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.

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.

A new method of quantitative fecal fat microscopy and its correlation with chemically measured fecal fat output.

Fecal fat microscopy using the Sudan stain has suffered from a relative lack of specificity, and results are "qualitative." Therefore, we developed a quantitative fecal fat microscopic method with hopes of improving diagnostic accuracy. One hundred eighty patients with chronic diarrhea collected stools for 1 to 3 days, and fecal fat output was measured by a standard chemical method, and microscopy was performed by the old qualitative and new quantitative methods. There was a highly statistically significant linear correlation between quantitative fecal fat microscopy and chemically measured fecal fat output. The quantitative microscopic method had a sensitivity of 94% and a specificity of 95%; the traditional method had a sensitivity and specificity of 76% and 99%, respectively. Fecal fat Sudan microscopy performed by a dedicated approach to counting and size measurement of fat globules can yield a quantitative result that correlates well with chemically measured fecal fat output and has a high diagnostic accuracy.

The prevalence, anatomic distribution, and diagnosis of colonic causes of chronic diarrhea.

BACKGROUND: The prevalence of chronic diarrhea from a colonic disease and the optimal method of its diagnosis have not been ascertained. METHODS: Eight hundred nine patients with chronic non-bloody diarrhea unassociated with human immunodeficiency virus (HIV) infection underwent colonoscopy with biopsy specimen taken from throughout the colon and, if reached, the terminal ileum. The prevalence and anatomic distribution of ileocolonic histopathology and whether flexible sigmoidoscopy or colonoscopy represents the safest and most cost-effective test for diagnosis were determined. RESULTS: 122 of 809 patients (15%) had colonic histopathology (microscopic colitis in 80 patients, Crohn's disease in 23, melanosis coli in 8, ulcerative colitis in 5, other forms of colitis in 5, and nodular lymphoid hyperplasia in 1). A correct assessment of colonic histology (normal or abnormal) could have been made from biopsies of the distal colon in 99.7% of patients. CONCLUSION: In a referral setting, colonic histopathology occurs in 15% of patients with chronic diarrhea without HIV infection. According to this prevalence and the nearly universal diffuse anatomic distribution of colonic disease in these patients, a diagnostic investigation for chronic colonic diarrhea using a 60 cm flexible sigmoidoscope is highly efficient and cost-effective.

Comparison of the color of fecal blood with the anatomical location of gastrointestinal bleeding lesions: potential misdiagnosis using only flexible sigmoidoscopy for bright red blood per rectum.

OBJECTIVE: Flexible sigmoidoscopy has been recommended for diagnosis of patients with bright red rectal bleeding. The purpose of this study was to determine whether lesions associated with bright red hematochezia are located in the distal 60 cm of the colorectum and, therefore, in reach of a flexible sigmoidoscope. METHODS: Three hundred-twelve consecutive patients presenting with hematochezia were shown a card containing three shades of red and asked to choose the color most representative of their fecal blood. Patients then underwent colonoscopy. The colonoscopist noted the length of the scope inserted when bleeding lesions were found. RESULTS: Of 217 patients with bright red hematochezia, 181 bled from the distal 60 cm of the colon, 20 had more proximal lesions (including eight with cancer), and 16 had no lesion found. However, 140 patients with rectosigmoid neoplasms or nonbleeding nonneoplastic lesions (e.g., hemorrhoids, diverticula, vascular anomalies, and fissures) if found by sigmoidoscopy would have subsequently required full colonoscopic surveillance. It was calculated that the average per patient medical charges employing an initial colonoscopic approach would save $12 or $116 over one beginning with sigmoidoscopy (depending on whether sigmoidoscopy is performed in an office setting or endoscopy suite, respectively), and would reduce the probability of perforation slightly. CONCLUSION: A diagnostic approach to hematochezia beginning with colonoscopy should be more effective, safer, and less costly than one beginning with flexible sigmoidoscopy, even when the blood is bright red.

Alpha-heavy chain disease, Mediterranean lymphoma, and immunoproliferative small intestinal disease: a review of clinicopathological features, pathogenesis, and differential diagnosis.

There are a number of clinical syndromes associated with chronic diarrhea, malabsorption, and lymphoplasmacytic proliferation of the small intestine. In Middle-Eastern and Mediterranean countries immunoproliferative small intestinal disease is endemic, whereas in other parts of the world (including Northwestern Europe and North America) celiac sprue, and other sprue-like syndromes refractory to dietary gluten withdrawal, predominate. All of these syndromes appear to involve chronic stimulation of intestinal mucosa-associated lymphoid tissue and are associated with a heightened risk of malignant transformation. The clinicopathological features of these diseases, and distinction of the Middle Eastern syndromes from those more common in the Western hemisphere, have been reviewed.

AGA technical review on the evaluation and management of chronic diarrhea.

This literature review and the recommendations therein were prepared for the American Gastroenterological Association Clinical Practice and Practice Economics Committee. The paper was approved by the committee on September 27, 1998.

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.

Effect of single dose resin-cathartic therapy on serum potassium concentration in patients with end-stage renal disease.

Hyperkalemia in patients with renal failure is frequently treated with a cation exchange resin (sodium polystyrene sulfonate, hereafter referred to as resin) in combination with a cathartic, but the effect of such therapy on serum potassium concentration has not been established. This study evaluates the effect of four single-dose resin-cathartic regimens and placebo on 5 different test days in six patients with chronic renal failure. Dietary intake was controlled. Fecal potassium output and serum potassium concentration were measured for 12 h. Phenolphthalein alone caused an average fecal potassium output of 54 mEq. The addition of resin caused an increase in insoluble potassium output but a decrease in soluble potassium output; therefore, there was no significant effect of resin on total potassium output. Sorbitol plus resin caused less potassium output than phenolphthalein plus resin. On placebo therapy, the average serum potassium concentration increased slightly (0.4 mEq/L) during the 12-h experiment. This rise was apparently abrogated by some of the regimens that included resin; this may have been due in part to extracellular volume expansion caused by absorption of sodium released from resin. Phenolphthalein regimens were associated with a slight rise in serum potassium concentrations (similar to placebo); this may have been due to extracellular volume contraction produced by high volume and sodium-rich diarrhea and acidosis secondary to bicarbonate losses. None of the regimens reduced serum potassium concentrations, compared with baseline levels. Because single-dose resin-cathartic therapy produces no or only trivial reductions in serum potassium concentration, and because this therapy is unpleasant and occasionally is associated with serious complications, this study questions the wisdom of its use in the management of acute hyperkalemic episodes.

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.

Efficacy of open-label bismuth subsalicylate for the treatment of microscopic colitis.

BACKGROUND & AIMS: The pathogenesis of the microscopic colitis syndrome is unknown but may involve bacteria, an intestinal luminal antigen, and/or autoimmunity. It was hypothesized that bismuth subsalicylate would resolve both diarrhea and colonic inflammation in microscopic colitis because it possesses antidiarrheal, antibacterial, and anti-inflammatory properties. METHODS: Thirteen patients with microscopic colitis (7 with subepithelial collagen deposition and 6 without) were treated with eight chewable 262-mg bismuth subsalicylate tablets per day for 8 weeks. Patients recorded the frequency of bowel movements daily. Forty-eight-hour stool collections and flexible sigmoidoscopy with 24 biopsies were performed before and after treatment in each patient. RESULTS: Twelve patients completed the trial. Eleven patients had a resolution of diarrhea and a reduction in fecal weight. The average time to respond was 2 weeks. In 9 patients, colitis resolved. When present before treatment, subepithelial collagen thickening disappeared. Those completing the trial experienced no side effects. Posttreatment follow-up for 7-28 months shows that 9 patients remain well having undergone no further treatment, 2 are well but required retreatment, and 1 has continued diarrhea. CONCLUSIONS: Bismuth subsalicylate treatment for 8 weeks is safe and well tolerated. This regimen appears to be efficacious for the treatment of microscopic colitis and is worthy of further study in a controlled trial.

Investigation and diagnosis of diarrhea caused by sodium phosphate.

Because there are no published reference values for fecal phosphate concentration or output, diagnosing surreptitious use of phosphate laxatives has been difficult. The purposes of this study were to determine normal fecal phosphate levels and to quantitate and chemically analyze diarrhea produced by sodium phosphate. Timed stool collections were obtained from 20 normal subjects during 25 study periods (normal controls), from 27 normal subjects with diarrhea induced by a variety of laxatives not containing phosphate during 234 study periods (diarrhea controls), and from 10 normal subjects during 14 periods after ingestion of 45 or 22.5 ml of a commercially available 66% sodium phosphate solution (Fleet Phospho-Soda). All stools were analyzed for soluble phosphate concentration, and daily output was calculated. The upper limits of normal for soluble fecal phosphate concentration and output, derived from the normal controls and diarrhea controls, respectively, were 33 mmol/liter and 15 mmol/day. Diarrhea produced by 45 ml of sodium phosphate was watery and voluminous, with fecal weights averaging 1078 g/day (range 601-1713 g/day). Measured fecal phosphate concentrations and outputs averaged 85 mmol/liter and 92 mmol/day, respectively, and all values were significantly elevated. Soft, less voluminous stools were produced with 22.5 ml of sodium phosphate but all had an abnormally high soluble phosphate concentration and 24-hr output. In conclusion, the upper limits of normal for soluble fecal phosphate concentration and output established in this study should be useful in the chemical diagnosis of phosphate-induced diarrhea.

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.

Successful treatment of chronic severe neutropenia with weekly recombinant granulocyte-colony stimulating factor.

Daily treatment for symptomatic chronic neutropenia with recombinant granulocyte-colony stimulating factor (rhG-CSF) filgrastim is costly and sometimes causes neutrophillia. We report the use of weekly filgrastim in a 40-year-old man with life-long symptomatic neutropenia. Baseline neutrophil counts were < 1 x 10(9)/l 60% of the time, and fell below 0.5 x 10(9)/l for 7d periods every 22 d. Following 1 year of weekly filgrastim treatment, the absolute neutrophil count was maintained > 1 x 10(9)/l (averaging 2 x 10(9)/l) and the frequency and severity of symptoms were reduced by 85%. Therefore the benefits of filgrastim for the treatment of at least one form of chronic severe neutropenia can be derived from weekly rather than daily doses.

Effect of fludrocortisone and spironolactone on sodium and potassium losses in secretory diarrhea.

The response of the colon to aldosterone is believed to be an important adaptive mechanism to excessive sodium losses in diarrhea. However, the degree to which mineralocorticoid activity actually influences fecal output of sodium in people with diarrhea is unknown. To gain insight into this question, 10 normal people were treated with placebo, fludrocortisone (an aldosterone agonist), and spironolactone (an aldosterone antagonist) during three experimental periods lasting nine days. On days 5-8, diarrhea was induced by ingestion of phenolphthalein. Diet was controlled. Fecal sodium was 40 meq/day on placebo and 29 meq/day on fludrocortisone, consistent with mineralocorticoid stimulation of intestinal sodium absorption. However, contrary to our expectations, spironolactone therapy was also associated with a fall in fecal sodium output, to 28 meq/day. To explain this paradoxical effect of spironolactone, we suggest that sodium depletion caused by spironolactone's natriuretic action on the kidney caused the release of an unknown stimulant of intestinal sodium absorption, whose action more than overcame the reduced colonic absorption resulting from inhibition of aldosterone activity by spironolactone. This interpretation implies that the intestinal adaptation to sodium depletion in diarrhea involves both aldosterone and an aldosterone independent factor, working in concert to reduce fecal sodium output.

The prevalence of occult gastrointestinal bleeding in celiac sprue.

BACKGROUND: Iron deficiency complicating celiac sprue is usually attributed to the malabsorption of dietary iron or the loss of iron from the intestinal mucosa. There has been little investigation of the role of intestinal loss of blood in patients with this condition. The purpose of this study was to determine the prevalence of occult gastrointestinal bleeding in patients with celiac sprue. METHODS: We tested one 48- or 72-hour stool collection from each of 8 patients with partial villous atrophy and 28 patients with total villous atrophy using a guaiac-impregnated card (Hemoccult). Serving as controls were 18 normal subjects, each studied before and during laxative-induced diarrhea; 17 patients with idiopathic chronic diarrhea; 63 patients with microscopic colitis; 23 patients with pancreatic steatorrhea; and 7 patients with treated celiac sprue who had normal intestinal histologic features. All the patients underwent a diagnostic workup that included esophagogastroduodenoscopy, colonoscopy, and barium radiography of the small bowel. RESULTS: Positive Hemoccult tests were infrequent in each of the control groups, occurring in 0 to 8 percent of the subjects, whereas 2 of the 8 patients with partial villous atrophy (25 percent) and 15 of the 28 patients with total villous atrophy (54 percent) had positive tests. When the patients with total villous atrophy were classified according to their subsequent responses to a gluten-free diet, 7 of the 17 who were responsive to gluten withdrawal (41 percent) were Hemoccult-positive, as compared with with 8 of the 11 who did not respond to the diet (73 percent). CONCLUSIONS: Occult gastrointestinal bleeding can be detected in about half of patients with celiac sprue and should be added to the list of factors that can contribute to iron deficiency in patients with this disorder.

Determinants of decreased fecal consistency in patients with diarrhea.

BACKGROUND/AIMS: Loose stools are a common and troublesome feature in diarrhea. The purpose of this study was to investigate factors that determine different degrees of stool looseness in diarrhea. METHODS: Fecal consistency was measured visually. Stools were analyzed for content of water and solids. Water-holding capacity of insoluble solids was measured in vitro. RESULTS: Formed stools from normal subjects had a near constant ratio of water to solids despite a sevenfold variation in daily stool weight. In diarrhea, loose consistency was correlated directly with percent fecal water. For any level of percent water, steatorrhea stools were looser than nonsteatorrhea stools. Ingestion of psyllium reduced stool looseness without changing the percent water. Both the effect of fat and psyllium could be explained by consideration of the ratio of fecal water to water-holding capacity of insoluble solids. CONCLUSIONS: (1) The normal intestine delivers stools that differ widely in quantity but maintains percent fecal water within a narrow range. (2) Stool looseness in diarrhea is determined by the ratio of fecal water to water-holding capacity of insoluble solids. (3) In patients with diarrhea with normal stool weight, loose stools are due to low output of insoluble solids without the concomitant reduction in water output that occurs in normal subjects when insoluble solids are low.

Effect of changing intestinal flow rate on a measurement of intestinal permeability.

BACKGROUND/AIMS: The flow rate of fluid through the proximal small intestine varies widely under normal physiological conditions. The aim of this study was to assess the effect of changes in flow rate on the passive permeability of the aqueous paracellular pathway of the human jejunum. METHODS: Normal subjects were studied in vivo during constant perfusion of 30-cm loops of jejunum at flow rates of 5, 10, or 20 mL/min. The permeability ratio of L-xylose/urea was used to assess apparent permeability of the mucosa and to calculate the average pore radius of the aqueous pathway for passive diffusion. RESULTS: Increasing jejunal flow rate from 5 to 20 mL/min significantly decreased the L-xylose/urea permeability ratio from 0.35 to 0.23 and decreased average calculated pore radius of the diffusion pathway from 13 A to 8 A. CONCLUSIONS: Increases in flow rate in the normal physiological range decrease the estimated pore size of normal healthy jejunal mucosa. Because increasing flow rate is known to increase exposure of luminal fluid to the intervillus space, the results of this study are best explained by postulating that cells lining the sides of villi are less permeable than cells lining the villus tips.