Untreated Celiac Sprue Research Articles

Transglutaminase Autoantibodies in Dermatitis Herpetiformis and Celiac Sprue

Dermatitis herpetiformis (DH) is an autoimmune blistering skin disorder that is associated with intestinal gluten sensitivity. Epidermal transglutaminase (TGe) and closely related tissue transglutaminase (tTG) are considered to be autoantigens in DH, because a majority of DH patients have IgA specific for TGe and for tTG. It is unknown where and how these autoantigen-specific IgAs are generated in DH. Results reported in this paper on nine DH patients on a gluten containing diet demonstrate that the levels of circulating anti-tTG IgA and anti-TGe IgA in DH are correlated with each other and that both appear to be correlated with the degree (extent) of enteropathy. An analysis of 15 untreated celiac sprue (CS) patients demonstrated that approximately 33% of CS patients had elevated levels of anti-TGe IgA. These results would indicate that intestinal damage is associated with the production of anti-tTG IgA and anti-TGe IgA in DH patients.

Immunohistochemical Analysis of ZO-1 in the Duodenal Mucosa of Patients with Untreated and Treated Celiac Disease

Background/Aim: ZO-1 is a good marker for tight junction integrity which may be damaged in many intestinal diseases. ZO-1 can also accumulate in the cellular nucleus in addition to sites of cell-cell contact, suggesting a potential role in cellular proliferation and differentiation. We evaluated the expression and distribution of ZO-1 in patients with celiac disease before and after a gluten-free diet. Methods: The ZO-1 expression was evaluated semiquantitatively by means of immunohistochemical analysis in duodenal bioptic specimens of 10 consecutive patients with celiac disease before and after a gluten-free diet and in 10 controls. Furthermore, the nuclear staining was analyzed quantitatively, evaluating 3,000 cells for each count, and it was expressed as a percentage of labeled nuclei over the total of analyzed cells. Results: The intestinal mucosa of untreated celiac disease patients shows a globally lower ZO-1 labeling than that of controls. The expression of ZO-1 in the treated celiac mucosa did not differ significantly from normal intestinal mucosa of healthy subjects. At the crypt level of untreated celiac mucosa, a low intensity of nuclear labeling (1.75 ± 0.32%) was found, while in both treated celiac disease patients and in normal subjects we observed a statistically significant higher percentage of strongly labeled nuclei (53.72 ± 6.30% and 56.79 ± 5.45%, respectively; p = 0.0002). Conclusions: Our data show a global underexpression of ZO-1 in the duodenal mucosa of active celiac disease patients. Gluten withdrawal allows a normalization of the ZO-1 expression in treated celiac disease patients. Furthermore, the particular pattern of ZO-1 resembles the cellular distribution in undifferentiated cells and may be the result of immaturity of the enterocytes in untreated celiac sprue.

Colonic histopathology in untreated celiac sprue or refractory sprue: Is it lymphocytic colitis or colonic lymphocytosis?

Colonic histopathology in some patients with untreated celiac sprue and refractory sprue has been said to be indistinguishable from lymphocytic colitis, but there have been no objective comparisons on which this is based. The purpose of this study was to determine the prevalence and to characterize the nature of colonic histopathology at the time of diagnosis in patients with celiac or refractory sprue. Colonoscopic biopsy specimens obtained at the time of diagnosis from 16 patients with celiac sprue, six patients with refractory sprue, nine patients with lymphocytic colitis, and five normal controls were analyzed blindly by histological and morphometric methods, quantitating the number and specific subtypes of inflammatory cells within the lamina propria and epithelium. Immunoperoxidase staining of intraepithelial lymphocytes with a monoclonal antibody to CD8 also was performed. Three of 16 patients with untreated celiac sprue (19%) were thought to have colonic histological abnormalities, which by morphometry consisted of slightly increased numbers of lymphocytes in the surface epithelium and lamina propria, many of which were CD8-positive. These abnormalities were distinguishable from lymphocytic colitis by the lack of increased overall lamina propria cellularity and surface epithelial abnormalities, and by fewer intraepithelial lymphocytes. In refractory sprue, colonic histological abnormalities were more frequent than in celiac sprue, occurring in four of six patients (67%), more pronounced, and identical to those in the lymphocytic colitis syndrome. However, colonic intraepithelial lymphocytes in lymphocytic colitis were mostly CD8-positive, whereas those in the colitis of refractory sprue rarely were. Mild colonic lymphocytosis in patients with untreated celiac sprue should be distinguished from lymphocytic colitis by the lack of surface epithelial abnormalities, the lack of increased cellularity of the lamina propria, and the lack of ongoing watery diarrhea after treatment with a gluten-free diet. In contrast, colonic histopathology in refractory sprue is indistinguishable from lymphocytic colitis, although immunohistochemical differences do exist.

Comparison of serum anti-gliadin, anti-endomysium, and anti-jejunum antibodies in adult celiac sprue.

We compared the diagnostic accuracy of a new immunological marker of celiac sprue (CS), the antijejunum antibody (JAB), with that of antigliadin (AGA) and antiendomysium (EmA) antibodies. One hundred untreated adults with biopsy-proven CS, 52 healthy controls, and 57 patients with inflammatory bowel disease, lymphoma of the small bowel, Whipple's disease, and irritable bowel syndrome were investigated. Only JAB and EmA were detected at a similar titer in all patients with untreated CS but in no controls (100% sensitivity and specificity). Sensitivity of AGA was, respectively, 55% for IgA and 78% for Ig class, with a 100 and 82% specificity. The differences in frequencies between both EmA and JAB with IgA and IgG AGA were highly significant. We conclude that JAB and EmA provide a reliable noninvasive screening test for clinically significant gluten-sensitive enteropathy. The lower cost of IgA-JAB is a major advantage, owing to the different availability of the lower third of the esophagus and jejunum from primates. The sensitivity and specificity of the two tests are almost identical, but we find interpreting EmA easier than JAB especially when the titer is low.

Disappearance of Mesenteric Lymphadenopathy with Gluten-Free Diet in Celiac Sprue

In an adult patient with untreated celiac sprue, mesenteric lymphadenopathy was detected by computerized tomography (CT). Although malignant lymphoma was suspected, the nodes disappeared after treatment with a gluten-free diet, as was documented by CT follow-up. This report demonstrates that mesenteric lymphadenopathy in celiac sprue might be benign. With the increased use of CT investigation, findings like these may be encountered more often.

Obstetric and Gynecological Problems in Women with Untreated Celiac Sprue

We investigated the obstetric and gynecological history of 54 consecutive women (aged 16-62 years, median of 35 years) with newly diagnosed celiac sprue and 54 healthy controls matched for age, origin, and sexual behavior. The mean age of menarche was significantly delayed in these untreated patients with respect to controls (13.5 vs. 12.1 years; p less than 0.0001). Of the patients, 38.8% complained of amenorrhea, compared with 9.2% of the controls (p less than 0.001). Thirty-eight patients and 38 controls were in reproductive age; they had a normal sexual life and did not use contraceptive measures. Five celiacs, but no controls, had repeated abortions (p less than 0.03). Eight celiacs and six controls were in menopause, the mean age at onset being 45.5 and 49.5 years respectively (not significant).

The intestinal and rectal epithelial lymphocyte in AIDS. An electron-microscopic study.

Injury to the gastrointestinal tract may be mediated in part by the intraepithelial lymphocyte. In this study, we utilized electron microscopy to define the morphological appearance of 86 intestinal and 55 rectal intraepithelial lymphocytes observed in 11 patients with acquired immunodeficiency syndrome (AIDS), and one patient with AIDS-related lymphadenopathy syndrome. The data obtained from intraepithelial lymphocytes of AIDS are compared to those from 106 normal intestinal epithelial lymphocytes and 52 untreated celiac sprue epithelial lymphocytes. The AIDS epithelial lymphocyte possesses more organelles and appears "activated." Eighty-four percent of AIDS epithelial lymphocytes and 44% of normal epithelial lymphocytes possess lysosomal granules. There are 3.3 lysosomal granules/AIDS epithelial lymphocyte and 1.0 lysosomal granule/normal epithelial lymphocyte. Lymphocytes in AIDS usually possess multiple surface projections, which indent and make point contact with adjacent epithelial cells. Thirty-four percent of AIDS epithelial lymphocytes, 23% of sprue epithelial lymphocytes, and 2% of normal epithelial lymphocytes appear "activated." Lymphocytes in AIDS are "activated" in both the presence and absence of gastrointestinal pathogens. Epithelial lymphocytes are increased in intestinal, but not in rectal, AIDS tissue. Mucosal injury, including single cell necrosis, is minimal in the AIDS tissue. We speculate that the "activated" epithelial lymphocyte in AIDS, often possessing large lysosomes, could function as a cytotoxic effector in the development of gastrointestinal immune injury reported to be present in some patients with AIDS.

Morphometric analysis of small intestinal mucosa. III. The quantitation of crypt epithelial volumes and lymphoid cell infiltrates, with reference to celiac sprue mucosae.

With the aid of computerised image-analysis, morphometric techniques were used to measure the volumes of crypt epithelium, with reference to a constant test area (10(4) microns2) of muscularis mucosae, in untreated and treated celiac sprue mucosae in comparison with four other groups of control jejunal specimens. Crypt epithelial lymphocyte populations were also analyzed in terms of absolute numbers (N), mean nuclear (DN) and cytoplasmic (DCYT) diameters, and mean nuclear (VN) and cell (VCELL) volumes. Untreated celiac sprue crypts, despite a 3-5 fold increase in volume over control mucosae, contained a markedly expanded population of lymphocytes which was localised predominantly to the upper crypt regions and comprised approximately 6% large lymphocytes (DN greater than 6 microns: DCYT greater than 9 micron). These changes were entirely reversed by dietary treatment and hence were considered to be gluten-driven. The infiltrate might reflect the expression of gluten receptors on maturing upper crypt enterocytes: but why these lymphocytes do not cause any apparent injury to crypt epithelium (unlike surface epithelium) or influence its well-known compensatory response, remains unclear.

Studies of Intestinal Lymphoid Tissue. VIII. Use of Epithelial Lymphocyte Mitotic Indices in Differentiating Untreated Celiac Sprue Mucosa from Other Childhood Enteropathies

The mitotic activity of epithelial lymphocytes (expressed as percentage mitotic figures/3,000 lymphocytes/mucosal biopsy) was determined in a random sample of jejunal biopsies performed on 44 children with malabsorption, diarrhoea, or failure to thrive. The mitotic index (MI) exceeded 0.2% in 19 biopsies obtained from children with untreated celiac sprue (CS); there were no false positives. The remaining 25 biopsies (MI of <0.2%) were considered to be "nonceliac" in origin, among which were several with a severe degree of villous flattening. Conditions in this latter category excluded by a low MI included cow's milk protein enteropathy, selective immunoglobulin A deficiency, combined variable immunodeficiency, Crohn's jejunitis, and intractable diarrhoea of infancy. A high MI (>0.2%) prospectively distinguishes mucosal lesions due to untreated CS from other causes of malabsorption, particularly those associated with villous flattening, but in which the MI is <0.2%. This index is therefore proposed as a simple, reliable, and prospective histological marker of CS, and one that could: (a) reduce the need to perform multiple biopsies during a gluten‐free diet; and (b) avoid the necessity for follow‐up "diagnostic" gluten challenges, especially in very young children.

A Quantitative Study of Enteric Endocrine Cells in Celiac Sprue

A quantitative morphological investigation of eight endocrine cell types in mucosal biopsies from adults with untreated celiac sprue was undertaken. The quantitative data expressed as cells per millimeter of epithelium most accurately reflected the changes seen in celiac disease, as it takes into account changes in mucosal thickness due to die absence of villi in celiac biopsies. The results showed significant increases in the number of cholecystokinin and enterochromaffin cells, a significant decrease in somatostatin, gastric inhibitory polypeptide and secretin cells, and no change in the motilin, gastrin, and glicentin cells Significant changes in cell size (cross‐sectional area) were also demonstrated in the somatostatin and gastrin cells which were smaller in the celiac biopsies.

A quantitative study of enteric endocrine cells in celiac sprue.

A quantitative morphological investigation of eight endocrine cell types in mucosal biopsies from adults with untreated celiac sprue was undertaken. The quantitative data expressed as cells per millimeter of epithelium most accurately reflected the changes seen in celiac disease, as it takes into account changes in mucosal thickness due to the absence of villi in celiac biopsies. The results showed significant increases in the number of cholecystokinin and enterochromaffin cells, a significant decrease in somatostatin, gastric inhibitory polypeptide and secretin cells, and no change in the motilin, gastrin, and glicentin cells. Significant changes in cell size (cross-sectional area) were also demonstrated in the somatostatin and gastrin cells which were smaller in the celiac biopsies.

Impairment of secretin release in celiac sprue.

Plasma secretin concentrations and pH in the second portion of duodenum were measured in the fasting state and during duodenal infusion of HCl in five patients with untreated celiac sprue, five celiac sprue patients after gluten-free diets, and five normal subjects. Mean fasting plasma secretin concentrations were insignificantly lower in untreated sprue patients (4.1 +/- 1.4 pg/ml) than in normal subjects (5.7 +/- 0.59 pg/ml). During 30-min intraduodenal infusions of 0.1 N HCl at 0.20 mEqH+/min, mean plasma secretin concentrations were significantly lower in untreated sprue patients (5.8 +/- 1.8 pg/ml) than in normal subjects (25.4 +/- 1.60 pg/ml, P less than 0.01). The increases in mean secretin concentrations over fasting were 2.1 +/- 0.82 pg/ml in untreated sprue patients compared to 19.7 +/- 1.47 pg/ml in normal subjects (P less than 0.01), a ninefold difference. The results indicate that endogenous release of secretin in response to duodenal acidification is impaired in patients with celiac sprue.

The Small Intestinal Mucosa in Dermatitis Herpetiformis

Proximal intestinal mucosal abnormalities are almost invariably found in dermatitis herpetiformis if a sufficient number of biopsies are taken. Fifteen patients (group 1) had flat lesions near the duodenojejunal junction indistinguishable from those seen in celiac sprue. Six patients (group 2) had lesions in this same area ranging in severity from almost normal to completely flat. Only 1 patient had normal intestinal biopsies (group 3). Sampling of the full length of the small intestine in 5 patients in group 1 showed the lesions to have a similar distribution to that seen in untreated celiac sprue, i.e., improvement toward normal as one proceeded from proximal to distal small bowel. Multiple biopsies of the proximal small bowel in 5 patients in group 2 demonstrated the patchy proximal mucosal involvement seen in some patients with dermatitis herpetiformis. Clinical and laboratory evidence of significant malabsorption was absent in most of the patients and this is best explained by the limited length of small intestine involved in this skin disorder.

Collagenous sprue--an unrecognized type of malabsorption.

Abstract Collagenous sprue is a distinctive lesion of the intestinal mucosa associated with progressive malabsorption. The intestinal pathology, as observed in a 51-year-old woman, was initially identical with the characteristic flat lesion of untreated celiac sprue. Thereafter, bands of eosinophilic hyaline material within the lamina propria became increasingly apparent. On electron microscopy this eosinophilic material was identified as collagen. As the disease progressed, the mucosa became progressively thinner. Nevertheless a few short segments of normal mucosa remained even at the time of death. Massive steatorrhea, water and electrolyte loss were the main problems. Corticosteroids reduced malabsorption somewhat but had deleterious side effects. All other therapy, including a gluten-free diet, failed. Extensive studies during life and careful post-mortem examination did not establish a known cause for collagenous sprue. Some cases currently designated refractory or unclassified sprue may prove ...