Abstract
Minimal lesions of the small bowel are mucosal changes characterized by an increased number of intraepithelial lymphocytes (with or without crypt hyperplasia) and normal villous architecture. Such changes are associated with a wide spectrum of conditions, ranging from food intolerances to infections, and from drugs to immune diseases, with different clinical profiles and manifestations, which complicates the formulation of a differential diagnosis. Patient history, symptom evaluation, and histopathology are the diagnostic features needed to establish a correct diagnosis. Physicians should assist pathologists in formulating a precise morphological evaluation by taking well-oriented small intestinal biopsies and collecting informative clinical findings that inform histopathology. In this current clinical controversy, the authors provide the reader with an appraisal of the small intestine minimal lesions through a careful analysis of the major conditions (e.g., celiac disease and other non-celiac disorders) responsible for such changes and their differential diagnosis. Also, we acknowledge that some of the diseases detailed in this article may progress from an early minimal lesion to overt mucosal atrophy. Thus, the timing of the diagnosis is of paramount importance.
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Peery AF, Crockett SD, Murphy CC, et al. Burden and cost of gastrointestinal, liver, and pancreatic diseases in the United States: update 2018. Gastroenterology. 2019;156:e11.
Wu RL, Vazquez-Roque M, Carlson P, et al. Gluten-induced symptoms in diarrhea-predominant irritable bowel syndrome are associated with increased myosin light chain kinase activity and claudin-15 expression. Lab Investig. 2017;97:14–23.
Caio G, Volta U, Sapone A, et al. Celiac disease: a comprehensive current review. BMC Med. 2019;17:142.
Al Toma A, Volta U, Auricchio R, et al. European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United Eur Gastroenterol J. 2019;7:583–613.
Volta U, Caio G, Stanghellini V, De Giorgio R. The changing clinical profile of celiac disease: a 15-year experience (1998–2012) in an Italian referral center. BMC Gastroenterol. 2014;14:194.
Husby S, Koletzko S, Korponay-Szabó I, et al. European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020. J Pediatr Gastroenterol Nutr. 2020;70:141–156.
Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancet. 2018;391:70–81.
Villanacci V, Ceppa P, Tavani E, Vindigni C, Volta U. Coeliac disease: the histology report. Dig Liver Dis. 2011;43:S385–S395.
Lagana SM, Bhagat G. Biopsy diagnosis of celiac disease: the Pathologist’s perspective in light of recent advances. Gastroenterol Clin North Am. 2019;48:39–51.
Oberhuber G, Granditsch G, Vogelsang H. The histopathology of coeliac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol. 1999;11:1185–1194.
Corazza GR, Villanacci V. Coeliac disease. J Clin Pathol. 2005;58:573–574.
Volta U, Caio G, Giancola F, et al. Features and progression of potential celiac disease in adults. Clin Gastroenterol Hepatol. 2016;14:686–693.
Kakar S, Nehra V, Murray JA, Dayharsh GA, Burgart LJ. Significance of intraepithelial lymphocytosis in small bowel biopsy samples with normal mucosal architecture. Am J Gastroenterol. 2003;98:1834–1837.
Brown I, Mino-Kenudson M, Deshpande V, Lauwers GY. Intraepithelial lymphocytosis in architecturally preserved proximal small intestinal mucosa: an increasing diagnostic problem with a wide differential diagnosis. Arch Pathol Lab Med. 2006;130:1020–1025.
Upton MP. “Give Us This Day Our Daily Bread” - Evolving Concepts in Celiac Sprue. Arch Pathol Lab Med. 2008;132:1594–1599.
Vande Voort JL, Murray JA, Lahr BD, et al. Lymphocytic duodenosis and the spectrum of celiac disease. Am J Gastroenterol. 2009;104:142–148.
Rostami K, Villanacci V. Microscopic enteritis: novel prospect in coeliac disease clinical and immunohistogenesis. Evolution in diagnostic and treatment strategies. Dig Liver Dis. 2009;41:245–252.
Hammer ST, Greenson JK. The clinical significance of duodenal lymphocytosis with normal villus architecture. Arch Pathol Lab Med. 2013;137:1216–1219.
Pai RK. A practical approach to small bowel biopsy interpretation: celiac disease and its mimics. Semin Diagn Pathol. 2014;31:124–136.
Lauwers GY, Fasano A, Brown IS. Duodenal lymphocytosis with no or minimal enteropathy: much ado about nothing? Mod Pathol. 2015;28:S22–S29.
Greenson JK. The biopsy pathology of non-coeliac enteropathy. Histopathology. 2015;66:29–36.
Owen DR, Owen DA. Celiac disease and other causes of duodenitis. Arch Pathol Lab Med. 2018;142:35–43.
Hayat M, Cairns A, Dixon MF, O’Mahony S. Quantitation of intraepithelial lymphocytes in human duodenum: what is normal? J Clin Pathol. 2002;55:393–394.
Ravelli A, Villanacci V. Tricks of the trade: how to avoid histological pitfalls in celiac disease. Pathol Res Pract. 2012;208:197–202.
Rostami K, Marsh MN, Johnson MW, et al. ROC-king onwards: intraepithelial lymphocyte counts, distribution & role in coeliac disease mucosal interpretation. Gut. 2017;66:2080–2086.
Sergi C, Shen F, Bouma G. Intraepithelial lymphocytes, scores, mimickers and challenges in diagnosing gluten-sensitive enteropathy (celiac disease). World J Gastroenterol. 2017;23:573–589.
Corazza GR, Villanacci V, Zambelli C, et al. Comparison of the interobserver reproducibility with different histologic criteria used in celiac disease. Clin Gastroenterol Hepatol. 2007;5:838–843.
Robert ME, Crowe SE, Burgart L, et al. Statement on best practices in the use of pathology as a diagnostic tool for celiac disease: a guide for clinicians and pathologists. Am J Surg Pathol. 2018;42:e44–e58.
Zanini B, Villanacci V, Marullo M, et al. Duodenal histological features in suspected non-celiac gluten sensitivity: new insights into a still undefined condition. Virchows Arch. 2018;473:229–234.
Ierardi E, Losurdo G, Iannone A, et al. Lymphocytic duodenitis or microscopic enteritis and gluten-related conditions: what needs to be explored? Ann Gastroenterol. 2017;30:380–392.
Kokkonen J, Holm K, Karttunen TJ, Mäki M. Children with untreated food allergy express a relative increment in the density of duodenal gammadelta + T cells. Scand J Gastroenterol. 2000;35:1137–1142.
Granito A, Muratori L, Muratori P, Petrolini N, Bianchi FB, Volta U. Antitransglutaminase antibodies and giardiasis. Am J Gastroenterol. 2004;99:2505–2506.
Goodgame RW, Kimball K, Ou CN, et al. Intestinal function and injury in acquired immunodeficiency syndrome-related cryptosporidiosis. Gastroenterology. 1995;108:1075–1082.
Memeo L, Jhang J, Hibshoosh H, Green PH, Rotterdam H, Bhagat G. Duodenal intraepithelial lymphocytosis with normal villous architecture: common occurrence in H. pylori gastritis. Mod Pathol. 2005;18:1134–1144.
Brown IS, Bettington A, Bettington M, Rosty C. Tropical sprue: revisiting an underrecognized disease. Am J Surg Pathol. 2014;38:666–672.
Riordan SM, McIver CJ, Wakefield D, Duncombe VM, Thomas MC, Bolin TD. Small intestinal mucosal immunity and morphometry in luminal overgrowth of indigenous gut flora. Am J Gastroenterol. 2001;96:494–500.
Shin SJ, Noh CK, Lim SG, Lee KM, Lee KJ. Non-steroidal anti-inflammatory drug-induced enteropathy. Intest Res. 2017;15:446–455.
Wallace JL, Syer S, Denou E, et al. Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis. Gastroenterology. 2011;141:1314–1322.
Marthey L, Cadiot G, Seksik P, et al. Olmesartan-associated enteropathy: results of a national survey. Aliment Pharmacol Ther. 2014;40:1103–1109.
Kokkonen J, Arvonen M, Vähäsalo P, Karttunen TJ. Intestinal immune activation in juvenile idiopathic arthritis and connective tissue disease. Scand J Rheumatol. 2007;36:386–389.
Carroccio A, Volta U, Di Prima L, et al. Autoimmune enteropathy and colitis in an adult patient. Dig Dis Sci. 2003;48:1600–1606. https://doi.org/10.1023/a:1024705032326
Brandtzaeg P. Update on mucosal immunoglobulin A in gastrointestinal disease. Curr Opin Gastroenterol. 2010;26:554–563.
Malamut G, Verkarre V, Suarez F, et al. The enteropathy associated with common variable immunodeficiency: the delineated frontiers with celiac disease. Am J Gastroenterol. 2010;105:2262–2275.
Diaz L, Hernandez-Oquet RE, Deshpande AR, Moshiree B. Upper gastrointestinal involvement in Crohn disease: histopathologic and endoscopic findings. South Med J. 2015;108:695–700.
Aziz I, Evans KE, Hopper AD, Smillie DM, Sanders DS. A prospective study into the aetiology of lymphocytic duodenosis. Aliment Pharmacol Ther. 2010;32:1392–1397.
Roy J, Platt JL, Weisdorf DJ. The immunopathology of upper gastrointestinal acute Graft-Versus-Host Disease. Lymphoid cells and endothelial adhesion molecules. Transplantation. 1993;55:572–578.
Carmack SW, Lash RH, Gulizia JM, Genta RM. Lymphocytic disorders of the gastrointestinal tract: a review for the practicing pathologist. Adv Anat Pathol. 2009;16:290–306.
Malamut G, Afchain P, Verkarre V, et al. Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II. Gastroenterology. 2009;136:81–90.
Mahadeva S, Wyatt JI, Howdle PD. Is a raised intraepithelial lymphocyte count with normal duodenal villous architecture clinically relevant? J Clin Pathol. 2002;55:424–428.
Shmidt E, Smyrk TC, Faubion WA, Oxentenko AS. Duodenal intraepithelial lymphocytosis with normal villous architecture in pediatric patients: Mayo Clinic experience, 2000–2009. J Pediatr Gastroenterol Nutr. 2013;56:51–55.
Losurdo G, Piscitelli D, Giangaspero A, et al. Evolution of nonspecific duodenal lymphocytosis over 2 years of follow-up. World J Gastroenterol. 2015;21:7545–7552.
Wahnschaffe U, Ullrich R, Riecken EO, Schulzke JD. Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome. Gastroenterology. 2001;121:1329–1338.
Wolters VM, Wijmenga C. Genetic background of celiac disease and its clinical implications. Am J Gastroenterol. 2008;103:190–195.
Biagi F, Luinetti O, Campanella J, et al. Intraepithelial lymphocytes in the villous tip: do they indicate potential coeliac disease? J Clin Pathol. 2004;57:835–839.
Arranz E, Bode J, Kingstone K, Ferguson A. Intestinal antibody pattern of coeliac disease: association with gamma/delta T cell receptor expression by intraepithelial lymphocytes, and other indices of potential coeliac disease. Gut. 1994;35:476–482.
Fernández-Bañares F, Carrasco A, Martín A, Esteve M. Systematic review and meta-analysis: accuracy of both gamma delta + intraepithelial lymphocytes and coeliac lymphogram evaluated by flow cytometry for coeliac disease diagnosis. Nutrients. 2019;11:1992.
Tosco A, Maglio M, Paparo F, et al. Immunoglobulin A anti-tissue transglutaminase antibody deposits in the small intestinal mucosa of children with no villous atrophy. J Pediatr Gastroenterol Nutr. 2008;47:293–298.
Koskinen O, Lindfors K, Collin P, et al. Intestinal transglutaminase 2 specific antibody deposits in non-responsive coeliac disease. Dig Liver Dis. 2010;42:692–697.
Volta U, De Giorgio R, Caio G, Uhde M, Manfredini R, Alaedini A. Nonceliac wheat sensitivity: an immune-mediated condition with systemic manifestations. Gastroenterol Clin North Am. 2019;48:165–182.
Volta U, Bardella MT, Calabrò A, Troncone R, Corazza GR. Study Group for Non-Celiac Gluten Sensitivity. An Italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity. BMC Med. 2014;12:85.
Carroccio A, Giannone G, Mansueto P, et al. Duodenal and rectal mucosa inflammation in patients with non-celiac wheat sensitivity. Clin Gastroenterol Hepatol. 2019;17:682–690.
Caio G, Riegler G, Patturelli M, et al. Pathophysiology of non-celiac gluten sensitivity: where are we now? Minerva Gastroenterol Dietol. 2017;63:16–21.
Smyrk TC. Practical approach to the flattened duodenal biopsy. Surg Pathol Clin. 2017;10:823–839.
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Volta, U., Caio, G., Ghirardi, C. et al. Minimal Lesions of the Small Intestinal Mucosa: More than Morphology. Dig Dis Sci 65, 2761–2768 (2020). https://doi.org/10.1007/s10620-020-06571-1
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DOI: https://doi.org/10.1007/s10620-020-06571-1