Incidence of inflammatory bowel disease in the province of Styria, Austria, from 1997 to 2007: a population-based study.

BACKGROUND: The incidence of inflammatory bowel disease (IBD) varies widely between different countries. This large variation is also observed for the incidence of its main two forms, ulcerative colitis (UC) and Crohn's disease (CD). Controversy exists whether IBD incidence is increasing, especially in western countries. Currently no data are available for Austria. This study therefore aimed to evaluate for the first time the incidence of IBD over an eleven-year period in Styria, a province of Austria with a population of 1.2 million. METHODS: All patients with an initial diagnosis of IBD between 1997 and 2007, who were Styrian residents, were eligible for this retrospective study. Data were acquired from electronically stored hospital discharge reports and individual reports by patients and physicians. According to population density Styria was divided into two rural and one urban area. RESULTS: Throughout the study period 1527 patients with an initial diagnosis of IBD were identified. The average annual incidence was 6.7 (95% CI 6.2-7.1) per 100,000 persons per year for CD and 4.8 (95% CI 4.5-5.2) for UC. The average annual incidence increased significantly (p<0.01) for both diseases during the 11 year study period. Median age at initial diagnosis was 29 years (range 3-87) for CD and 39 years (range 3-94) for UC. At diagnosis, 8.5% of all IBD patients were <18 years of age. The incidence of both CD and UC was significantly higher in the urban area than in rural areas (CD: 8.8, 95% CI 7.8-9.8 versus 5.5, 95% CI 4.7-6.4 and 5.9, 95% CI 5.3-6.7; [p<0.001]; UC: 5.8, 95% CI 5.1-6.6 versus 4.0, 95% CI 3.4-4.7 and 4.7, 95% CI 4.1-5.4; [p=0.04]). CONCLUSION: We observed an overall increase in the incidence of ulcerative colitis and Crohn's disease in a part of Austria during an eleven year period. IBD was more predominant in the largest urban area than in rural areas.

Mycophenolate mofetil for Crohn's disease: short-term efficacy and long-term outcome.

AIM: To assess the long-term efficacy of the antimetabolite agent mycophenolate mofetil in patients with Crohn's disease. METHODS: Twenty patients with complicated Crohn's disease were treated with mycophenolate mofetil, 1 g b.d., for up to 7 years. Twelve patients were intolerant to azathioprine, seven were resistant to azathioprine and one had a history of mesalazine-induced pancreatitis. The response to mycophenolate mofetil was determined by calculation of the Harvey-Bradshaw index, the ability to taper steroids and the grading of fistula activity. RESULTS: After 6 months, 11 of the 20 patients had responded. Seven of the 11 responders relapsed after a median of 18 months, three have an ongoing response at month 17, 19 and 82, and one discontinued mycophenolate mofetil owing to toxicity. After initial treatment failure, mycophenolate mofetil was continued in 12 of 17 patients for a further 2-41 months without inducing a stable remission. Mycophenolate mofetil was of benefit in nine of the 12 patients intolerant to azathioprine and in two of the seven patients resistant to azathioprine. Perianal fistulas improved in seven of eight patients; five of the seven subsequently deteriorated, but only one due to reactivated perianal disease. CONCLUSIONS: Mycophenolate mofetil was initially effective in a sizeable fraction of patients with complicated Crohn's disease, but relapse within 18 months was common. Nevertheless, mycophenolate mofetil could be a useful alternative in patients intolerant to azathioprine.

Effect of oral tacrolimus (FK 506) on steroid-refractory moderate/severe ulcerative colitis.

BACKGROUND: Steroid refractory ulcerative colitis is most commonly treated with intravenous ciclosporin to avoid colectomy. In search for an alternative drug that can be administered orally we investigated oral tacrolimus (FK 506) for this indication. METHODS: Nine patients with active, moderate/severe steroid refractory UC were treated with oral tacrolimus with a daily dose of 0.15 mg/kg body weight. After patients had responded azathioprine was added for long-term immunosuppression. RESULTS: All patients responded within 1-2 weeks. After 12 weeks of tacrolimus therapy six patients (67%) were in complete remission, two patients (22%) had mild to moderate disease activity, and one patient (11%) underwent colectomy. After a mean follow up of 21 months six of the nine patients (67%) had their colon in situ. Two patients developed severe side-effects, one thrombopenia with intestinal bleeding, and one bicytopenia. Mild side-effects were common. CONCLUSION: Oral tacrolimus may be an effective alternative to intravenous ciclosporin for the therapy of steroid-refractory ulcerative colitis. Patients receiving tacrolimus need to be watched carefully for side-effects.

Examination, prevention and treatment of osteoporosis in patients with inflammatory bowel disease: recommendations and reality.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk of developing osteopenia and osteoporosis. Our aim was to evaluate the current practices of examination, prevention and treatment of osteoporosis in IBD patients in a routine clinical setting. METHODS: A total of 154 consecutive patients with IBD (63 female, 91 male; 36 ulcerative colitis, 115 Crohn's disease, 3 indeterminate colitis), referred to two gastroenterological units for scheduled follow-up examinations, were included. Patient charts were evaluated regarding bone densitometry already performed and any prophylactic or therapeutic interventions in cases of low bone mineral density. RESULTS: Bone mineral density (BMD) measurements had been performed only in 38 patients (25%). BMD was abnormally low in 27 of the examined patients (71%), 20 of whom had osteopenia and seven had osteoporosis. Among the subgroup of patients on long-term steroid therapy (77 patients), 30 had been referred to bone densitometry during the course of disease, and 21 of them were found to have low bone mineral density. Preventive measures were prescribed in 12 patients (9% of the whole study population). In the majority of the patients with low bone mineral density, calcium and vitamin D were used as treatment. CONCLUSIONS: Despite the high prevalence of osteopenia and osteoporosis in patients with IBD, only a minority of these patients were included in a structured program in accordance with modern guidelines for diagnosing and preventing this extraintestinal complication in a routine clinical setting.

Gut-derived bone infection in the neonatal rat.

The risk of osteomyelitis is increased in the premature and critically ill neonate. Although potential sites of bacterial entry are present in many of these infants, the source of infection frequently cannot be established. This study was performed to assess the possible role of bacterial translocation from the intestine in the origin of bone infection using models of breast-fed and formula-fed rat pups. Newborn Sprague-Dawley rats suckled either ad libitum by the dam (n = 30), or were fed a rat milk-simulated formula (n = 30). After 3 d, the animals were killed, and the left femur, heart blood, mesenteric lymph nodes, liver, spleen, and terminal ileum were excised. Organs were analyzed for bacteria by standard microbiologic procedures. Bacterial translocation occurred in 23% of breast-fed rats; the bone was not infected in any of these animals. After feeding of formula diet, bacterial counts of the ileum were markedly elevated (p < 0.001), and the composition of the gut flora was disrupted. Bacterial translocation was noted in all formula-fed rats. Bone cultures were positive in 23 of 30 (77%) rats after formula-feeding (p < 0.001 versus breast-feeding). Organisms translocated to the bone included Enterococci, Proteus, Enterobacter, and Escherichia coli. Bacterial species cultured from the bone correlated with the individual colonization pattern of other extraintestinal organs and with the composition of the ileal flora. Members of the gut flora can escape the intestine and colonize the bone in formula-fed rats. The gut should be considered as a potential source for osteomyelitis in the neonate.

Time course of spontaneous bacterial translocation from gastrointestinal tract and its relationship to intestinal microflora in conventionally reared infant rats.

Whereas the developed gut mucosal barrier prevents luminal bacteria from invading the host, bacterial translocation appears to be facilitated in the neonate. The aim of this study was to determine the extent to which bacteria spontaneously translocate from the gut to extraintestinal organs during the neonatal period and to relate translocation to the evolving intestinal flora in the rat. Newborn Sprague-Dawley rats suckled ad libitum and ate regular chow after weaning. A total of 167 rats were killed either immediately or at 1, 9, 14, 21, 26, or 42 days after delivery. Mesenteric lymph nodes (MLN), liver, heart blood, and the terminal ileal loop were harvested under sterile conditions and analyzed for aerobic and facultatively anaerobic bacteria by standard microbiologic procedures. Bacterial translocation to the MLN and liver began soon after birth and peaked during the second week. On day 14, translocation to any organ was present in 85% of rats. All cultures from the liver were sterile after day 26. By contrast, the fall in translocation to the MLN was incomplete, as 50% of pups still had positive MLN on day 42. Blood cultures were positive in three of the 167 rats. The intensity of translocation as determined by the number of organs infected significantly increased with the number of gram-negative enterics and gram-positive cocci in the gut and was negatively correlated with the percentage of lactobacilli from the total measured intestinal flora (P < 0.0001). In conclusion, bacterial translocation from the gut is a physiological and age-dependent phenomenon in the neonatal rat. Translocation appears to be facilitated when intestinal concentrations of gram-negative enterics and gram-positive cocci are high and when the concentration of lactobacilli is low.

Anti-cardiolipin antibodies in patients with inflammatory bowel disease.

Elevated levels of anti-cardiolipin antibodies are associated with an increased risk for venous and arterial thrombosis. In patients with inflammatory bowel disease thrombosis is a well known complication. We determined the prevalence of elevated anti-cardiolipin antibodies in 136 patients with inflammatory bowel disease compared with 136 healthy controls and analyzed thromboembolic complications in patients with increased anti-cardiolipin antibody levels. Anti-cardiolipin antibody titers were significantly elevated in patients with Crohn's disease (5.7 units/ml) and ulcerative colitis (5.3 units/ml) compared to the control group (2.5 units/ml). We found no correlation between disease activity and anti-cardiolipin antibody levels. Seven patients had deep venous thrombosis in their history, in three of them this was complicated by pulmonary embolism. In only two of the seven patients with deep venous thrombosis were anti-cardiolipin antibody levels increased. In conclusion, anti-cardiolipin antibody titers were significantly increased in patients with inflammatory bowel disease. Elevated anti-cardiolipin antibody levels appear to play no role in the pathogenesis of thromboembolic events in patients with inflammatory bowel disease.

Mycophenolate mofetil in patients with Crohn's disease.

OBJECTIVE: Intolerance to azathioprine is a rare but important problem in treating chronically active Crohn's disease. We performed this study to evaluate mycophenolate mofetil as an alternative immunosuppressive therapy for patients with Crohn's disease who did not tolerate azathioprine. METHODS: Four patients with highly active perianal Crohn's disease and two patients with chronically active, steroid-dependent Crohn's disease were included. All patients consumed 2 g/day of mycophenolate mofetil for a median of 8 months (range, 6-12 months). Disease activity was measured by the Perianal Crohn's Disease Activity Index in patients with perianal disease and by the Crohn's Disease Activity Index in patients with chronically active Crohn's disease. RESULTS: Azathioprine-induced side effects disappeared after the drug was discontinued. All patients improved during treatment with mycophenolate mofetil, as shown by a remarkable reduction in the respective clinical scores. Five patients showed no side effects during treatment with mycophenolate mofetil. After 4 months' treatment one patient developed diarrhea that was probably not due to mycophenolate mofetil. CONCLUSION: Mycophenolate mofetil could be an alternative therapy to azathioprine in patients with Crohn's disease.

A comparison of stool characteristics from normal and constipated people.

In people with constipation, it is not known if decreased frequency of defecation is associated with abnormalities in the weight or in the consistency of stools or if the weight or the consistency of stools correlates with the severity of various discomforts associated with bowel movements. In neither normal nor constipated subjects has the consistency of stools been carefully correlated with their relative contents of water and solids. Our aim was to gain insight into these questions. Twenty subjects with idiopathic chronic constipation and 20 age- and sex-matched control subjects were recruited by advertisement. Stools were collected for one week. After each bowel movement, the subject's perception of various discomforts associated with the bowel movement were recorded. The stools were then analyzed. The results and conclusions were as follows: (1) Stool weight per bowel movement was similar in the two groups but stool weight per week was markedly reduced in constipated subjects. (2) Reduced stool weight per week in constipated subjects was due to a nearly proportional reduction in stool water and stool solids output. (3) Using data from both groups, there was a curvilinear correlation between percent insoluble stool solids and stool hardness, as measured by a texture analyzer; hardness increased only slightly as percent insoluble solids increased between 7 and 20%, but hardness increased dramatically when percent insoluble solids exceeded 25%. (4) Only 6% of stools from constipated subjects (2 of 34) had abnormally high values for percent stool solids and physical hardness. (5) In subjects with constipation, the severity of various discomforts associated with bowel movements (such as straining) correlated poorly with the weight or the hardness of stool that was produced by the bowel movement.

Short-term efficacy and long-term outcome of cyclosporine treatment in patients with severe ulcerative colitis.

Cyclosporine A (CyA) has been recommended for the treatment of severe steroid-resistant ulcerative colitis, however, long-term results are scarce. We prospectively followed a treatment plan in 14 patients with severe ulcerative colitis receiving intravenous CyA after failure to respond to at least eight days of standard therapy with prednisolone (1-1.5 mg/kg/day). CyA was delivered in a daily dose of 5 mg/kg i.v. for a mean of 14 days (range 7-28) in addition to ongoing medical therapy. CyA whole blood levels were monitored by HPLC and maintained between 100 ng/ml and 400 ng/ml. Responders were switched to oral CyA (5-7.5 mg/kg/day) for a mean of two months, and steroids were gradually tapered. Eleven patients (79%) initially responded to i.v. CyA, three patients failed to respond and underwent urgent colectomy. Time until response averaged seven days (range 3-13). Four of the eleven responders underwent colectomy because of severe relapse after one, eleven, twelve and 13 months of follow-up. The remaining seven patients were followed for a median of 48 months. During the first year of follow-up three out of seven had a severe relapse and responded to steroids (two patients) or to a further course of i.v. CyA (one patient). During CyA therapy one patient developed staphylococcal sepsis, other adverse events were mild and reversible. The results confirm that CyA is effective in severe steroid-refractory ulcerative colitis. Severe relapse and colectomy are uncommon after the first year of follow-up and the colon preserving effect of CyA can be maintained in up to 50% of patients over a period of four years.

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.

Effect of early nutritional deprivation and diet on translocation of bacteria from the gastrointestinal tract in the newborn rat.

The gastrointestinal (GI) barrier function is immature in the preterm neonate and might thus facilitate translocation of enteric bacteria and gut-derived septicemia. Circumstantial evidence suggests that bacterial uptake from the intestine may be further enhanced by an alteration of the host nutritional status. To test this hypothesis, neonatal rats were fed normal or restricted amounts of either breast milk or of a rat milk-simulated formula for 3-5 d. At the end of the study, various sections of the GI tract, mesenteric lymph nodes, liver, spleen, and blood were analyzed for bacteria using standard microbiologic procedures. Normal breast feeding was associated with bacterial translocation to mesenteric lymph nodes and in some cases to liver or spleen in 27% of rats, whereas all bacterial cultures were negative in a control group killed immediately after birth. Restricted breast feeding did not increase translocation compared with normal breast feeding. By contrast, feeding normal or restricted amounts of formula increased the numbers of gut bacteria by 2-3 logs, altered the morphology of the small intestinal mucosa, and resulted in ample bacterial translocation to the mesenteric lymph nodes and to systemic organs including the blood. Bacterial translocation may normally occur in suckling neonatal rats and is not increased by food restriction. Artificial feeding dramatically enhances translocation of gut bacteria.

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.