Collagenous Sprue

In 1970, Weinstein and associates¹ described a distinctive abnormality in small bowel biopsies from a 51-year-old woman initially thought to have celiac disease. The changes in the present case report by Xiao and colleagues² are similar to this original case study. In the original report, biopsies stained with hematoxylin and eosin showed a prominent band of subepithelial eosinophilic hyaline material in the lamina propria. The deposits were notable due to their histochemical features of collagen, and ultrastructural evaluation confirmed the presence of an electron-dense material with the typical 640 A axial periodicity of collagen fibers. Prior biopsies showed changes of untreated celiac disease with flattened villi, but response to a gluten-free diet failed to occur. Later, her clinical course worsened with severe diarrhea, malabsorption, and weight loss. Symptoms transiently improved with corticosteroids. She died approximately 4 years later, and a postmortem examination showed abnormal and very extensive pathologic changes in the proximal small intestine with subepithelial eosinophilic hyaline of varying degrees of thickness. In addition, short segments of normal intestine were present in the distal small intestine. The investigators noted two earlier reports by Schein³ in 1947 and Hourihane⁴ in 1963 possibly representing the identical biopsy lesion (though in the latter, ileal involvement was evident).

Thus, this distinctive and intriguing disorder was initially shown to have the following features: persistent diarrhea with pan-malabsorption causing nutrient deficiency and weight loss; distinctive histopathologic changes that include a unique morphologic marker, a subepithelial band with the histochemical (and ultrastructural) features of collagen; other histopathologic changes similar to untreated celiac disease but not responsive to a gluten-free diet; and diffuse and patchy mucosal changes of variable severity, localized mainly in the proximal small intestine. In the case presented by Xiao and coworkers, the diagnosis of collagenous sprue was supported by at least the first two features (though ultrastructural studies were not performed). However, a gluten-free diet provided for only 2 weeks would not be adequate to exclude concomitant celiac disease, as duodenal biopsy improvement may require months or even years, particularly in older adults.⁵ Finally, overall severity and extent of the changes along the length of the small intestine could not be fully detailed.

This case emphasizes a very important clinical issue. The diagnosis of celiac disease (or gluten sensitive enteropathy) is pathologically-based and has traditionally depended upon two sequential criteria: documentation of the typical histopathologic features of untreated disease in small bowel mucosal biopsies; and response to a gluten-free diet. Otherwise, celiac disease, even if present, cannot be defined. In some cases, a “flattened” biopsy appearance may be present, but a gluten-free diet response has not been documented. Some of these cases have been loosely labeled as refractory celiac disease, but this label should be reserved for those that show an initial response to a glu-ten-free diet followed by later development of recurrent symptoms and biopsy changes. The most common causes for this scenario in celiac disease include poor dietary compliance or inadvertent ingestion of a ubiquitous gluten-containing food source (eg, pill capsules, communion wafers). A second cause or a superimposed cause (eg, infection, folate or zinc deficiency) for recurrence could also occur. Moreover, a different cause for a “flattened” biopsy appearance may be responsible,⁶ the initial correct diagnosis (eg, Crohn’s disease in the duodenum without mucosal granulomas) may have been missed,⁷ or an associated or complicating disease (eg, collagenous colitis, lymphoma) may have developed. Finally, a miscellaneous or “wastebasket” group with a “flat” biopsy appearance may be present with no evidence that a gluten-free diet response had ever occurred. This group does not meet the two traditional criteria for celiac disease (or even refractory celiac disease). More precise terms are sprue-like intestinal disease or unclassified sprue.⁸ In the present case, a specific cause for clinical and pathologic changes could be defined because of the unique pathologic features found in collagenous sprue.

The possible relationship to celiac disease was also raised here. Some physicians originally believed that increased subepithelial collagen may simply represent only a prognostic pathologic marker for a poor outcome in celiac disease.⁹ Others, however, viewed collagenous sprue as an entirely new, previously unrecognized small bowel disorder that is poorly responsive to a gluten-free diet.¹⁰ More recent studies have also noted some other shared elements between celiac disease and collagenous sprue. For example, common clinical features have been documented (eg, hyposplenism, positive endomysial anti-bodies)¹¹ as well as complications, including both T-cell and B-cell lymphoma in both entities.^12,13

The present case also illustrates another intriguing aspect of collagenous sprue that continues to be explored. Collagen deposition was also present in the colon as in earlier reports demonstrating collagen deposits in the colon (ie, collagenous colitis) or even the stomach (ie, collagenous gastritis).¹⁴ An associated inflammatory process in either colonic or gastric mucosa, or both, is usually present, often including epithelial lymphocytosis. Interestingly, collagenous or lymphocytic colitis or gastritis have all been associated with biopsy-defined celiac disease.^14-16 Together, these findings suggest a far more extensive pathologic process and may also represent an important clue to a far more heterogeneous process than has been previously appreciated.

Historically, published reports have suggested that the natural history of collagenous sprue is characterized by worsening malabsorption, usually of multiple nutrients, with an inevitably fatal outcome. In most cases, diarrhea and progressive weight loss were documented, and on rare occasions, abdominal pain, sometimes severe, was present, often with vasculitis.¹⁷ However, independent reports with extensive biopsy studies have also demonstrated complete histologic resolution of the lesion and disappearance of the abnormal collagen deposits after steroid therapy for prolonged periods of time.^18,19 This suggests that the lesion may occasionally be reversible, in some patients, at least temporarily for extended periods of years. In the present report, steroids were also used and a response was noted in the colon, but not in the small bowel. This differential treatment response suggests that these collagen deposits and their accompanying inflammatory processes could be quite heterogeneous along the length of the gastrointestinal tract.

The cause of these collagenous deposits may also be quite different from case to case. In addition to celiac disease, collagenous sprue has not only been complicated by T-cell lymphoma, but has been associated with its occur-rence.¹³ Finally, collagen deposits in both the small and large intestines were detected with an apparently coincidental, but localized, colorectal cancer.²⁰ Later, clinical and histopathologic changes resolved after the cancer was resected, suggesting that these collagen deposits could represent an important paraneoplastic morphologic marker of occult malignant disease.

Summary

Collagenous sprue is a small intestinal disorder marked by severe to variably severe architectural disturbance and distinctive subepithelial collagen deposits. Recent studies suggest that this disorder may be more heterogeneous than previously appreciated, as reflected in frequently associated collagenous mucosal inflammation elsewhere in the gastrointestinal tract, differential responses to treatment, particularly with steroids, and its association with other conditions, including malignant disease as a paraneoplastic morphologic marker.