High prevalence of celiac sprue-like HLA-DQ genes and enteropathy in patients with the microscopic colitis syndrome

OBJECTIVE: Celiac sprue is associated with specific HLA-DQ genes (mainly DQ2). Because there are epidemiological and histopathological similarities between celiac sprue and microscopic colitis, we hypothesized that these syndrome may share an HLA genetic predisposition and pathogenesis. METHODS: The HLA-DQ genes of 25 patients with celiac sprue, 53 patients with the microscopic colitis syndrome, and 429 normal controls were typed and compared. Serum was analyzed for antigliadin and antiendomysial antibodies. Small intestinal biopsies were analyzed for signs of histopathology. RESULTS: HLA-DQ2 or DQ1,3 (the latter as DQ1,7,DQ1,8, or DQ1,9) were seen more frequently in both patient groups relative to controls. In patients with the microscopic colitis syndrome, serological tests for celiac sprue were weakly positive in 17%; mild inflammation of the small intestine without villous atrophy was present in 43%, and inflammation plus partial or subtotal villous atrophy was present in 27%. CONCLUSIONS: A shared set of predisposing HLA-DQ genes account for the epidemiological overlap of celiac sprue and microscopic colitis. Mild to moderate mononuclear cell inflammation of the small intestine, often accompanied by partial or subtotal villous atrophy, is frequent in patients with the microscopic colitis syndrome. Although further studies will be necessary to determine if this enteropathy is induced by dietary gluten, we speculate that the small intestinal but not colonic histopathology in patients with microscopic colitis is caused by immunological gluten sensitivity.     

The prevalence and causes of chronic diarrhea in patients with celiac sprue treated with a gluten-free diet

BACKGROUND & AIMS: The majority of patients with celiac sprue experience diarrhea before diagnosis. There have been no studies of the prevalence or causes of chronic diarrhea in these patients after treatment with a gluten-free diet. METHODS: Seventy-eight patients with celiac sprue (59 women and 19 men) treated with a gluten-free diet for at least 12 months were surveyed about their bowel habits. Those with chronic diarrhea, defined as passage of loose stools three or more times per week for 6 months, underwent an extensive diagnostic evaluation to determine its cause. RESULTS: Sixty-two of the 78 patients (79%) experienced diarrhea before treatment, and 13 (17%) had chronic diarrhea (of lesser severity) after treatment. The causes of diarrhea in 11 patients consenting to this study were microscopic colitis, steatorrhea secondary to exocrine pancreatic insufficiency, dietary lactose or fructose malabsorption, anal sphincter dysfunction causing fecal incontinence, and the irritable bowel syndrome. Only 1 patient had antigliadin antibodies detected in serum or small intestinal villous atrophy. CONCLUSIONS: After treatment of celiac sprue with a gluten-free diet, chronic diarrhea persists in a substantial percentage of patients. Although ongoing gluten ingestion is one possible cause, other causes may be more frequent. Therefore, diagnostic investigation of diarrhea in celiac sprue after treatment seems warranted. (Gastroenterology 1997 Jun;112(6):1830-8)     

Approaching the patient with chronic malabsorption syndrome.

The causes of chronic malabsorption may be categorized as decreased intestinal absorption, most commonly caused by celiac sprue; or maldigestion caused by pancreatic insufficiency. The initial step in the evaluation of these patients should include stool studies to confirm fat malabsorption. If fat malabsorption is confirmed, endoscopy with small-bowel biopsies and aspirates for bacterial culture usually follows. A normal endoscopic examination should lead to assessment of pancreatic function. In the setting of normal pancreatic function and the absence of bile acid deficiency, a barium radiograph of the small bowel should be made, looking for anatomical abnormalities. Celiac sprue is an intolerance to gluten caused by a combination of genetic, environmental, and immunologic factors. It classically causes malabsorption. However, it is likely that many patients who exhibit only minor manifestations of the disease go unrecognized and untreated. A presumed diagnosis of celiac sprue is confirmed after a clinical and endoscopic response to a gluten-free diet. Serological markers are available with high degrees of sensitivity and specificity, but duodenal biopsy remains the gold standard for diagnosis. A minority of patients are unresponsive to a gluten-free diet, and intestinal lymphoma should be suspected in these cases.     

Celiac disease--a severe disease

Celiac disease (Celiacal sprue = gluten-sensitive enteropathy = netropic sprue) is the all-life genetically determined autoimmune disease with permanent intolerance to gluten, which damages the intestinal mucous membrane and alterates the immune system. The atrophy and typical inflammatory changes of mucous membrane results in malabsorption with diarrhea, general weakness, anemia and weight loss. The clinical picture of celiac disease is considerably heterologous. Only 20-30% of patients suffer from active-classical form of the disease. Non-diagnosed, inactive forms of the disease form 70-80% of cases of celiac disease in adult individuals. The therapy is based on diet without gluten. Application of the diet usually results in clinical improvement and signs of the disease are diminished. The relapse of celiac disease occurs after a gluten load. Celiac disease and dermatitis Duhring are considered to be two equal forms how gluten enteropathy becomes manifest. Celiac disease is often associated with other autoimmune diseases (e.g. insulin-dependent diabetes mellitus, autoimmune thyreoiditis). Untreated celiac disease still represents a serious medical risk, since it is an important precancerosis. Introduction of highly sensitive methods for the determination of antibodies against endomysium and tissue transglutaminase significantly extended possibilities of diagnosis and screening for celiac disease. It became obvious that the real incidence of celiac disease including the non-diagnosed forms of the disease in the European population is greater than 1:200 to 1:250.     

Celiac sprue

Celiac sprue, celiac disease, or gluten-sensitive enteropathy, is a malabsorption disorder of the small intestine that occurs after ingestion of wheat gluten in genetically susceptible individuals. This disease is characterized by intestinal malabsorption associated with villous atrophy of the small intestinal mucosa, clinical and histological improvement after adherence to strict gluten free diet, and relapse when gluten is reintroduced. Celiac sprue has a high prevalence in Western Europe and North America where it is estimated to affect 1:120 to 1:300 individuals. The pathogenesis of celiac sprue is related to inappropriate intestinal T-cell activation in HLA-DQ2 positive individuals triggered by antigenic peptides from wheat gluten or prolamins from barley and rye. Although previously thought to be mainly a disease of childhood onset, the diagnosis is increasingly being made in adults. There are a wide variety of presentations, which range from asymptomatic forms to severe diarrhea, weight loss and nutritional deficiencies. Extraintestinal manifestations including anemia, osteopenia or neurological disorders and associated conditions such as diabetes or hypothyroidism are commonly present. The availability of highly sensitive and specific serologic markers has dramatically facilitated the diagnosis of celiac sprue. However, the demonstration of characteristic histological abnormalities in a biopsy specimen of the small intestine remains the mainstay of diagnosis. Treatment consists of life-long avoidance of dietary gluten to control symptoms and to prevent both immediate and long-term complications.     

Maladie cœliaque

Celiac disease is an enteropathy due to gluten intake in genetically predisposed individuals (HLA DQ2/DQ8). Celiac disease occurs in adults and children at rates approaching 1% of population in Europe and USA. Clinical features observed in celiac disease are extremely various and anaemia, oral aphthous stomatis, amenorrhea or articular symptoms may be the only presenting manifestations. Diagnosis relies on the evidence of histological villous atrophy in proximal small bowel and the presence of specific serum antibodies. Treatment relies on eviction of gluten (wheat, barley, rye) from diet. Gluten free diet allows prevention of malignant complications such as small bowel adenocarcinoma and lymphoma, and osteopenia. The main cause of resistance to gluten free diet is its poor observance. If not the case, serious complications of celiac disease, such as clonal refractory celiac sprue and intestinal T-cell lymphoma should be suspected. Current therapeutic challenges concern alternative to gluten free diet and new efficient treatments of lymphomatous complications.     

Collagenous colitis and small intestinal villous atrophy: manifestations of the same disorder?

We describe the case of a 64-year-old woman with a previous diagnosis of celiac sprue and no clinical or histological response to gluten withdrawal. The patient presented a history of longstanding recurrent watery diarrhea and was found to have collagenous colitis after further investigation of her diarrhea. Immunological study was incompatible with celiac disease and no other cause of villous atrophy was found. We suggest that this patient may have a separate disease entity unrelated to celiac sprue and consisting of a pan-intestinal inflammatory disorder characterized by the combination of a chronic inflammatory infiltrate in the small and lower bowel together with a subepithelial collagenous band in the colon.     

Celiac disease and irritable bowel-type symptoms

OBJECTIVES: Previous reports have linked irritable bowel syndrome (IBS) etiologically with various forms of mucosal inflammation, including infectious enterocolitides and inflammatory bowel disease. The mechanism is uncertain but may involve sensitization by inflammatory mediators. The enteropathy of celiac disease has theoretical advantages as a study model because it can be controlled with dietary gluten exclusion; however, whether it also predisposes to functional bowel disorders is unclear. Therefore, we assessed the prevalence of IBS-type symptoms in adult celiac patients and correlated this with dietary compliance with gluten exclusion. METHODS: Adult patients (n = 150; 106 women and 44 men) with confirmed celiac disease were randomly selected from a computerized database of >350 patients, and were asked to complete a bowel questionnaire and the Short Form 36 Health Survey (SF-36). The control group (n = 162; 133 women and 29 men) had no history of celiac disease and had similar mean age and sex profile. RESULTS: Of 150 celiac patients reviewed, 30 of 150 (20%) fulfilled the Rome criteria compared with eight of 162 (5%) ontrols. Of the celiac patients 10 of 46 (22%) had partial or no compliance with a gluten-free diet, whereas 20 of 104 patients (19%) adhered to the diet; this difference did not achieve statistical significance. Celiac patients with IBS-type symptoms had a markedly lower quality of life than those without, all eight domains being impaired to a clinically significant extent. Dietary gluten exclusion improved QOL in four of eight scales measured. CONCLUSIONS: The hypothesis that mucosal inflammation in celiac disease may have a sensitizing effect or may predispose to IBS-type symptoms is supported by these results. Failure to attain optimal subjective well-being is common in celiac patients, particularly in those with coexisting IBS. Compliance with a gluten-free diet confers some benefit.     

Treatment and management of celiac disease

In most patients the clinical course of celiac disease is unproblematic after the diagnosis has been made and a strict gluten-free diet is established. However, in rare cases complications like refractory sprue or lymphoma can occur. Individual management is required since the clinical presentation of celiac disease can be very heterogeneous. For example, it is a matter of controversy if asymptomatic patients, who have the same typical histological changes in their small bowel like patients with symptomatic celiac disease, should adhere to a gluten-free diet. A major problem is the compliance and the unintentional intake of gluten. A 100 % gluten-free diet is not possible since most food components are contaminated with trace amounts of gluten. Fortunately most patients tolerate these contaminations. Furthermore, the threshold for gluten contamination can differ highly among patients. One central point in patient care is the monitoring of a gluten-free diet and the timely recognition of complications. Therefore, the role of antibodies and duodenal histology in monitoring the course of the disease will be discussed.     

Refractory celiac disease and sprue-like intestinal disease

Celiac disease is a gluten-dependent small intestinal mucosal disorder that causes malabsorption, often with diarrhea and weight loss. Diagnosis is based on detection of typical biopsy changes in the proximal small bowel, followed by evidence for an unequivocal response to a gluten-free diet. Refractoriness in celiac disease may be due to poor diet compliance, sometimes intentional, or consumption of ubiquitious sources of gluten. Alternatively, the original diagnosis may not be correct （eg., duodenal Crohn＇s disease）, or a second cause for symptoms may be present （eg., collagenous colitis, functional bowel disorder）. In some with recurrent symptoms, a complication may be present （eg., collagenous sprue, small bowel carcinoma, lymphoma）. In some, a response to a gluten-free diet can not be unequivocally defined, and more precise historical terms have been used including ＂sprue-like intestinal disease＂ or ＂unclassified sprue＂. Although a ＂wastebasket diagnosis＂, these likely represent a heterogeneous group, and some, but not all, may develop lymphoma. Precise definition will be critical in the future as an array of new treatments, including biological agents, may emerge.     

Gluten Sensitivity in Patients With Primary Biliary Cirrhosis

Objective : Whereas celiac disease and primary biliary cirrhosis have been reported to coexist in the same patient, the frequency of this relationship has not been clarified. Nowadays, the concept of celiac disease has been extended from that of a severe enteropathy to a broader concept of gluten-driven intestinal immunological response. In this study we assessed features of gluten sensitivity in a cohort of patients with primary biliary cirrhosis. Methods : Ten patients with primary biliary cirrhosis were evaluated a mean of 2 yr after diagnosis. The following features of gluten sensitivity were assessed: serum antigliadin and endomysial antibodies, small bowel histology (degree of atrophy and quantitative histological parameters), the presence of the typical celiac HLA genotype (DQ2), and intraepithelial lymphocyte response in the rectal mucosa after local gluten instillation (rectal gluten challenge). Results : Overall, three patients presented evidence of gluten sensitivity. AH three had abnormal liters of antigliadin antibody type IgA and one was positive for endomysial antibody. Two patients had partial villous atrophy. The rectal gluten challenge showed a celiac-like response, evidenced by an increase in intraepithelial lymphocyte infiltration after gluten exposure, in the three patients. The characteristic celiac HLA genotypes (DQA1 0501 and DQB1 0201) were identified in three patients. One of them also exhibited other features of gluten sensitivity. However, despite evidence of gluten intolerance, patients had minimal or no symptoms characteristic of celiac disease. Conclusion : We detected features of gluten sensitivity in a high proportion of patients with primary biliary cirrhosis. Further studies should be performed to elucidate the clinical significance of this association.     

Association of Gluten Enteropathy and Irritable Bowel Syndrome in Adult Turkish Population

PURPOSE: Irritable bowel syndrome is generally diagnosed according to the symptoms of the patient, and gluten enteropathy can also be presented with similar symptoms (diarrhea and/or constipation) of irritable bowel syndrome. Aimed to assess the association and the frequency of gluten enteropathy in a group of Turkish patients diagnosed as irritable bowel syndrome. RESULTS: Found anti-gliadin IgA positivity only in four patients among patients with irritable bowel syndrome. However, none of these four patients had anti-endomycium positivity or any histopathological findings specific for gluten enteropathy. All these four patients had normal histology in their small bowel biopsies. CONCLUSION: Irritable bowel syndrome is a common problem in the population, but gluten enteropathy is not associated with the vast majority of subjects with irritable bowel syndrome as expected. The need for screening gluten enteropathy among these patients is still unclear, and screening with serology only without small bowel biopsy may lead to false positive results.     

Seroreactivity against Saccharomyces cerevisiae in patients with Crohn′s disease and celiac disease

AIM:To explore whether there was anti-Saccharomyces cerevisiae antibodies (ASCA) positivity in our patients with biopsy-confirmed celiac disease.METHODS: A cohort of patients with inflammatory bowel diseases (42 patients with Crohn's disease and 10 patients with ulcerative colitis) and gluten sensitive enteropathy (16patients) from Debrecen, Hungary were enrolled in the study.The diagnosis was made using the formally accepted criteria.Perinuclear antineutrophil cytoplasmic antibodies (pANCA)and antiS-accharomyces cerevisiae antibodies (ASCA),antiendornysium antibodies (EMA), antigliadin antibodies (AGA) and anti human tissue transglutaminase antibodies (tTGA) were investigated.RESULTS: The results showed that ASCA positivity occurred not only in Crohn's disease but also in Celiac disease and in these cases both the IgG and IgA type antibodies were proved.CONCLUSION: It is conceivable that ASCA positivity correlates with the (auto-) immune inflammation of small intestines and it is a specific marker of Crohn's disease.     

Seroreactivity against Saccharomyces cerevisiae in patients with Crohn＇s disease and celiac disease

AIM: To explore whether there was anti-Saccharomyces cerevisiae antibodies (ASCA) positivity in our patients with biopsy-confirmed celiac disease. METHODS: A cohort of patients with inflammatory bowel diseases (42 patients with Crohn‘‘s disease and 10 patients with ulcerative colitis) and gluten sensitive enteropathy (16 patients) from Debrecen, Hungary were enrolled in the study.The diagnosis was made using the formally accepted criteria.Perinuclear antineutrophil cytoplasmic antibodies (pANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA),antiendomysium antibodies (EMA), antigliadin antibodies(AGA) and anti human tissue transglutaminase antibodies(tTGA) were investigated.RESULTS: The results showed that ASCA positivity occurred not only in Crohn‘‘s disease but also in Celiac disease and in these cases both the IgG and IgA type antibodies were proved.CONCLUSION: It is conceivable that ASCA positivity correlates with the (auto-) immune inflammation of small intestines and it is a specific marker of Crohn‘‘s disease.     

Celiac Sprue Among US Military Veterans (Associated Disorders and Clinical Manifestations)

The present study aimed to describe the clinicalmanifestations of celiac sprue related to malnutritionand to analyze the associations between celiac sprue andother diagnoses. A case-control study compared the occurrence of comorbid diagnoses in caseand control subjects with and without celiac sprue,respectively. All patients with a primary or secondarydiagnosis of celiac sprue (ICD-579.0) who weredischarged from hospitals of the Department of VeteransAffairs between 1986 and 1995 were selected as casesubjects. In a multivariate logistic regressionanalysis, the occurrence of celiac disease served asoutcome variable, while age, gender, ethnicity, and thecomorbid occurrences of other diagnoses served aspredictor variables. A total of 458 individual patientswith celiac sprue were identified. The data confirmed the known associations of celiac sprue withdermatitis herpetiformis, lactase deficiency,enlargement of lymph nodes, and lymphoma. Celiac spruewas also found to be statistically significantlyassociated with pancreatic insufficiency, Crohn's disease,functional bowel symptoms, chronic nonalcoholichepatitis, and pulmonary eosinophilia. The nutritionalmanifestations associated with celiac disease included nutritional marasmus, cachexia, weight loss,hypocalcemia, osteoporosis, vitamin B-complexdeficiency, and various types of iron- andvitamin-deficiency anemias. The large variety of complexassociations clearly indicates that celiac sprue is asystemic disease that involves multiple organs andexceeds an isolated nutritional intolerance togluten.     

Guía clínica para diagnóstico y tratamiento de la enfermedad celíaca en México

Celiac disease, celiac sprue, or gluten-sensitive enteropathy, is a generalized autoimmune disease characterized by chronic inflammation and atrophy of the small bowel mucosa. It is caused by dietary exposure to gluten and affects genetically predisposed individuals. In Mexico, at least 800,000 are estimated to possibly have the disease, prompting the Asociación Mexicana de Gastroenterología to summon a multidisciplinary group of experts to develop the “Clinical guidelines on the diagnosis and treatment of celiac disease in Mexico” and establish recommendations for the medical community, its patients, and the general population. The participating medical professionals were divided into three working groups and were given the selected bibliographic material by the coordinators (ART, LUD, JMRT), who proposed the statements that were discussed and voted upon in three sessions: two voting rounds were carried out electronically and one at a face-to-face meeting. Thirty-nine statements were accepted, and once approved, were developed and revised by the coordinators, and their final version was approved by all the participants. It was emphasized in the document that epidemiology and risk factors associated with celiac disease (first-degree relatives, autoimmune diseases, high-risk populations) in Mexico are similar to those described in other parts of the world. Standards for diagnosing the disease and its appropriate treatment in the Mexican patient were established. The guidelines also highlighted the fact that a strict gluten-free diet is essential only in persons with confirmed celiac disease, and that the role of gluten is still a subject of debate in relation to nonceliac, gluten-sensitive patients.     

Clinical features and diagnosis of celiac disease

Celiac disease is a life-long enteropathy caused by an intolerance to gluten. The pathologic lesion of the small intestinal mucosa is characterized by the loss of absorptive villi, crypt cell hyperplasia, and infiltration of the lamina propria with inflammatory cells. The clinical presentation of celiac disease varies greatly depending on patient's age, duration and extent of the disease, and the presence of extraintestinal manifestations. The classical symptoms like diarrhea, weight loss and abdominal pain are seen less common. Unfortunately, most patients with celiac disease have either silent or atypical presentations, thus escaping diagnosis for several years. The pathologic changes and symptoms resolve when gluten is excluded from the diet for a sustained period. Untreated celiac disease is associated with significant risk of the development of enteropathy-associated intestinal lymphoma.     

Utility of a Rapid Fecal Latex Agglutination Test Detecting the Neutrophil Protein, Lactoferrin, for Diagnosing Inflammatory Causes of Chronic Diarrhea

Objective: The utility of tests for fecal neutrophils in the setting of chronic diarrhea has not been established. The purpose of this study was to determine the causes of chronic diarrhea associated with fecal neutrophils.
Methods: One fecal specimen from each of 10 normal subjects, 26 patients with known microscopic colitis, 13 with celiac sprue, eight with Crohn's disease, four with ulcerative colitis, and 103 with chronic diarrhea of unknown origin, as well as 10 fecal specimens from a patient with chronic nongranulomatous enterocolitis were analyzed blindly for the presence of a neutrophil granule protein called lactoferrin using a commercial latex agglutination kit. Diagnostic evaluation of the 103 patients with chronic diarrhea was carried out to determine the diagnostic accuracy of this test for chronic inflammatory bowel disease.
Results: None of the normal control subjects, three of 39 patients with microscopic colitis or celiac sprue, all 10 specimens from the patient with enterocolitis, and all 12 control patients with ulcerative colitis or Crohn's disease had a positive fecal lactoferrin test. Eleven of 103 patients with chronic diarrhea presenting without a diagnosis had a positive test, and all were diagnosed with an inflammatory condition of the colon (five-, ulcerative colitis; four-, Crohn's disease; one-, ischemic colitis; and one-, microscopic colitis). Only one patient with inflammatory bowel disease had a negative lactoferrin test. The sensitivity, specificity, and positive and negative predictive values of the fecal lactoferrin test for ulcerative or Crohn's colitis were 90%, 98%, 82%, and 99%, respectively.
Conclusion: The major cause of fecal neutrophils in patients with chronic diarrhea is chronic inflammatory bowel disease of the colon. The latex agglutination test for fecal lactoferrin offers a highly sensitive, specific, and simple means for detection of fecal neutrophils in these patients.     

Small bowel malignant lymphoma complicating celiac sprue and the mesenteric lymph node cavitation syndrome

Malignant small intestinal lymphoma may complicate or antedate clinical recognition of celiac sprue. However, histologic diagnosis of lymphoma is made especially difficult in the presence of small bowel ulceration. A 70-yr-old man with celiac sprue and a history of dermatitis herpetiformis was initially seen for recurrent diarrhea; panmalabsorption with steatorrhea and protein-losing enteropathy were documented. Subsequent studies showed ectopic gastric mucosa in the small bowel, hyposplenism with mesenteric lymph node cavitation, and small bowel erosions and ulceration. Despite strong clinical suspicion for more than 2 yr, only 1 of 88 small bowel biopsy specimens was positive for lymphoma. At autopsy, shortly after histologic diagnosis of lymphoma, extensive small bowel involvement and infiltration were observed. This is the first report of lymphoma complicating the recently described nonneoplastic lymphoreticular syndrome associated with celiac sprue characterized by splenic atrophy and mesenteric lymph node cavitation.     

Adenocarcinoma of the jejunum in association with celiac sprue

An increased incidence of small bowel lymphoma in patients with long-standing celiac sprue is well documented in the literature. Less common is the association of adenocarcinoma of the small intestine. We report a patient with celiac sprue who initially responded to a gluten-free diet. Eighteen months later, diarrhea, abdominal cramps, and bloating was found to have its origin in partial small bowel obstruction. At laparotomy, two distinct adenocarcinomas of the jejunum were resected. Celiac patients who initially respond to gluten withdrawal and subsequently suffer exacerbation while adhering to strict dietary therapy should be carefully evaluated for evidence of a small bowel malignancy.