Milk and lactose intolerance in healthy Orientals.

Nineteen of 20 healthy Oriental adults living in the United States developed abdominal cramps and diarrhea after ingesting an amount of lactose equivalent to that in one quart of milk; 14 reported similar symptoms after one or two glasses of milk; all had consumed milk as infants without having such symptoms. Two of 20 Caucasians tested were intolerant to milk and lactose. Many Orientals therefore may have a genetically determined lactase deficiency that may lead to intolerance to milk. Since lactase deficiency is also common among Negroes, the bulk of the world's adult population is probably intolerant to milk.

An SNP linkage scan identifies significant Crohn's disease loci on chromosomes 13q13.3 and, in Jewish families, on 1p35.2 and 3q29.

Inflammatory bowel disease (IBD) is a complex genetic disorder of two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC), with increased risk in Ashkenazi Jews. Twelve genome-wide linkage screens have identified multiple loci, but these screens have been of modest size and have used low-density microsatellite markers. We, therefore, performed a high-density single-nucleotide polymorphism (SNP) genome-wide linkage study of 993 IBD multiply affected pedigrees (25% Jewish ancestry) that contained 1709 IBD-affected relative pairs, including 919 CD-CD pairs and 312 UC-UC pairs. We identified a significant novel CD locus on chromosome 13p13.3 (peak logarithm of the odds (LOD) score=3.98) in all pedigrees, significant linkage evidence on chromosomes 1p35.1 (peak LOD score=3.5) and 3q29 (peak LOD score=3.19) in Jewish CD pedigrees, and suggestive loci for Jewish IBD on chromosome 10q22 (peak LOD score=2.57) and Jewish UC on chromosome 2q24 (peak LOD score=2.69). Nominal or greater linkage evidence was present for most previously designated IBD loci (IBD1-9), notably, IBD1 for CD families at chromosome 16q12.1 (peak LOD score=4.86) and IBD6 in non-Jewish UC families at chromosome 19p12 (peak LOD score=2.67). This study demonstrates the ability of high information content adequately powered SNP genome-wide linkage studies to identify loci not observed in multiple microsatellite-based studies in smaller cohorts.

Plasma postheparin diamine oxidase. Sensitive provocative test for quantitating length of acute intestinal mucosal injury in the rat.

Diamine oxidase (DAO; EC 1.4.3.6) is an enzyme found in high activity in the mature cells of the upper villus of rat small intestinal mucosa and in very much lower activity in all other tissues in the nonpregnant rat. This study was designed to determine whether a provocative test for increasing the level of plasma DAO activity by heparin administration could be used to monitor the extent and severity of acute, severe, small intestinal mucosal injury. In adult rats, small intestinal loops of varying lengths were perfused with 2,100 mosM sodium sulfate solution for 60 min to produce selective damage to villus epithelium. Plasma postheparin DAO (PHD) activity (180 min after 400 U/kg i.p. heparin) was measured 7 h after initiation of perfusion. With increasing length of intestinal mucosal injury, there was a progressive decrease in both basal and plasma PHD activity. The decrease in plasma PHD activity closely reflected the length of intestinal mucosa injured (n = 128, r = 0.86, P less than 0.001), and it was much more sensitive (threshold limit of detection = 13% of total length, range = 67 U/ml for 100% length of injury) than unstimulated basal levels of plasma DAO (threshold = 40%, range = 2.1 U/ml). Our previous data have suggested that DAO is unique among intestinal mucosal enzymes in that circulating levels can serve as a marker of mucosal injury; this study illustrates that the addition of a low-dose heparin administration enhances the use of DAO even further as a sensitive, quantitative, circulating marker for monitoring the extent of small intestinal mucosal injury in the rat.

Diamine oxidase (histaminase). A circulating marker for rat intestinal mucosal maturation and integrity.

Diamine oxidase (histaminase) is an enzyme found in high concentrations in the intestinal mucosa of humans and other mammalian species. We investigated whether plasma and mucosal levels of diamine oxidase activity reflect both the maturational status of the mucosa during its development in the newborn rate and the degree of mucosal damage during its injury in the adult rat. Litter mates were reared under identical conditions and killed at different ages from day 0 to day 40 after birth. Diamine oxidase in the small intestine was low at birth, increased gradually with age, reached a peak at 22 d, and then remained at normal adult levels, similar to the developmental patterns of maltase and sucrase. Plasma diamine oxidase rose in parallel with intestinal levels (n = 500, r = 0.84, P less than 0.001), reached a peak at 24 d, and then remained at normal adult levels. Diamine oxidase activity in 15 nonintestinal tissues was less than 5% of ileal mucosal activity, and no nonintestinal activities showed increase with age. Adult rat intestinal loops were perfused with hyperosmolar sodium sulfate solutions to produce selective damage to villus mucosa. With increasing mucosal damage, there was a progressive decrease in the enzyme activities studied; first, lactase levels fell, then maltase and sucrase, and finally mucosal and plasma diamine oxidase activity levels fell. The decrease in plasma diamine oxidase reflected the degree of mucosal damage (n = 29, P less than 0.04). Diamine oxidase activity is thus unique among intestinal mucosal enzymes studied to date in that circulating levels can serve as a marker of mucosal maturation and integrity.

Neurologic disease in patients with treated Whipple's disease.

Four patients with Whipple's disease which had responded to antibiotic therapy, later developed neurologic disease identical to that seen in patients with Whipple's disease who died without treatment. Dementia, myoclonus, ataxia, and supranuclear ophthalmoplegia were the main neurologic features. Restarting antibiotics has been followed by stabilization of disease in all four. Two have improved. In three, the previously diagnosed and treated Whipple's disease was not considered as a possible cause of the neurologic disease until the symptoms and signs were far advanced. It is advisable to periodically evaluate all patients with Whipple's disease, even after successful treatment. Signs of neurologic disease should be considered a possible recurrence of Whipple's disease and antibiotics restarted.

Disaccharidase deficiency.

PIP: This review of the literature and current knowledge concerning a nutritional disorder of disaccharidase deficiency discusses the following topics: 1) a description of disorders of disaccharide digestion; 2) some historical perspective on the laboratory and bedside advances in the past 10 years that have helped define a group of these digestive disorders; 3) a classification of conditions causing disaccharide intolerance; and 4) a discussion of some of the specific clinical syndromes emphasizing nutritional consequences of these syndromes. The syndromes described include congenital lactase deficiency, acquired lactase deficiency in teenagers and adults, acquired generalized disaccharidase deficiency secondary to diffuse mucosal damage, acquired lactose intolerance secondary to alterations in the intestinal transit, sucrase-isomaltase deficiencies, and other disease associations connected with lactase deficiency such as colitis.^ieng

Relationship of milk consumption to blood glucose rise in lactose intolerant individuals.

Lactose intolerant populations are heterogeneous with respect to their milk-drinking habits. A gradation of lactase activity in the intolerant population may result in sufficient lactose hydrolysis to obviate symptoms and lead to continued milk consumption. This paper reports on differences in maximum blood sugar rise in lactose intolerant children who are observed to consume or reject milk. Of the 89 black elementary school children, 48 (54 per cent) evidenced a flat lactose tolerance curve. Twenty-eight of these 48 children (58 per cent) were defined as nonmilk drinkers. The maximum blood sugar rise was 12.3 mg/100 in the 20 lactose malabsorbers who were defined as milk drinkers. It appears that some lactose malabsorbing children may have sufficient, albeit lower, levels of lactase to hydrolyze moderate amounts of milk.

Lactose hydrolyzed milk.

Lactose intolerance is being reported in many populations. Yet, milk is highly nutritious and methods are being explored to use milk while limiting the lactose content. Thirty-two blacks 13-19 years of age were studied to determine a blood sugar rise with 8 ounces of the following test milks: 1) untreated whole milk (12 g/lactose); 2) 90% lactose hydrolyzed milk (1.2 g/lactose); and 3) 50% lactose hydrolyzed milk (6 g/lactose). In the 22 lactose malabsorbers, the peak blood sugars were: 1) untreated whole milk--4.4 mg/100 ml, 2) 90% lactose hydrolyzed milk--14.5 mg/100 ml, and 3) 50% lactose hydrolyzed milk--8.8 mg/100 ml. The 10 blacks with normal lactose absorption had a comparably high peak blood sugar on all three test milks. Differences between the blood sugar in the lactose absorbing and malabsorbing subjects when drinking untreated whole milk are significant (P less than 0.001); so are differences in the lactose malabsorbing subjects consuming untreated whole milk and 90% lactose hydrolyzed milk (P less than 0.001) as well as 50 and 90% lactose hydrolyzed milk. Symptoms were reported by three lactose malabsorbing subjects with untreated whole milk with two of the three symptomatic with 90% lactose hydrolyzed milk and none with 50% lactose hydrolyzed milk. No symptoms were reported by the lactose absorbers. Significant improvement in absorption with 90% lactose hydrolyzed milk is seen in low lactase subjects. Lactose hydrolyzed milk may serve as an important alternative for food planners wanting to provide milk to high risk populations with low lactase levels.

Lactose malabsorption in preschool black children.

One hundred sixteen healthy black children ages 13 to 59 months, representing high and low socioeconomic deciles, were studied for lactose malabsorption. A fasting lactose tolerance test using 2 g of lactose/kg of body weight was carried out. Glucose was determined at 0, 15, 30, and 60 min. Of the 116 preschoolers 34 (29%) evidenced lactose malabsorption as determined by a blood glucose rise of less than 26 mg/100 ml. Clinical signs of diarrhea, gas, and cramps were noted singly or in combination in 18% of the 34 lactose-malabsorbing children. Of the 82 lactose absorbers, 12% demonstrated similar signs. The nature and length of the initial infant milk feeding failed to show any relationship to the onset of malabsorption. Current milk drinking patterns were reported as being similar. Eight-seven percent of the malabsorbers and 92% of the absorbers report drinking 240 ml or more of milk/day. Socioeconomic status, education, marital status, and medical assistance of the parent is similarly distributed between lactose absorbers and malabsorbers.

Blood glucose rise after lactose tolerance testing in infants.

Lactose tolerance tests are used clinically to screen children and infants. It is assumed that absorption of a lactose challenge in infants would occur in a predictable pattern prior to weaning. Twenty-one infants from 3 to 12 months of age were studied. The maximum blood glucose rise over fasting levels ranged from 11.0 to 62.0 mg/100 ml; the mean was 32.6 mg/100 ml. Six infants had a maximum rise of less than 20 mg/100 ml. Eleven infants (52%) had a maximum rise of greater than 30 mg/100 ml. Signs of intolerance were not noted in any subject. Weight and length were normally disturbed. Results indicate the variance in glucose rise existing within a population of infants growing normally and consuming milk. Gastric emptying, digestion, and absorption may influence the blood glucose rise after a lactose test. Established glucose levels used as an index to lactose absorption in older children and adults may not accurately reflect lactase activity in infants.

Effect of yogurt on symptoms and kinetics of hydrogen production in lactose-malabsorbing children.

Lactase-deficient adults demonstrate improved lactose absorption and fewer symptoms when consuming yogurt than when consuming milk containing equivalent amounts of lactose. To examine this effect and its mechanisms in children, we compared symptoms and hydrogen production as an index of lactose malabsorption after typical servings of milk, pasteurized yogurt, and yogurt containing active live culture in 14 lactose-malabsorbing children (mean age 9.5 y). Symptoms and interval breath-hydrogen concentrations were recorded for 8 h after ingestion of 12 g lactose served as milk and yogurts. Lactose-malabsorbing children experienced significantly fewer symptoms after consuming yogurt containing active cultures than after consuming milk (P < 0.005). Pasteurized yogurt showed an intermediate effect. Lactose from yogurt was not better absorbed than was lactose from milk, as indicated by similar areas under the hydrogen curve; however, yogurt was associated with a delayed time to rise and lower rate of rise of the hydrogen curve. The rate of hydrogen rise correlated with the degree of symptoms. In children, mechanisms other than enhanced lactose absorption from yogurt may lead to changes in the kinetics of hydrogen production, which in turn are associated with improved tolerance.

Acute and late radiotherapy toxicity in patients with inflammatory bowel disease.

PURPOSE: To evaluate the incidence of gastrointestinal complications in patients with inflammatory bowel disease (IBD) receiving radiotherapy (RT) and to identify possibly avoidable factors associated with these complications. METHODS AND MATERIALS: Twenty-four patients were identified and their records reviewed; all had a history of IBD before receiving RT to fields encompassing some portion of the gastrointestinal tract (Crohn's disease) or to the abdomen or pelvis (ulcerative colitis or IBD not otherwise specified). RESULTS: Five of 24 patients (21%) experienced Grade > or =3 acute gastrointestinal toxicity; all 5 received concurrent chemotherapy. Two of 24 patients (8%) experienced Grade > or =3 late gastrointestinal toxicity. There were no significant correlations between complications and IBD type, prior IBD-related surgery, use of medications for IBD, or status of IBD. CONCLUSION: Patients with IBD may have an increased risk for severe acute RT-related gastrointestinal complications that is more modest than generally perceived, because all patients who had Grade > or =3 acute complications in this study had received concurrent chemotherapy (p = 0.04). Further study is needed to assess this risk, as well as the impact of RT on these patients' future gastrointestinal morbidity.

Intolerance of eight ounces of milk in healthy lactose-intolerant teen-agers.

The ability of lactose-intolerant individuals to tolerate 8 ounces of milk was determined in healthy teen-agers. Thirty-two blacks were studied with 50-gm lactose tolerance tests. Nineteen (59%) had a flat blood sugar curve and 13 (39%) also developed bloating, cramps, loose stools, or diarrhea with the test. These latter 13 were defined as lactose-intolerant. Seven of the 13 lactose-intolerant teen-agers (54%) developed abdominal bloating and/or cramps after drinking 8 ounces of milk (half-pint). None had diarrhea. Eight were symptomatic with the equivalent amount of lactose (12 gm) while only one had symptoms with the monosaccharide components of lactose, glucose and galactose. The symptoms with milk and 12 gm of lactose were less severe than with the 50-gm tolerance test. A history of a prior awareness of milk intolerance was obtained from 11 of the 13 lactose-intolerant subjects. At least one half of lactose intolerant teen-agers might be expected to be symptomatic after drinking 8 ounces of milk without other food. Milk intolerance should be considered in the nutritional planning for teen-agers with special attention to members of population groups with a high prevalence of lactose intolerance.

Colorectal cancer in ulcerative colitis: survival in patients with and without colorectal cancer symptoms.

: Patients with ulcerative colitis are at increased risk for colorectal adenocarcinoma compared with the general population. Although surveillance for colorectal malignancy and dysplasia (a premalignant lesion) has been recommended, a benefit in reducing mortality from colorectal cancer via surveillance or prophylactic colectomy is still being debated. We reviewed the outcome of 40 consecutive patients with ulcerative colitis with colorectal adenocarcinoma diagnosed between 1956 and 1991 at The Johns Hopkins Hospital. The diagnosis of ulcerative colitis and the tumor, node, metastasis (TNM) stage of colorectal cancer were obtained from clinicopathologic records. Follow-up information was complete for all patients. Patients were divided into two groups: 18 asymptomatic patients who had colorectal cancer detected by colonoscopy, biopsies for dysplasia, or barium enema, or had undergone "prophylactic" colectomy as part of a colorectal cancer-prevention strategy (asymptomatic group), whereas 22 patients did not undergo cancer-prevention testing or prophylactic surgery and had symptoms of colorectal cancer (symptomatic group). Colorectal cancer was diagnosed at a statistically significantly earlier cancer stage in the asymptomatic group [12 (67%) of 18 at stage I or II] compared with those in the symptomatic group [two (9%) of 22 at stage I or II] (Wilcoxon test, p < 0.01). Colorectal cancer 5-year survival in the asymptomatic group was 89% [confidence limit (CL), 6197%] and in the symptomatic group, 19% (CL, 6-39%). Patients with ulcerative colitis and asymptomatic colorectal cancer detected as part of a prevention strategy had malignancies that were less invasive and showed greatly increased survival compared with patients with symptomatic colorectal cancer.

Cancer risk in collagenous colitis.

Collagenous colitis is a recently described form of chronic inflammatory bowel disease. Other inflammatory bowel disorders are associated with increased risk of colorectal and extracolonic malignancies, but this has not been evaluated in collagenous colitis. Colorectal and extracolonic malignancies were identified in 117 patients with collagenous colitis from the Johns Hopkins Registry. The incidence rates of identified tumors, overall incidence rate of tumors, and overall mortality were then compared with general population through person year analysis with adjustment for population. No cases of colorectal cancer were found in collagenous colitis patients during a mean follow-up period of 7.0 years (range 2-12 years) after the diagnosis of colitis. Two patients developed colorectal cancer prior to the diagnosis of colitis, but no increase in life-time relative risk of colorectal cancer was found (relative risk 0.52; 95% confidence limits 0.05-1.5). An increased relative risk of lung cancer in women (relative risk 3.7; 95% confidence limits 1.0-9.6; p = 0.048) was noted. The relative risk of overall malignancy and overall mortality was not different than the general population. In collagenous colitis patients the life-time relative risk of colorectal cancer and the relative risk after the diagnosis of colitis with a mean observation period of 7 years was not increased. An increase in relative risk of lung cancer in women with collagenous colitis argues for further investigation of the role of smoking and other factors in this disorder.

Enhanced bioavailability of azathioprine compared to 6-mercaptopurine therapy in inflammatory bowel disease: correlation with treatment efficacy.

BACKGROUND: Azathioprine and 6-mercaptopurine have proven efficacy in the treatment of Crohn's disease. Immunosuppression is mediated by their intracellular metabolism into active 6-thioguanine metabolites, and clinical responsiveness to therapy in patients with inflammatory bowel disease has been correlated with the measure of erythrocyte 6-thioguanine levels. AIMS AND METHODS: To perform a dosing equivalency analysis and comparison of clinical efficacy in 82 patients with inflammatory bowel disease on long-term (> 2 months) therapy with either branded azathioprine (Imuran) (n=26), generic azathioprine (n=38), or 6-mercaptopurine (n=18), based on the measurement of erythrocyte 6-thioguanine metabolite levels. RESULTS: Disease remission was achieved in 51% (42 out of 82) of patients treated with either azathioprine or 6-mercaptopurine therapy, and correlated well with high erythrocyte 6-thioguanine levels (> 250 pmoles/8 x 108 RBCs). Patients treated with either branded azathioprine or 6-mercaptopurine achieved significantly higher erythrocyte 6-thioguanine levels than patients treated with generic azathioprine, thereby suggesting that branded azathioprine has improved oral bioavailability compared to generic azathioprine. These data are consistent with the putative immunosuppressive role of 6-thioguanine metabolites in the treatment of inflammatory bowel disease, and provides a basis for developing a therapeutic index of clinical efficacy based on the measurement of erythrocyte 6-thioguanine metabolite levels. CONCLUSIONS: Our results suggest that differences in bioavailability may have clinical relevance when considering the need to optimize erythrocyte 6-thioguanine metabolite levels in patients deemed unresponsive to treatment on conventional drug dosages.

Chronic colitis with thickening of the subepithelial collagen layer (collagenous colitis): histopathologic findings in 15 patients.

The histopathologic features of collagenous colitis were studied in 14 women and one man. All but one patient presented with chronic watery diarrhea: 10 had a history of thyroid disease or unspecified arthritis. All 15 patients showed characteristic thickening of the subepithelial collagen layer (SCL) in colorectal biopsy specimens, but in the distal colorectum the thickening was sometimes absent or borderline. Patchy or diffuse injury to the surface epithelium was seen in all cases and was independent of SCL thickening. The injured surface epithelium was infiltrated by lymphocytes and variably by eosinophils and neutrophils, causing it to resemble the surface epithelial injury seen in the small intestine in celiac disease. Crypts were commonly infiltrated by lymphocytes but without associated epithelial injury. The lamina propria in all patients was expanded by lymphocytes, plasma cells, and eosinophils. Neutrophilic cryptitis was seen in seven patients but was usually sparse. Watery diarrhea abated in eight patients treated with corticosteroids or sulfasalazine and was often paralleled by restoration of surface epithelium, reduction in surface epithelial lymphocytes, diminished SCL thickening, and reduced lamina propria eosinophils. Therapy did not consistently alter other inflammatory changes. The possible role of autoimmunity in collagenous colitis should be investigated because of the following circumstantial evidence: the overwhelming female predominance; the frequent presence of possible immunologically mediated disorders such as thyroid and joint disease; the resemblance of surface epithelial changes to those in celiac disease; and the response to corticosteroids.

Pitfalls in the diagnosis of collagenous colitis: experience with 75 cases from a registry of collagenous colitis at the Johns Hopkins Hospital.

Collagenous colitis is a relatively rare disorder presenting mainly in middle-aged women as watery diarrhea. Endoscopic and radiographic studies of the colon are usually normal, and diagnosis must be made by biopsy. The characteristic biopsy findings are a combination of increased mucosal inflammation (collagenous colitis) as well as subepithelial collagenous thickening. The mucosal inflammatory changes include increased lamina propria plasma cells, prominent intraepithelial lymphocytes, and in some cases, numerous eosinophils. The collagenous thickening has qualitative as well as quantitative differences from normal, and may be highlighted by Masson trichrome stains. Simply quantitating the thickness of a subepithelial collagen layer is neither adequate nor necessary for the diagnosis of collagenous colitis. Major problems in diagnosing collagenous colitis arise from focusing solely on the subepithelial region without attention to inflammatory changes. For example, tangential sectioning of normal colon results in an artifactually thickened basement membrane, and such cases have been wrongly interpreted as collagenous colitis. If biopsies lack the characteristic inflammatory pattern, a tangentially cut thick basement membrane should be ignored. The key to correct diagnosis of collagenous colitis is analyzing the summation of various inflammatory changes plus subepithelial collagenization, rather than focusing on any single feature in isolation.

Lymphocytic ("microscopic") colitis: a comparative histopathologic study with particular reference to collagenous colitis.

Lymphocytic colitis, previously termed "microscopic colitis", is a clinicopathologic syndrome of watery diarrhea, grossly normal colonoscopy, and mucosal inflammatory changes. Since lymphocytic colitis is a new, incompletely characterized entity, a histopathologic study was performed to compare lymphocytic colitis (n = 16), collagenous colitis (n = 17), idiopathic inflammatory bowel disease (n = 16), acute colitis (n = 16), and histologically normal colon (n = 12). The study was a blinded semiquantitative analysis of histologic features in the surface epithelium, lamina propria, and crypts. The most distinctive feature of lymphocytic colitis was increased intraepithelial lymphocytes, particularly in the surface epithelium (P = .0001 v idiopathic inflammatory bowel disease, acute colitis, and normal colon). Other prominent features of lymphocytic colitis included surface epithelial damage (P less than .005 v idiopathic inflammatory bowel disease and normal colon), increased lamina propria chronic inflammation (P less than .01 v normal), and minimal crypt distortion or active cryptitis. There were striking similarities between lymphocytic colitis and collagenous colitis, but subepithelial collagen thickening was seen only in collagenous colitis. Idiopathic inflammatory bowel disease showed prominent crypt distortion and greater active inflammation, in addition to minimal intraepithelial lymphocytes. Acute colitis occasionally demonstrated prominent surface epithelial damage, but was otherwise dissimilar from lymphocytic colitis. We reached the following conclusions: (1) the entity "microscopic colitis" shows characteristic histopathology including prominent lymphocytic infiltration of epithelium, and thus, a more appropriate designation is lymphocytic colitis; (2) although lymphocytic colitis closely resembles collagenous colitis, each entity is distinct on biopsy; and (3) lymphocytic colitis is readily distinguishable from idiopathic inflammatory bowel disease, acute forms of colitis, and normal colorectum.

Crohn's disease: are enteroenteral fistulas an indication for surgery?

Currently many physicians consider enteroenteral fistulas an indication for surgery in Crohn's disease. In an attempt to document the natural history of these fistulas, the courses of 64 patients with Crohn's disease complicated by enteroenteral fistulas were reviewed. The fistulas were diagnosed radiologically in 48 patients (75%) and at operation or by examination of the resected specimen in 16 (25%). Twenty-four of the 48 patients whose fistulas were diagnosed radiologically underwent early operation. The remaining 24 initially had nonoperative management and thus provided information about the natural history of enteroenteral fistulas. Ten of these 24 patients had nonoperative treatment for less than 1 year. All required surgery because of intestinal obstruction, enterovesical fistula, or failed response to medical therapy. Fourteen patients were managed nonoperatively for a mean period of 3.5 years (range 1 to 9 years). Eight of these patients eventually required operation, but the remaining six have to date not needed surgery. In two of these patients the fistulas can no longer be demonstrated radiographically. Patients who initially received nonoperative therapy and later required operation did not have any increased mortality or morbidity as compared with those treated with early surgery. Enteroenteral fistulas are frequently associated with and are the result of active inflammatory disease. The fistulas are usually asymptomatic and are by themselves not considered an indication for operation.