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.     

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.     

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.     

Etiology of nonresponsive celiac disease: results of a systematic approach

OBJECTIVES: Nonresponse or relapse of symptoms is common in patients with celiac disease treated with gluten free diet. Refractory sprue (RS) is defined as initial or subsequent failure of a strict gluten-free diet to restore normal intestinal architecture and function in patients who have celiac-like enteropathy. The aims of this study were: 1) to identify causes of persistent symptoms in patients referred with presumed diagnosis of nonresponsive celiac disease (NCD); and 2) to characterize patients with true RS. METHODS: Patients were identified who had been systematically evaluated for NCD between January 1997, and May 2001. Patient records and small bowel biopsy results were reviewed. RESULTS: A total of 55 patients were referred with a presumed diagnosis of NCD. Six did not have celiac disease and had other diseases responsible for their symptoms. Diarrhea, abdominal pain, and weight loss were the most common reasons for evaluation in cases of NCD, whereas weight loss, steatorrhea, and diarrhea were the most common presenting features of RS (nine patients). Of the 49 patients with celiac disease, 25 were identified as having gluten contamination. Additional diagnoses accounting for persistent symptoms included: pancreatic insufficiency, irritable bowel syndrome, bacterial overgrowth, lymphocytic colitis, collagenous colitis, ulcerative jejunitis, T-cell lymphoma, pancreatic cancer, fructose intolerance, protein losing enteropathy, cavitating lymphadenopathy syndrome, and tropical sprue. CONCLUSIONS: Based on this study, we conclude the following: 1) gluten contamination is the leading reason for NCD; 2) of NCD cases, 18% are due to RS; and 3) alternative diseases or those coexistent with celiac disease and gluten contamination should be ruled out before a diagnosis of RS is made.     

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.     

Persistent diarrhea in the returning traveler: think beyond persistent infection

The report describes a young female United Nations worker, stationed in East Timor for an extended duration, who presented with persistent travelers' diarrhea and who was convinced that she was harboring a persistent infestation. In fact, careful history, laboratory evaluation and endoscopy with duodenal biopsies found all the classical hallmarks of unmasked celiac sprue. The patient then had a dramatic response to a gluten-free diet, with complete resolution of symptoms. Persistent travelers' diarrhea is an entity which carries an interesting and extensive differential diagnosis beyond persistent enteric infections or infestations. Rather, many sufferers have long been cleared of the initial offending pathogen and are left with either a post-infectious disorder of absorption, digestion, motility or visceral sensation or carry a chronic gastrointestinal disorder which has been unmasked by an enteric infection, such as idiopathic inflammatory bowel disease, gastrointestinal malignancy or celiac sprue. Other key issues raised by the case include the vanishing incidence of tropical sprue, an entity to which most clinicians would have mistakenly attributed this malabsorptive syndrome arising in a traveler, and the under-recognition of the protean manifestations of celiac sprue, to which we would add persistent travelers' diarrhea.     

Profile of chronic small-bowel diarrhea in adults in Western India: a hospital-based study.

BACKGROUND: Small-bowel diarrhea is reported to account for 10% of all cases of chronic diarrhea. Data on the etiology and clinical presentation of chronic small-bowel diarrhea in adult Indians is scarce. METHODS: 50 patients (mean age 32.8 years; 26 men) with chronic small bowel diarrhea were evaluated clinically, and investigated to determine etiology. The diagnosis of small-bowel diarrhea was based on history, stool volume and associated symptoms. RESULTS: Abdominal pain (n=22, 44%) and weight loss (n=37, 74%) were the most common symptoms, apart from diarrhea. Anemia (70%) and hypoalbuminemia (48%) were other important biochemical abnormalities. Intestinal tuberculosis (26%) and celiac disease (26%) were the most common causes of chronic small-bowel diarrhea. CONCLUSION: Tuberculosis of intestine and celiac disease are common causes of small-bowel diarrhea in our population. Tropical sprue seems to be a rare cause.     

Multifocal small bowel lymphoma and latent celiac sprue

Malignant small intestinal lymphoma may complicate or antedate clinical recognition of celiac sprue, a disorder becoming increasingly diagnosed as a subclinical or occult disease. A 73-yr-old woman with previously resected jejunoileal lymphoma and normal proximal small bowel biopsy specimens was given a high-gluten diet containing 40 g of added gluten daily for 4 wk. This caused small intestinal biopsy abnormalities typical of celiac sprue; the abnormalities resolved 6 wk later with a gluten-free diet. This indicates that latent celiac sprue may be present in some patients with lymphoma and suggests that the association of celiac sprue and lymphoma may be more frequent than is currently appreciated.     

Colonic volvulus as a complication of celiac sprue

Colonic volvulus has been a rarely reported complication of celiac sprue. We describe two patients with long-standing celiac sprue, one in whom a recurrent sigmoid volvulus developed, and in the other, a cecal volvulus. Following surgery, both are now asymptomatic on a gluten-free diet. The association between celiac sprue and colonic volvulus was first reported in 1953. There have been only a few isolated cases documented, surprisingly so because the two major predisposing conditions for colonic volvulus are often seen in patients with celiac sprue. Colonic bacterial fermentation of malabsorbed carbohydrate (in celiac sprue) leads to excess gas production. Flaccid bowel loops with sigmoid redundancy, a long mesentery, or cecal hypermobility are not uncommon. A motility disorder in celiac sprue has also been proposed. Thus these factors together would suggest that the likelihood of development of colonic volvulus in celiac sprue would be relatively great. The possibility of underlying celiac sprue should be considered in patients with colonic volvulus who have a background history of recurrent abdominal distention or malabsorptive symptoms.     

Diagnosis of celiac sprue

Celiac sprue is a common lifelong disorder affecting 0.3-1% of the Western world and causing considerable ill health and increased mortality, particularly from lymphoma and other malignancies. Although high prevalence rates have been reported in Western Europe, celiac sprue remains a rare diagnosis in North America. Whether celiac sprue is truly rare among North Americans or is simply underdiagnosed is unclear, although serological screening of healthy American blood donors suggests that a large number of American celiacs go undiagnosed. Celiac sprue is an elusive diagnosis, and often its only clue is the presence of iron or folate deficiency anemia or extraintestinal manifestations, such as osteoporosis, infertility, and neurological disturbances. The challenge for gastroenterologists and other physicians is to identify the large population of undiagnosed patients that probably exists in the community and offer them treatment with a gluten-free diet that will restore the great majority to full health and prevent the development of complications. The advent of highly sensitive and specific antiendomysium and tissue transglutaminase serological tests has modified our current approach to diagnosis and made fecal fat and D-xylose absorption testing obsolete. A single small bowel biopsy that demonstrates histological findings compatible with celiac sprue followed by a favorable clinical and serological response to gluten-free diet is now considered sufficient to definitely confirm the diagnosis. We review the wide spectrum of celiac sprue, its variable clinical manifestations, and the current approach to diagnosis.     

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.     

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.     

Collagenous colitis as the presenting feature of biopsy-defined celiac disease

BACKGROUND: Prior case reports have linked celiac disease with collagenous colitis, but serological and retrospective pathologic survey studies of small intestinal biopsies have produced conflicting results. METHODS: In this report, consecutive patients with chronic diarrhea and the initial finding of collagenous colitis were evaluated to determine if occult celiac disease was also present. All 36 patients with no exclusions were offered upper endoscopy and biopsies. If the changes of untreated celiac disease were detected in the small intestinal biopsies, then a gluten-free diet was instituted. Diet response was based on resolution of diarrhea and normalization of repeated small intestinal biopsies. RESULTS: Eight patients, or over 20%, had severely abnormal small bowel biopsy changes characteristic of untreated celiac disease. In some, lymphocytic or collagenous gastritis were also detected with or without celiac disease. All 8 patients were treated with a gluten-free diet alone and, in all, diarrhea improved and small intestinal biopsies normalized. In 5, however, repeated colonic biopsies showed persistent collagen deposits. Autoimmune thyroid disease or neoplastic diseases, like lymphoma known to be associated with celiac disease were also noted in this cohort with collagenous colitis, often in the absence of celiac disease. CONCLUSIONS: This study indicates that collagenous colitis may be the presenting clinical and pathologic feature of celiac disease. Diagnosis of collagenous colitis should lead the clinician to consider exclusion of underlying occult celiac disease.     

Disappearance of endomysial antibodies in treated celiac disease does not indicate histological recovery

OBJECTIVE: Although serum IgA-class endomysial antibody (EmA) has high sensitivity for villous atrophy (VA) in patients with untreated celiac disease, few studies have attempted to correlate EmA seroconversion with histological recovery after starting a gluten-free diet. We prospectively studied changes in EmA status and in duodenal histology of seropositive patients after dietary treatment. METHODS: Patients with VA and EmA had repeat EmA testing at 3, 6, and 12 months after starting gluten-free diet, plus assessment of dietary compliance by dietitians and follow-up duodenal biopsy at 12 months. VA before and after treatment was classified as partial (P), subtotal (ST), and total (T). RESULTS: Of 77 patients with newly diagnosed VA and without IgA deficiency, 62 (81%) had EmA: 46 of 57 (81%) with T or STVA and 16 of 20 (80%) with PVA. Of 53 initially EmA-positive patients who completed study criteria, EmA was undetectable in 31 patients (58%) after 3 months' diet, in 40 (75%) after 6 months, and in 46 (87%) after 12 months. However, only 21 patients (40%), all seronegative by 12 months, had complete villous recovery. Only three (33%) of 10 patients with persisting ST or TVA and two (9%) of 22 with PVA remained EmA positive. Four of the five patients with persisting EmA had poor dietary compliance. CONCLUSIONS: EmA is a poor predictor of persisting VA after patients have started gluten-free diet, although it may be of value in monitoring dietary compliance. Although there are no clear guidelines regarding the need for follow-up biopsy, EmA seroconversion cannot substitute. The apparent association between dietary compliance and seroconversion suggests that gluten intake may determine whether untreated celiac patients are EmA positive or negative for a given degree of small bowel damage.     

Celiac sprue: another autoimmune syndrome associated with hepatitis C

OBJECTIVE: Celiac sprue is being diagnosed with increasing frequency by screening individuals with epidemiologically associated autoimmune syndromes. We sought to test our hypothesis that hepatitis C also may predispose to celiac sprue because it can trigger autoimmune reactions. METHODS: Two hundred fifty-nine consecutively evaluated patients with chronic hepatitis C infection, 59 with autoimmune liver disease, 137 with other hepatic diseases, 356 with various GI syndromes, and 221 normal volunteers underwent serologic screening for celiac sprue. Patients with antigliadin, antiendomysial, and antitissue transglutaminase antibodies in serum underwent duodenoscopy and biopsy. RESULTS: There was a statistically significantly higher prevalence of antigliadin antibody in all groups of patients with liver disease compared with GI controls and normal controls. However, only patients with hepatitis C (n = 3; 1.2%) or autoimmune liver disease (n = 2; 3.4%) had antiendomysial/antitissue transglutaminase antibody in serum. One of 221 normal volunteers (0.4%) was antigliadin, antiendomysial, and antitissue transglutaminase positive; this individual also was found to have hepatitis C (previously undiagnosed). Each of these six individuals had mild intestinal symptoms, duodenal histopathology consistent with celiac sprue, and the celiac-associated HLA-DQ2 allele. Five of the six followed a prescribed gluten-free diet and experienced symptomatic improvement. CONCLUSION: Celiac sprue is epidemiologically associated with chronic hepatitis C infection and with autoimmune liver disease. Because hepatitis C is much more frequently encountered than autoimmune liver disease, hepatitis C appears to be the most common hepatic disease associated with the development of celiac sprue.     

Variation in small bowel biopsy performance among diverse endoscopy settings: results from a national endoscopic database

BACKGROUND: The diagnostic gold standard for celiac sprue requires performance of small bowel biopsy to identify characteristic mucosal changes. The current biopsy practice among endoscopists for celiac sprue is unknown. METHODS: The CORI (Clinical Outcomes Research Initiative) national endoscopic database was analyzed to determine the rate of small bowel biopsy in patients undergoing EGD for the evaluation of anemia, iron deficiency without anemia, weight loss, and diarrhea. RESULTS: Between January 2000 and September 2003, 3,992 patients underwent EGD for the evaluation of anemia, iron deficiency, weight loss, and diarrhea with normal EGD findings. Overall, 438 patients (11%) underwent small bowel biopsy. Small bowel biopsy performance varied with procedure indication: anemia 10%, iron deficiency 7%, weight loss 6%, and diarrhea 19%, p < 0.0001. Biopsy rates declined with advancing patient age; 12% (<50 yr), 12% (50-69 yr), and 9% (> or =70 yr), p= 0.002, and also differed with patient race (12%, Whites vs 8%, non-Whites), p= 0.0007. Biopsy performance varied among endoscopy sites: community (9%), academic (13%), and VAMC (15%), p < 0.0001. Multivariate analysis identified age > or =70 yr (OR: 0.52, p= 0.0007), non-White race (OR: 0.60, p= 0.0007) and an indication of weight loss (OR: 0.60, p= 0.01) to be associated with not performing a biopsy. CONCLUSION: Among diverse endoscopy sites, the majority of patients with anemia, iron deficiency, weight loss, and diarrhea do not undergo small bowel biopsy at EGD. The diagnosis of celiac sprue should be considered in such cases. Endoscopy provides an opportunity to obtain tissue to diagnose sprue, and should be strongly considered in this setting.     

Azathioprine in refractory sprue: results from a prospective,open-label study

OBJECTIVE: Refractory sprue is a rare and severe malabsorptive disorder that mimics celiac disease but is refractory to a gluten-free diet and is without initial evidence of overt lymphoma. Treatment is largely empiric and often ineffective, with steroids and immunosuppression being the mainstream therapeutic options. The aim of this study was to evaluate prospectively the effect of azathioprine on a group of patients diagnosed with refractory sprue. METHODS: We studied seven consecutive patients (five women and two men) with a well-defined diagnosis of refractory sprue and a lack of response to oral or parenteral steroids. At diagnosis, five patients had endoscopic evidence of ulcerative jejunitis, and five underwent exploratory laparotomy for exclusion of malignancies. The characteristic monoclonal TCRgamma gene rearrangement was shown in five of six patients studied. Patients were treated for a mean of 11 months (range 8-12 months), and clinical, biochemical, molecular, and histological parameters were reassessed at the end of the trial. The study was a prospective, open-label, non-placebo-controlled study using azathioprine (2 mg/kg/ day) plus oral prednisone (1 mg/kg/day). A gluten-free diet (n = 7) as well as enteral (n = 6) and parenteral nutrition (n = 5) were administered during the trial. RESULTS: After treatment, five patients had a complete clinical remission, and biochemical and nutritional parameters were significantly improved. Steroids were tapered after the onset of azathioprine, and no patient was on steroids at the end of the trial. Intestinal histology improved significantly in all cases (normal histology in three cases and minor infiltration in the lamina propria in two). Two patients did not respond to treatment at any time and died in months 10 and 9, of an irreversible ventricular fibrillation and sepsis, respectively. No overt lymphoma was demonstrated during the follow-up. CONCLUSIONS: The present study confirms earlier anecdotal reports on the efficacy of azathioprine in refractory sprue, with clear clinical and histological improvement shown in most patients. However, monoclonality persisted after treatment. We consider that a larger number of patients should be evaluated before a definitive recommendation is adopted for use of this drug in refractory sprue.     

Refractory sprue

Celiac disease is a T cell-mediated disorder that results from intolerance to gluten. The major cause of failure to respond to a gluten-free diet is continuing gluten ingestion. In poorly responsive patients diagnosis of refractory sprue can be established after exclusion of a limited number of conditions. Refractory sprue may occur after an initial response to the diet or without evidence of preexisting celiac disease. The detection of aberrant, clonally expanded, intraepithelial lymphocytes has led to better definition and classification of patients with refractory sprue. Only a few series of patients with well-characterized refractory sprue have been reported in the literature. The prognosis is poor, though some patients respond to corticosteroids and immunosuppressive agents. The presence of an aberrant clonal intraepithelial T-cell population has led to the designation of refractory sprue as a cryptic intestinal T-cell lymphoma.     

Diarrhea in a patient with Down syndrome and endemic sprue

BACKGROUND: Down syndrome is associated with disorders such as celiac disease, hypothyroidism, and insulin-dependent diabetes mellitus. In patients with mono- or oligosymptomatic celiac disease the time interval between the onset of symptoms and diagnosis often is unacceptably long. CASE REPORT: A female patient with Down syndrome is presented who had acute watery diarrhea, which spontaneously ceased but recurred after a few days. After endoscopic and histologic evaluation and measurement of gliadin, endomysium, and reticulin antibodies celiac sprue was diagnosed. Further investigation showed findings of autoimmune hypothyroidism and secondary hyperparathyreoidism. After the patient was put on a gluten-free diet her state quickly improved. CONCLUSION: Associations between Down syndrome and autoimmune diseases exist. Patients with acute gastrointestinal symptoms should be evaluated as to celiac disease. The time interval between the onset of symptoms and diagnosis of celiac disease can be shortened, if all diagnostic tools are used at the appropriate time.     

Clinical, biochemical and histological abnormalities in adult celiac patients on gluten-free diet

Twenty-six adult patients with histologically confirmed celiac disease on gluten-free diet after apparent disease remission were reexamined at 4-6 months intervals for a mean period of 55.4 months (range 13-137). Eight patients remained clinically well with normal blood tests. Eighteen patients had clinical or biological abnormalities. Eleven patients reported repeated episodes of meteorism and abdominal pain and/or diarrhea which disappeared in 2 after lactose withdrawal. Iron deficiency and macrocytic anemia were sometimes observed in 5 and 4 patients respectively. Altered plasma calcium, phosphorus and alkaline phosphatase and/or bone densitometry findings were detected in 7 patients. Seventeen patients (12 presenting some of the above findings) agreed to a repeat biopsy: 13 of these showed grade II and 4 grade III abnormalities. Although adult celiac patients may show marked improvement during gluten-free diet, minor clinical disturbances and biochemical abnormalities may still be present.