in a graded, adverse reaction between particular genes and wheat proteins. Given these varied influences, the Marsh Classification broadly itemises those stages through which a normal mucosa (Marsh 0) evolves in becoming ‘flat’ (Marsh I, II, III).

Background: Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. Objectives: To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). Methods: Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in μm), crypt depth (CrD, in μm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. Results: The median VH in NCGS was significantly shorter (600, IQR: 400–705) than controls (900, IQR: 667–1112) (p < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390–620) vs. 427 µm (IQR: 348–569, p = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls (p < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, p < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. Conclusion: NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.

The diagnosis of celiac disease (CD) no longer rests on a malabsorptive state or severe mucosal lesions. For the present, diagnosis will always require the gold-standard of a biopsy, interpreted through its progressive phases (Marsh classification). Marsh classification articulated the immunopathological spectrum of gluten-induced mucosal changes in association with the recognition of innate (Marsh I infiltration) and T cell-based adaptive (Marsh II, and the surface re-organisation typifying Marsh III lesions) responses. Through the Marsh classification the diagnostic goalposts were considerably widened thus, over its time-course, permitting countless patients to begin a gluten-free diet but who, on previous criteria, would have been denied such vital treatment. The revisions of this classification failed to provide additional insight in the interpretation of mucosal pathology. Morever, the subclassification of Marsh 3 imposed an enormous amount of extra work on pathologists with no aid in diagnosis, treatment, or prognosis. Therefore, it should now be apparent that if gastroenterologists ignore these sub-classifications in clinical decision-making, then on that basis alone, there is no need whatsoever for pathologists to persist in reporting them. Since new treatments are under critical assessment, we might have to consider use of some other higher level histological techniques sensitive enough to detect the changes sought. A promising alternative would be to hear more voices from imaginative histopathologists or morphologists together with some more insightful approaches, involving molecular-based techniques and stem cell research may be to evaluate mucosal pathology in CD. Cite this article as: Ensari A, Marsh MN. Diagnosing celiac disease: A critical overview. Turk J Gastroenterol 2019; 30(5): 389-97.

Our experiences, through day and night, are not as clear-cut as might seem on first thought. Considerable aspects of life comprise illusory phenomena, some of which are realised, while others are not. Moreover, the boundaries between illusion and hallucination can be very blurred. This essay considers specific situations exemplary of these aberrations – the phantom limb phenomenon, the effects of migraine and temporal lobe epilepsy, sleep disturbances, out-of-body and near-death experiences, conjuring, and the technique of pick-pocketing. Life is never as certain or as sure as we think.

The evolving history of the small intestinal biopsy and its interpretation—and misinterpretations—are described in this paper. Certain interpretative errors in the technical approaches to histological assessment are highlighted—even though we may never be rid of them. For example, mucosal “flattening” does not reduce individual villi to their cores, as still seems to be widely believed. Neither is the mucosa undergoing an atrophic process—since 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‐villous ridges: this is associated with considerable increases in crypt volumes. Sections through mosaic plateaus gives an erroneous impression of the presence of stunted, flat‐topped villi which continues to encourage both the continued use of irrelevant “atrophy” 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‐operating characteristic (ROC)‐curve analysis. From that perspective, it appears that counting IEL/100 enterocyte nuclei in routine haematoxylin and eosin (H&E) sections provides the most useful discriminator of celiac mucosae at histological level, with an effective cut‐off of 27 IEL, and offering a very high sensitivity with few false negatives. ROC‐curve analysis also revealed the somewhat lesser accuracies of either CD3+ or γδ+ IEL counts. Current official guidelines seem to be somewhat inadequate in clearly defining the spectrum of gluten‐induced 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‐D printing and computerised modelling in order to exemplify the subtle micro‐anatomical features associated with the crypt‐villus interzone. The latter needs precise delineation with use of mRNA in‐section 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‐zone, such as wells, basins and hypertrophic alterations in the size of inter‐villous ridges. The 3‐D computerised models could considerably expand our understandings of the microvasculature and its changes—in relation both to crypt hypertrophy, in addition to the partial attrition and subsequent regrowth of villi from the inter‐villous ridges during the flattening and recovery processes, respectively.

This paper critically reviews assertions that near-death and out-of-body experiences (ND/OBE) offer proof of extra-corporeal existence when the brain is supposedly “dead”. While this field has almost moved away from mere anecdotal recording, the current trend is focussed on demonstrating existence without functional brains. These endeavours have fallen far short of anticipated results—that cardiac patients would report on strategically-placed markers around acute resuscitation units. Two problems arise: a failure to produce corroborative empirical evidence for extra-corporeal cognition (a) when the brain is “dead”, (or “clinically dead”, so-called) and (b) how the memory required for recall could paradoxically be set down at that critical time-point. The view advanced here is that ND/OBE occur as subjects’ states are returning to complete resumption of conscious-awareness and which, from several published accounts, is particularly abrupt but which nevertheless accounts perfectly for memory—and recall. Similar transcendental adventures accompanying returns to conscious-awareness occur with other preceding states of reduced consciousness. Most recollections are intensely geo-physical, anthropomorphic, banal and illogical: their dream-like fantasy provides nothing revelatory about life without a brain, or importantly, about other supposed cosmic contexts. Additionally, it is proposed that since prevalence rates are so extremely low (<1% globally), the few subjects undergoing ND/OBE may have predisposed brains, genetically, structurally or resulting from previous psychological stress. In a somewhat similar vein to post-traumatic stress disorder, subjects with predisposed brains exhibit markedly changed post-experiential phenotypes, so that the ND/OBE itself could be viewed as a transient, accompanying epiphenomenon.