Kenneth D. Fine

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.

Intestinal absorption of magnesium from food and supplements.

The purpose of this study was to measure magnesium absorption over the wide range of intakes to which the intestine may be exposed from food and/or magnesium-containing medications. Net magnesium absorption was measured in normal subjects after they ingested a standard meal supplemented with 0, 10, 20, 40, and 80 mEq of magnesium acetate. Although absorption increased with each increment in intake, fractional magnesium absorption fell progressively (from 65% at the lowest to 11% at the highest intake) so that absorption as a function of intake was curvilinear. This absorption-intake relationship was almost perfectly represented by an equation containing a hyperbolic function plus a linear function. Our results are statistically compatible with a magnesium absorption process that simultaneously uses a mechanism that reaches an absorptive maximum, plus a mechanism that endlessly absorbs a defined fraction (7%) of ingested magnesium. Compared to previous studies of calcium absorption, much less magnesium that calcium was absorbed at intakes above 8 mEq/meal, apparently due to greater restriction of intestinal permeability to magnesium. We also found that magnesium from a high magnesium-containing food source, almonds, was just as bioavailable as from soluble magnesium acetate. In contrast, magnesium absorption from commercially available enteric-coated magnesium chloride was much less than from magnesium acetate, suggesting that enteric coating can impair magnesium bioavailability.

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.

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, Crohns 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.

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 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 ra...

Effect of D-glucose on intestinal permeability and its passive absorption in human small intestine in vivo

BACKGROUND Based on studies in animals, it has been proposed that carrier-mediated D-glucose absorption markedly enhances passive permeability of the jejunal mucosa, allowing the majority of D-glucose absorption to proceed passively. In this study, we evaluated this hypothesis in the human jejunum in vivo. METHODS Using the constant perfusion, nonabsorbable marker technique, permeability of jejunal mucosa was assessed by measuring the ratio of diffusion rates of urea/L-xylose and mannitol/L-xylose. Passive D-glucose absorption was quantitated using L-glucose and mannitol as probes for D-glucose. RESULTS Addition of D-glucose to perfused solutions did not change the diffusion ratios, indicating that D-glucose has no effect on the size of channels for passive diffusion across the jejunal mucosa. The fraction of total D-glucose absorption that could be attributed to a passive mechanism averaged 5%. In the human ileum in vivo, we detected no evidence of passive D-glucose absorption. CONCLUSIONS Carrier-mediated D-glucose absorption does not increase passive permeability of human jejunal mucosa to solutes with molecular radii between 2.6 and 4.0 A. The amount of D-glucose absorbed passively from the human jejunum is trivial compared with the overwhelmingly dominant mechanism, carrier-mediated transport. Our results do not support the concept that sodium-dependent nutrient transport increases tight junction permeability.

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.

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.

Carbohydrate malabsorption. Its measurement and its contribution to diarrhea.

The major purpose of this research was to gain insight into the effect of carbohydrate malabsorption on fecal water output. To do this we measured daily fecal output of total carbohydrate, reducing sugars, and organic acids (a product of bacterial fermentation). Normal subjects were studied in their native state and when diarrhea was induced by mechanisms that did and did not involve carbohydrate malabsorption. Patients with malabsorption syndrome were also studied. We concluded that: (a) Excretion of carbohydrate and its breakdown products can be expressed as a single number by converting organic acids to their monosaccharide equivalents. (b) Diarrhea per se causes only a trivial increase in fecal carbohydrate excretion. (c) The molar output of osmotic moieties in feces due to unabsorbed carbohydrate can be determined by adding fecal reducing sugars to organic acids and their obligated cations. This expression parallels almost exactly the effect of increasing doses of lactulose (a nonabsorbable sugar) on fecal water output; one excreted millimole obligates 3.5 g of stool water. This relationship can be used to predict the effect of carbohydrate malabsorption on stool water output in patients with diarrhea. (d) 12 of 19 patients with malabsorption syndrome due to various diseases had excessive fecal excretion of carbohydrate and its breakdown products; of the diseases that cause malabsorption syndrome, combined small and large bowel resection is most likely to result in excessive fecal excretion of carbohydrate and monosaccharide equivalents. In 6 of these 19 patients carbohydrate malabsorption appeared to be the major cause of diarrhea.