Celiac disease (gluten-sensitive enteropathy).

Celiac disease may be initially detected in either children or adults, even in the elderly. This small intestinal mucosal disorder is gluten-dependent and causes nutrient malabsorption, often with diarrhea and weight loss. Diagnosis depends on detection of typical biopsy changes in the proximal small bowel along with an unequivocal response to a gluten-free diet. Recurrent changes usually result from poor adherence to the gluten-free diet, sometimes intentional, or from consumption of unsuspected gluten sources. In others, the original diagnosis may not be correct (e.g., duodenal involvement with Crohn's disease) or another cause for symptoms may have supervened (e.g., collagenous colitis, functional bowel disease). Rarely, a complication may occur (e.g., collagenous sprue, lymphoma). In some, the gluten-dependent nature of the small bowel disorder was not initially documented and biopsy changes continued despite a gluten-free diet. These have a sprue-like intestinal disorder, also labeled unclassified sprue. This represents a small, but likely, heterogeneous group, and in these, intractable symptoms may be present and, in some, lymphoma is eventually diagnosed.

Relevance of segmental colitis with diverticulosis (SCAD) to other forms of inflammatory bowel disease.

A well localized inflammatory process involving only the sigmoid colonic segment associated with diverticulosis (SCAD), has become increasingly recognized as a distinct clinical and pathological disorder, usually described in older adults, often with rectal bleeding. Although some resolve spontaneously, most patients appear to respond to treatment only with 5-aminosalicylate. Endoscopic evaluation reveals a nonspecific inflammatory process localized in the sigmoid colon that usually completely resolves with histologically normal colonic mucosa. Recurrent symptoms with evidence of recurrent segmental colitis may occur, but most have an entirely benign clinical course. Further definition of the underlying molecular signalling that occurs in this apparently distinctive disorder may be critically important to understand the elements of a colonic inflammatory process that can completely and spontaneously resolve.

Pearls and pitfalls in the diagnosis of adult celiac disease.

In adults with diarrhea or suspected malabsorption, a diagnosis of celiac disease requires that two criteria be fulfilled: first, a demonstration of typical pathological changes of untreated disease in biopsies from the proximal small bowel; and second, evidence should exist that clinical (and/or pathological) changes are gluten-dependent, most often as an unequivocal response to a gluten-free diet. Pathological abnormalities of celiac disease may include severe ('flat') or variably severe (mild or moderate) small bowel mucosal architectural abnormalities that are associated with both epithelial cell and lymphoid cell changes, including intraepithelial lymphocytosis. Architectural changes tend to be most severe in the duodenum and proximal jejunum and less severe, or absent, in the ileum. These findings, while characteristic of celiac disease, are not specific because several other conditions can produce similar changes. Some serological assays (eg, tissue transglutaminase antibody assays) are very useful screening tools in clinical practice because of their high specificity and sensitivity, but these do not provide a definitive diagnosis. The most critical step in the diagnosis of celiac disease is the demonstration of its gluten-dependent nature. The clinical response to gluten restriction in celiac disease is usually reflected in the resolution of diarrhea and weight gain. Normalization of biopsy changes can be first shown in the most distal intestinal sites of involvement, and later, sometimes only after prolonged periods (months to years) in the duodenum. Rarely, recurrent (or refractory) celiac disease may occur after an initial gluten-free diet response. Finally, some with 'sprue-like intestinal disease' cannot be classified because a diet response fails to occur. This may be a heterogeneous group, although some are eventually found to have a malignant lymphoma.

Intestinal assimilation of a proline-containing tetrapeptide. Role of a brush border membrane postproline dipeptidyl aminopeptidase IV.

The mechanism of hydrolysis and absorption of a proline-containing tetrapeptide, Leu-Pro-Gly-Gly (10 mM) by rat intestine was examined in vivo by using jejunal perfusion methods. The peptide substrate and hydrolysis products were analyzed by use of an automated amino acid analyzer. Leucine, proline, and glycine were absorbed by the intestine at a significantly higher rate from the tetrapeptide than from an equivalent amino acid mixture. The analysis of the hydrolytic products in the lumen during in vivo perfusion of the tetrapeptide showed that two dipeptides, Leu-Pro and Gly-Gly, were the major products. These two dipeptides were also the major hydrolytic products when a purified rat intestinal brush border membrane preparation was incubated with Leu-Pro-Gly-Gly. The rate of hydrolysis of the tetrapeptide was much higher than that for several other proline-containing peptides (Leu-Pro, Pro-Leu, and Pro-Gly-Gly) that were tested. Studies using Gly-Pro-beta-naphthylamide, a specific substrate for postproline dipeptidyl aminopeptidase IV, showed that this enzyme is mainly localized to the brush border membrane and is responsible for the hydrolysis of the tetrapeptide into the two dipeptides Leu-Pro and Gly-Gly. Thus, brush border membrane dipeptidyl aminopeptidase IV very likely plays an important role at the intestinal mucosal cell surface in the final stages of digestion of proline-containing peptides.

Effects of differing purified cellulose, pectin, and hemicellulose fiber diets on fecal enzymes in 1,2-dimethylhydrazine-induced rat colon carcinogenesis.

The fecal microflora enzymes, beta-glucuronidase and beta-glucosidase, as well as fecal bacterial counts, were examined during colon carcinogenesis in rats administered parenteral 1,2-dimethylhydrazine and fed nutritionally equivalent diets free of fiber or containing one of three single sources of dietary fiber (cellulose, hemicellulose, and pectin). Whereas pectin-fed animals had increased fecal beta-glucuronidase activities, those fed cellulose and hemicellulose, two fibers protective in dimethylhydrazine colon neoplasia, had decreased activities. Although fecal bacterial counts were not significantly changed, similar differential changes in fecal beta-glucosidase activity were noted: cellulose but not pectin or hemicellulose feeding was associated with reduced activity. Although cellulose fiber may cause differing physiological effects resulting in a reduction in colonic neoplasia development in this experimental animal model, decreased bacterial metabolic enzyme activation of carcinogens or cocarcinogens may lead to diminished exposure of colonic cells to exogenous or endogenous mutagens.

Use of unscheduled DNA synthesis in freshly isolated human intestinal mucosal cells for carcinogen detection.

Mucosal cells freshly isolated from human intestine with pronase retain the capacity to undergo DNA repair synthesis (unscheduled DNA synthesis) during a 2-hr exposure to the carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine, and the procarcinogen, aflatoxin B1. This procedure combining the use of human intestinal mucosal cells and the measurement of unscheduled DNA synthesis may provide a highly relevant and convenient test system for the detection of cell-specific, direct-acting, and activation-dependent chemical carcinogens. The use of whole-cell preparations in such in vitro studies may be of additional significance in view of growing evidence for artefactual metabolism by subcellular fractions.

Differential effects of surgical suture materials in 1,2-dimethylhydrazine-induced rat intestinal neoplasia.

The incidence, distribution, size, and histopathology of rat small and large bowel tumors induced by sequential administration of 1,2-dimethylhydrazine followed by cecal placement of one of six differing types of suture materials were systematically examined. In addition, measurements of beta-glucuronidase activities in large bowel contents followed by fecal trace metal determinations were done. The results indicate that specific slowly absorbed and nonabsorbable suture materials in the absence of a surgical anastomosis promote tumor induction locally in the rat cecum. In addition, cecal suture material composed of multifilament stainless steel wire enhanced tumor development at a "downstream" site in the distal colon, paralleling increased fecal beta-glucuronidase activities at this site and implicating a possible luminally mediated mechanism for colon tumor development in this animal model.

A double-blind study on the effect of purified cellulose dietary fiber on 1,2-dimethylhydrazine-induced rat colonic neoplasia.

The incidence, distribution, size, and histopathology of grossly visible colonic tumors induced by parenteral administration of 1,2-dimethylhydrazine were examined in rats fed either a chemically defined fiber-free diet or a nutritionally and calorically equivalent diet containing a purified fiber component, microcrystalline cellulose. This double-blind study indicates that cellulose ingestion was associated with reduced numbers of animals involved with colonic neoplasia as well as a reduction in the total numbers of colonic tumors. Furthermore, this protective effect of cellulose appears to be time dependent and associated with a shift in tumor distribution from the proximal colon to a more distal site. Cellulose fiber had no apparent effect on colonic tumor size, histopathology, or the incidence of other tumors known to occur in this experimental animal model. This study strongly supports the hypothesis that fiber is an important protective agent against colonic neoplasia development. While the mechanism for this protective effect remains obscure, it appears to be temporally related to the duration of fiber ingestion as well as to a differential fiber effect on either the luminal content or the mucosa of the proximal and distal colon.

A double-blind study on the effects of differing purified cellulose and pectin fiber diets on 1,2-dimethylhydrazine-induced rat colonic neoplasia.

The incidence, distribution, size, and histopathology of colonic tumors induced by parenteral administration of 1,2-dimethylhydrazine were examined in rats fed a chemically defined fiber-free diet or nutritionally and calorically equivalent diets containing either 4.5 or 9.0% purified cellulose or pectin. This double-blind study indicates that cellulose is protective against experimental colonic neoplasia. Although the precise mechanism for this protective effect remains to be elucidated, it was not cellulose dose dependent and appeared to depend on administration during injection of carcinogen. Furthermore, this study provides strong evidence that identical amounts of cellulose and pectin fed as the sole source of fiber in chemically defined diets exert strikingly different effects in relation to development of intestinal neoplasia in this animal model.

beta-Hexosaminidase isoenzymes in tissues, cultured cells, and media from human fetal intestine and colonic adenocarcinoma.

Isoelectric focusing of tissue homogenates revealed a predominance of beta-hexosaminidase B in colonic adenocarcinoma, whereas beta-hexosaminidase A was greater in paired normal-appearing colonic mucosa from the same patients as well as in a specimen of human fetal colonic mucosa. Because of the recognized cellular heterogeneity of these tissues, our studies were extended to an examination of these isoenzymes in 20 cultured epithelial cell lines derived from human fetal intestine and colonic carcinoma as well as the secreted enzymes in their culture media. While the B:A isoenzyme ratio was higher in human cancer cells as compared to fetal cells, some of the cancer cell lines had a greater proportion of the A isoenzyme. Examination of the isoenzyme profiles in the media of these cells revealed a greater B:A ratio whether of fetal or cancer cell origin. These studies parallel the apparent biological differences of neoplastic colonic epithelium occurring in vivo and are reminiscent of reported oncodevelopmental changes in enzymatic properties present in some malignant tissues. The differential stabilities of these two isoenzymes derived from the culture media of both types of cell lines in vitro may limit their value as markers of human colonic neoplasia.

Recent advances in dietary fiber and colorectal diseases.

Dietary fiber has emerged in the past decade as a factor in nutrition that appears to have complex physiological and clinical implications. A great deal of research has focused on its effect on colorectal diseases. Some human epidemiological studies on colon cancer point to a possible preventive role of dietary fiber, but the results are confounded by the difference in the intake of many other food substances such as fat and the overall differences in the dietary pattern of the populations investigated. Animal studies using chemical carcinogens, such as 1,2-dimethylhydrazine, have lent support to a protective role of certain components of fiber, such as purified cellulose. Other fiber polymers, such as pectin, have not shown any protective effect. Perhaps the strongest evidence for a protective role of fiber in the colon comes from studies relating low dietary fiber intake to the higher incidence of diverticular disease of the colon; addition of dietary fiber to the diet of patients with symptomatic diverticular disease seems to relieve pain effectively. Recently, some preliminary studies have shown the possible correlation of low dietary fiber intake with a greater incidence of ulcerative colitis and Crohn's disease, but these studies are too limited in number and scope to allow any conclusion to be reached at this time.

Protein digestion and absorption in man. Normal mechanisms and protein-energy malnutrition.

Protein is an essential nutrient normally assimilated in an efficient manner following the action of gastric, pancreatic and small intestinal enzymes. After hydrolysis, protein digestion products in the form of amino acids and small peptides undergo mucosal uptake by distinct transport mechanisms. Although gastric and pancreatic enzymes are important, the small intestine appears to be the critical rate-limiting tissue in this process. Impaired intake, assimilation or excessive enteric protein loss may occur with several diseases leading to protein-energy malnutrition. Although the clinical and laboratory features of this condition are nonspecific and wide ranging in spectrum, their presence may provide a clue to underlying disease and serve as an index of patient nutritional status. Disease of the exocrine pancreas or small intestine may cause significant protein-energy malnutrition which, in turn, can cause major structural and functional abnormalities in these tissues.

Lectin histochemistry of 1,2-dimethylhydrazine-induced rat colon neoplasia.

Lectins linked to fluorescein were used as carbohydrate probes to examine the goblet cell mucin and epithelial cell surface glycoconjugate alterations in an experimental rodent model of colonic neoplasia induced with parenteral 1,2-dimethylhydrazine dihydrochloride. Lectins derived from Triticum vulgare (WGA), Ricinus communis (RCA1), and Limulus polyphemus (LPA) showed reduced labeling of goblet cell mucin in these tumors, while binding with peanut lectin from Arachis hypogaea (PNA), a lectin ordinarily failing to bind to mucin in normal colon, was positive. In addition, RCA1 and LPA showed increased cell surface labeling of neoplastic epithelial cells. Finally, alterations were observed in lectin binding to "transitional" colonic mucosa adjacent to colonic tumors from carcinogen-treated rats. These findings indicate that significant alterations in both membrane and mucin glycoconjugates occur in colonic tumors and mucosa adjacent to tumors in a chemically induced experimental animal model of human colon cancer.

Epidemiology and clinical features associated with Blastocystis hominis infection.

A retrospective chart review was performed on 100 patients infected with Blastocystis hominis (Bh) and 50 randomly selected age and sex matched controls to examine the clinical and epidemiologic features associated with this organism. The finding of greater than 5 Bh per oil immersion field (1,000 X) was significantly associated with acute presentation of symptoms but was not predictive of the presence of gastrointestinal symptoms. Of patients infected with Bh, 57.5% had recently travelled to the tropics or had consumed untreated water as compared to 12.2% of controls (p less than 0.001). Forty Bh-positive patients were assessed on more than one occasion. No significant differences appeared to exist in the clinical responses of those treated with Metronidazole (14/18; 77.8%) or with dietary management (6/6; 100%) as compared with those not receiving treatment (13/16:81.2%). Patients tended to become less symptomatic with time and in the absence of specific treatment, and therefore treatment with Metronidazole may not be warranted in light of the natural history of Bh infection.

Small intestinal mucosal biopsy for investigation of diarrhea and malabsorption in adults.

The use of small intestinal biopsy for diagnosis in diarrhea and suspected malabsorption depends on an optimal interaction between the clinician-endoscopist and the pathologist. This necessitates open and interactive communication between involved physicians and an appreciation for correct tissue handling and biopsy orientation in the endoscopy unit and the pathology laboratory. Classification of biopsy changes on the basis of architectural abnormalities in the small intestinal biopsy may be helpful in defining the diagnosis and include severe (flat) or variably severe (mild or moderate) abnormalities. For some small intestinal disorders that are characterized by diarrhea or malabsorption, the biopsy findings may be distinctive and lead to a specific diagnosis. For others, like celiac disease, the changes are less specific, and it has become better recognized that an increasing number of conditions can produce similar histopathologic changes. Definition of typical gluten-sensitive biopsy changes in this disorder is critical.

Postural hypotension and labile blood pressure associated with severe hypophosphatemia.

We present a patient with postural hypotension and labile blood pressure due to severe hypophosphatemia. There was no evidence for other causes of postural hypotension in our patient. The blood pressure abnormalities responded to phosphate replacement.

Perinuclear antineutrophil cytoplasmic antibodies in collagenous or lymphocytic colitis with or without celiac disease.

Microscopic forms of colitis, including lymphocytic and collagenous colitis, have been observed in both those with and without celiac disease. Although perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) occur in most patients with ulcerative colitis, investigations in microscopic, particularly lymphocytic, colitis are still needed. In this study atypical p-ANCA was evaluated in 55 patients, including 27 with celiac disease alone, 13 with celiac disease and concomitant lymphocytic colitis, and 15 with microscopic forms of colitis, including lymphocytic and collagenous colitis. Nine patients (16.3%) had atypical p-ANCA, including six with celiac disease and three with a microscopic form of colitis alone. Although five of the six positive celiac disease patients had lymphocytic colitis, all three celiac disease patients with associated primary sclerosing cholangitis--a separate risk factor for a positive assay result--were serologically positive for atypical p-ANCA. These results indicate for the first time that this serological marker may occur in histologically defined celiac disease with or without concomitant lymphocytic colitis. Furthermore, these results suggest that the pathogenesis of ulcerative colitis differs from that of lymphocytic colitis and further emphasizes the heterogeneous nature of these newly recognized types of colonic inflammatory mucosal disorders.

Inflammatory bowel diseases in Indo-Canadians with and without antineutrophil cytoplasmic autoantibodies.

A sequentially evaluated cohort of Indo-Canadians with either ulcerative colitis or Crohn's disease were prospectively examined for antineutrophil cytoplasmic autoantibodies (ANCA). Of 84 patients, 62 had ulcerative colitis and 22 had Crohn's disease. About one-third were born in Canada, and two-thirds were migrants from India or other countries, particularly East African nations. There was a disease-based and geographically based male predominance. The mean age of Canadian-born patients was significantly less than that of those born in other countries. Moreover, for migrants, the mean duration of residence in Canada before developing disease was 8.9 years for Crohn's disease patients and 13.5 years for ulcerative colitis patients. Moderate to severe disease was present; virtually all those with Crohn's disease had colonic involvement, and most of those with ulcerative colitis had extensive colonic disease. Overall, 40 of 84 (48%) were seropositive for ANCA, including a majority of those with ulcerative colitis but not Crohn's disease. In addition, eight had cytoplasmic ANCA, a reported seromarker for extensive colitis. Seropositive and seronegative patients were similar in age, sex, birth or duration of residence in Canada, site and severity of disease, familial history and complications, including pouchitis. This study supports the view that these diseases arise in individuals with a genetic predisposition following exposure to some, as yet unknown, environmental factor.

T cell lymphoma of the thyroid gland in celiac disease.

Previous studies have reported the association between celiac disease and T cell lymphoma of the intestine as well as hepatosplenic lymphoma, a specialized peripheral type of T cell lymphoma. In this report, a 66-year-old woman with dermatitis herpetiformis and biopsy-defined celiac disease developed a thyroid mass that proved to be a T cell lymphoma. A T cell lymphoma in the setting of celiac disease appears to be unique. The thyroid gland, due to its shared embryological developmental links with the gastrointestinal tract, is possibly another site of extranodal lymphoma linked to celiac disease.