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ISSN 1007-9327 CN 14-1219/R  World J Gastroenterol  2010 January 21; 16(3): 296-298


Update on collagenous sprue

Hugh James Freeman

Hugh James Freeman, Department of Medicine, University of British Columbia Hospital, 2211 Wesbrook Mall, Vancouver, BC, V6T 1W5, Canada

Author contributions: Freeman HJ contributed all to this paper.

Correspondence to: Dr. Hugh James Freeman, MD, CM, FRCPC, FACP, Department of Medicine, University of British Columbia Hospital, 2211 Wesbrook Mall, Vancouver, BC, V6T 1W5, Canada.

Telephone: +1-604-8227216   Fax: +1-604-8227236

Received: May 11, 2009         Revised: December 9, 2009

Accepted: December 16, 2009

Published online: January 21, 2010



Collagenous sprue has traditionally been defined as a small intestinal mucosal disorder characterized by persistent diarrhea, severe malabsorption with multiple nutrient deficiencies and progressive weight loss. Pathologically, a severe to variably severe “flattened” mucosal biopsy lesion with distinctive sub-epithelial deposits in the lamina propria region is detected. Histochemical stains and ultrastructural studies have confirmed that these deposits contain collagens. Often, an initial diagnosis of celiac disease is considered but no continued response to treatment with a gluten-free diet occurs. Recent reports indicate an intimate relationship between collagenous sprue and celiac disease, sometimes with concomitant T-cell enteropathy. In addition, permanent disappearance of these deposits after resection of a localized colon cancer suggested that this disorder could actually represent a paraneoplastic morphologic marker of an occult malignancy. Studies showing either gastric or colonic involvement (or both) with this unusual collagenous inflammatory mucosal process may also reflect a far more extensive and heterogeneous process than previously appreciated.


© 2010 Baishideng. All rights reserved.


Key words: Collagenous sprue; Celiac disease; Lymp­homa; Paraneoplastic disease


Peer reviewer: Dr. Marco Silano, MD, Division of Food Science, Human Health and Nutrition, Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Roma, Italy


Freeman HJ. Update on collagenous sprue. World J Gastroenterol 2010; 16(3): 296-298  Available from: URL:  DOI:



In 1970, Weinstein et al[1] reported on a small intestinal mucosal biopsy lesion from a 51-year-old female initially thought to have celiac disease as histopathological changes included severely flattened villi. However, a long-term response to a gluten-free diet failed to develop. Subsequently, routine hematoxylin-eosin stained biopsies showed a prominent band-like deposit of sub-epithelial hyaline material in the lamina propria region of the small bowel. The deposit had the histochemical features of collagen and ultrastructural studies confirmed an electron-dense material with the typical 640 A axial periodicity of collagen fibers. Her symptoms transiently improved with corticosteroids, but she then developed worsening diarrhea, severe malabsorption and progressive weight loss. Post-mortem examination showed very extensive pathologic changes in the proximal small intestine with sub-epithelial eosinophilic hyaline deposits of varying thickness. Short segments of normal mucosa were present in the distal small intestine. Two earlier reports by Schein[2] in 1947 and Hourihane[3] in 1963  may have  reflected the same biopsy lesions (although in the latter, ileal involvement was also present).

    Collagenous sprue was thought to be a “new” form of malabsorptive disorder with the specific clinical and pathological features: (1) persistent diarrhea with pan-malabsorption causing nutrient deficiencies and progressive weight loss; (2) a biopsy lesion included a unique morphologic marker, a sub-epithelial band-like deposit with histochemical and ultrastructural features of collagen; (3) other pathologic changes of untreated celiac disease were present, but not responsive to a gluten-free diet; and (4) diffuse and patchy mucosal changes of variable severity, localized mainly in the proximal small intestine.



Traditionally, the diagnosis of celiac disease (or gluten-sensitive enteropathy) has been established pathologically and depended on two sequential criteria: first, documentation of the typical histopathologic features of untreated disease in small bowel biopsies, and, second, a response to a gluten-free diet. Otherwise, celiac disease, even if present, cannot be diagnosed with certainty. In some cases, a “flattened” biopsy appearance may be present, but a gluten-free diet response has not been documented. This may require months to years[4]. Some investigators have loosely labeled these cases as refractory celiac disease, but this label should be reserved for those who show an initial (and documented) response to a gluten-free diet followed by later development of recurrent symptoms and biopsy changes. The most commonly reported causes for recurrent symptoms and biopsy changes include poor dietary compliance or inadvertent ingestion of a ubiquitous gluten-containing food (e.g. pill capsules, communion wafers). In these cases, removal of the offending gluten should be sufficient to resolve symptoms and biopsy changes. A second or superimposed cause (e.g. infection, folate or zinc deficiency) could also develop. In addition, another entirely separate cause for a “flat” biopsy lesion could be present[5], as the initial true diagnosis (e.g. Crohn’s disease in duodenum without mucosal granulomas) may have been missed[6] or an associated or complicating disease (e.g. collagenous colitis, lymphoma) could have developed. In these patients, symptoms and biopsy changes may be improved with specific treatment, but not with a gluten-free diet. Finally, another “wastebasket” group with a “flat” biopsy appearance that has never been responsive to a gluten-free diet may be present, so-called sprue-like intestinal disease or unclassified sprue[7].



Collagenous sprue has a “flat” biopsy appearance, like untreated celiac disease, but fails to show a persistent response to a gluten-free diet. In addition, collagenous sprue is characterized by the appearance of distinctive subepithelial collagen deposits. Some believed that this histopathological change might simply represent a prognostic pathologic marker for a poor outcome in celiac disease[8]. Others, however, viewed collagenous sprue as a new and previously unrecognized small bowel disorder[9]. Later reports have also described further elements between celiac disease and collagenous sprue. Common clinical features include hyposplenism and positive endomysial antibodies that have been documented in both entities[10]. In collagenous sprue, similar complications recorded in celiac disease may also occur, including both T-cell and B-cell lymphomas[11,12].



Collagen deposits may also be present in the colon (i.e. collagenous colitis) or even stomach (i.e. collagenous gastritis)[13]. An associated inflammatory process in either colonic or gastric mucosa, or both, is also present, usually with epithelial lymphocytosis. Interestingly, collagenous or lymphocytic colitis as well as collagenous or lymphocytic gastritis are all associated with biopsy-defined celiac disease[13-15]. These pathological changes also suggest that a far more extensive pathologic process may occur elsewhere in the gastrointestinal tract with collagenous sprue.

    Previously published reports noted that the natural history of collagenous sprue was characterized by worsening malabsorption with an inevitably fatal outcome. In most patients, diarrhea and progressive weight loss occurred, and rarely, severe abdominal pain, sometimes with an associated vasculitis, was recorded[16]. However, more recently, independent reports with extensive biopsy studies have documented complete resolution of the lesion for prolonged periods after corticosteroid treatment[17,18] suggesting that the lesion may be reversed, at least temporarily, for extended periods, even years. Immunosuppressants have also been used in some cases.



The etiology and pathogenesis of these collagenous deposits are not known, however, different causes could be responsible. In addition to celiac disease, collagenous sprue has not only been complicated with T-cell lymphoma[12], but associated with its co-occurrence[19]. Finally, collagen deposits in both small and large intestines were detected with an apparently coincidental, but localized, colon cancer[20]. Later, clinical and histopathological changes were resolved after the cancer was resected, suggesting that these collagen deposits could represent a paraneoplastic morphologic marker of occult malignant disease.



Recent reports suggest that collagenous sprue may be more heterogeneous than previously appreciated. This has been reflected in frequently associated, but variable collagenous mucosal inflammatory changes elsewhere in the gastrointestinal tract, differential responses to treat­ment, particularly with steroids, and its association with other conditions, including malignant disease as a possible paraneoplastic morphologic marker.

    Treatment of this condition remains an empirical exercise. Steroids and/or immunosuppressant agents have been used, but, to date, this approach has resulted in only rare success.



1      Weinstein WM, Saunders DR, Tytgat GN, Rubin CE. Coll­agenous sprue--an unrecognized type of malabsorption. N Engl J Med 1970; 283: 1297-1301   PubMed

2      Schein J. Syndrome of nontropical sprue with hitherto undescribed lesions of the intestine. Gastroenterology 1947; 8: 438-460

3      Hourihane DO. Diarrhoea of small bowel origin. The histology of intestinal biopsies. Proc R Soc Med 1963; 56: 1073-1077   PubMed

4      Tursi A, Brandimarte G, Giorgetti GM, Elisei W, Inchingolo CD, Monardo E, Aiello F. Endoscopic and histological findings in the duodenum of adults with celiac disease before and after changing to a gluten-free diet: a 2-year prospective study. Endoscopy 2006; 38: 702-707   PubMed    DOI

5      Freeman HJ. Small intestinal mucosal biopsy for investigation of diarrhea and malabsorption in adults. Gastrointest Endosc Clin N Am 2000; 10: 739-753, vii   PubMed

6      Schuffler MD, Chaffee RG. Small intestinal biopsy in a patient with Crohn’s disease of the duodenum. The spectrum of abnormal findings in the absence of granulomas. Gastroenterology 1979; 76: 1009-1014   PubMed

7      Freeman HJ. Refractory celiac disease and sprue-like intestinal disease. World J Gastroenterol 2008; 14: 828-830   PubMed    DOI

8      Bossart R, Henry K, Booth CC, Doe WF. Subepithelial collagen in intestinal malabsorption. Gut 1975; 16: 18-22   PubMed    DOI

9      Perera DR, Weinstein WM, Rubin CE. Symposium on pathology of the gastrointestinal tract-Part II. Small intestinal biopsy. Hum Pathol 1975; 6: 157-217   PubMed    DOI

10    Freeman HJ. Hyposplenism, antiendomysial antibodies and lymphocytic colitis in collagenous sprue. Can J Gastroenterol 1999; 13: 347-350   PubMed

11    Robert ME, Ament ME, Weinstein WM. The histologic spectrum and clinical outcome of refractory and unclassified sprue. Am J Surg Pathol 2000; 24: 676-687   PubMed    DOI

12    Freeman HJ. Collagenous sprue associated with an extensive T-cell lymphoma. J Clin Gastroenterol 2003; 36: 144-146   PubMed    DOI

13    Freeman HJ. Collagenous mucosal inflammatory diseases of the gastrointestinal tract. Gastroenterology 2005; 129: 338-350   PubMed    DOI

14    Wolber R, Owen D, DelBuono L, Appelman H, Freeman H. Lymphocytic gastritis in patients with celiac sprue or spruelike intestinal disease. Gastroenterology 1990; 98: 310-315   PubMed

15    Wolber R, Owen D, Freeman H. Colonic lymphocytosis in patients with celiac sprue. Hum Pathol 1990; 21: 1092-1096   PubMed    DOI

16    Doe WF, Evans D, Hobbs JR, Booth CC. Coeliac disease, vasculitis, and cryoglobulinaemia. Gut 1972; 13: 112-123   PubMed    DOI

17    Schreiber FS, Eidt S, Hidding M, Schmidt-Walczuch J, Werning C. Collagenous duodenitis and collagenous colitis: a short clinical course as evidenced by sequential endoscopic and histologic findings. Endoscopy 2001; 33: 555   PubMed    DOI

18    Freeman HJ, Davis JE, Myers DM. Complete histological resolution of collagenous sprue. Can J Gastroenterol 2004; 18: 333-336   PubMed

19    Medlicott SA, Beck PL, Loken S, Crabtree T. Synchronous collagenous sprue and enteropathy-type T cell lymphoma: variants of the same disease. Can J Gastroenterol 2004; 18: 329-332   PubMed

20    Freeman HJ, Berean KW. Resolution of paraneoplastic collagenous enterocolitis after resection of colon cancer. Can J Gastroenterol 2006; 20: 357-360   PubMed


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