Kjell-Arne Ung

Prevention of ulcers by esomeprazole in at-risk patients using non-selective NSAIDs and COX-2 inhibitors

OBJECTIVES:Proton pump inhibitors reduce ulcer recurrence in non-steroidal anti-inflammatory drug (NSAID) users, but their impact in at-risk ulcer-free patients using the current spectrum of prescribed agents has not been clearly defined. We assessed esomeprazole for ulcer prevention in at-risk patients (≥60 yr and/or ulcer history) taking NSAIDs, including COX-2 inhibitors. Such studies are particularly relevant, given that concerns regarding adverse cardiovascular outcomes among COX-2 inhibitor users may prompt re-evaluation of their use.METHODS:We conducted two similar double-blind, placebo-controlled, randomized, multicenter studies; VENUS (United States) and PLUTO (multinational). A total of 844 and 585 patients requiring daily NSAIDs, including COX-2 inhibitors were randomized to receive esomeprazole (20 or 40 mg) or placebo, daily for 6 months.RESULTS:In the VENUS study, the life table estimated proportion of patients who developed ulcers over 6 months (primary variable, intent-to-treat population) was 20.4% on placebo, 5.3% on esomeprazole 20 mg (p < 0.001), and 4.7% on esomeprazole 40 mg (p < 0.0001). In the PLUTO study, the values were 12.3% on placebo, 5.2% with esomeprazole 20 mg (p= 0.018), and 4.4% with esomeprazole 40 mg (p= 0.007). Significant reductions were observed for users of both non-selective NSAIDs and COX-2 inhibitors. Pooled ulcer rates for patients using COX-2 inhibitors (n = 400) were 16.5% on placebo, 0.9% on esomeprazole 20 mg (p < 0.001) and 4.1% on esomeprazole 40 mg (p= 0.002). Esomeprazole was well tolerated and associated with better symptom control than placebo.CONCLUSIONS:For at-risk patients, esomeprazole was effective in preventing ulcers in long-term users of NSAIDs, including COX-2 inhibitors.

Role of bile acids and bile acid binding agents in patients with collagenous colitis

BACKGROUND In a retrospective study bile acid malabsorption was observed in patients with collagenous colitis. AIMS To study the occurrence of bile acid malabsorption and the effect of bile acid binders prospectively in patients with chronic diarrhoea and collagenous colitis. METHODS Over 36 months all patients referred because of chronic diarrhoea completed a diagnostic programme, including gastroscopy with duodenal biopsy, colonoscopy with biopsies, and the 75Se-homocholic acid taurine (75SeHCAT) test for bile acid malabsorption. Treatment with a bile acid binder (cholestyramine in 24, colestipol in three) was given, irrespective of the results of the 75SeHCAT test. RESULTS Collagenous colitis was found in 28 patients (six men, 22 women), 27 of whom had persistent symptoms and completed the programme. Four patients had had a previous cholecystectomy or a distal gastric resection. The 75SeHCAT test was abnormal in 12/27 (44%) of the collagenous colitis patients with 75SeHCAT values 0.5–9.7%, and normal in 15 patients (56%). Bile acid binding treatment was followed by a rapid, marked, or complete improvement in 21/27 (78%) of the collagenous colitis patients. Rapid improvement occurred in 11/12 (92%) of the patients with bile acid malabsorption compared with 10/15 (67%) of the patients with normal 75SeHCAT tests. CONCLUSION Bile acid malabsorption is common in patients with collagenous colitis and is probably an important pathophysiological factor. Because of a high response rate without serious side effects, bile acid binding treatment should be considered for collagenous colitis, particularly patients with bile acid malabsorption.

Intravenous iron sucrose is superior to oral iron sulphate for correcting anaemia and restoring iron stores in IBD patients: A randomized, controlled, evaluator-blind, multicentre study.

Objective. Patients with inflammatory bowel disease (IBD) often have low iron stores or anaemia. There is controversy about whether iron should be supplemented orally or intravenously (i.v.). The purpose of this study was to investigate whether treatment with intravenous iron is superior to treatment with oral iron. The primary end-points were response and remaining anaemia at the end of treatment (EOT). Material and methods. Ninety-one patients with IBD and anaemia (B-Hb <115 g/L) were randomized to oral iron sulphate (n=46) or intravenous iron sucrose (n=45) treatment for 20 weeks. Results. Forty-three patients in the intravenous iron group completed the study compared to 35 patients in the oral iron group (p=0.0009). Only 22 patients (48%) tolerated the prescribed oral dose, and 52% reduced the dose or withdrew from treatment because of poor tolerance. At EOT, 47% patients in the oral iron group increased their B-Hb by ≥20 g/L, compared with 66% in the intravenous iron group (p=0.07). In the oral iron group, 41% still had anaemia versus 16% of the patients in the intravenous iron group (p=0.007), and 22% versus 42% reached their reference B-Hb level (p=0.04). Treatment with intravenous iron sucrose improved iron stores faster and more effectively than oral iron (p=0.002). Under treatment with intravenous iron, 74% of the patients had no anaemia and normal S-ferritin levels (>25 µg/L) at EOT compared with 48% of patients receiving oral iron (p=0.013). Conclusions. Treatment with intravenous iron sucrose is effective, safe, well tolerated and superior to oral iron in correcting haemoglobin and iron stores in patients with IBD.

Increased colonic bile acid exposure: a relevant factor for symptoms and treatment in IBS

Objective Bile acids may play a role in the pathogenesis of IBS. We investigated the potential effects of bile acids entering the colon and its role in the symptom pattern in IBS. Design We measured 75Se-labelled homocholic acid-taurine (75SeHCAT) retention, and serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor (FGF) 19 in patients with IBS (n=141) and control subjects (75SeHCAT n=29; C4 and FGF19 n=435). In patients with IBS stool frequency and form, as well as GI symptom severity were registered, and in a proportion of patients colonic transit time and rectal sensitivity were measured (n=66). An 8-week open-label treatment with colestipol was offered to patients with 75SeHCAT <20%, and the effect of treatment was evaluated with IBS severity scoring system and adequate relief of IBS symptoms. Results Compared with controls, patients with IBS had lower 75SeHCAT values (p=0.005), higher C4c levels (C4 corrected for cholesterol) (p<0.001), but similar FGF19 levels. Abnormal 75SeHCAT retention (<10%) was seen in 18% of patients, whereas 23% had elevated C4c levels. Patients with IBS with 75SeHCAT retention <10% had more frequent stools, accelerated colonic transit time, rectal hyposensitivity, a higher body mass index, higher C4c and lower FGF19 levels. Colestipol treatment improved IBS symptoms (IBS severity scoring system 220±109 vs 277±106; p<0.01), and 15/27 patients fulfilled criteria for treatment response (adequate relief ≥50% of weeks 5–8). Conclusions Increased colonic bile acid exposure influences bowel habit and colonic transit time in patients with IBS. A high response rate to open label treatment with colestipol supports this, but placebo-controlled studies are warranted.

Accelerated regional bowel transit and overweight shown in idiopathic bile acid malabsorption.

OBJECTIVES:Overweight has recently been shown to accelerate small bowel transit. The role of gut transit and body weight in idiopathic bile acid malabsorption (IBAM) is unclear. We have prospectively studied gastrointestinal transit and body mass index (BMI) in patients with IBAM.METHODS:One hundred and ten patients with chronic diarrhea were prospectively included for transit measurements. All patients underwent a gastroscopy and colonoscopy, 75SeHCAT test for detection of bile acid malabsorption and calculation of BMI. Forty-three patients (15 men) had IBAM. A newly developed radiological procedure was used to measure gastrointestinal transit during one visit. The results were compared to results obtained in 83 healthy subjects.RESULTS:Colonic transit in women with IBAM was 0.8 (0.3–1.5) days versus 1.5 (1.0–3.7) days in healthy women (median and percentile 10 and 90; p < 0.0001). In men with IBAM it was 0.8 (0.1–1.0) days; in healthy men it was 1.3 (0.8–1.9) days, p < 0.0001. Segmental colonic transit was accelerated only in the distal colon in men and women with IBAM compared with healthy subjects. Small bowel transit time in women with IBAM was 1.9 (1.1–3.0) h versus 3.3 (1.5–6.3) h in healthy women, p = 0.0002. In men with IBAM it was 2.1 (1.2–3.2) h and 2.5 (1.4–4.3) h in healthy men (p = 0.04). BMI in patients with IBAM was 27.3 (20.4–33.8) kg/m2 and in healthy subjects it was 23.8 (20.5–26.2) kg/m2, p < 0.0001.CONCLUSION:Accelerated small bowel and distal colonic transit as well as overweight are probably involved in the pathophysiology of IBAM.

Colonic mucosal tears in collagenous colitis

In general, the colonic mucosa is macroscopically normal in collagenous colitis, although minor, non-specific abnormalities may be found. Significant endoscopic abnormalities, “mucosal tears” representing longitudinal mucosal lacerations, have been reported in a few patients with collagenous colitis. We report the cases of three women with collagenous colitis and mucosal tears detected at the index colonoscopy in order to illustrate the endoscopic characteristics and review the literature. Including the present cases, a total of 12 patients with mucosal tears and collagenous colitis have been reported. In 10 patients, the mucosal lacerations involved the ascending or the transverse colon. Three of the 12 patients had a colonic perforation immediately after the colonoscopy. The colonoscopist should be aware that the risk of perforation is likely to be increased when mucosal tears are present.

Effect of budesonide enema on remission and relapse rate in distal ulcerative colitis and proctitis.

Background: Glucocorticosteroid enemas are equally effective as 5-ASA enemas in the treatment of active distal ulcerative colitis (UC). With the introduction of budesonide, the risk of systemic side effects may be reduced. We investigated whether budesonide enema, 2 mg/100 ml, administered twice daily (b.i.d.) could increase the remission rate in comparison with the once daily (o.d.) standard regimen. Furthermore, we evaluated whether 2 mg budesonide enema, given twice weekly, could have a relapse preventing effect. Methods: 149 patients with active distal UC were treated in a controlled, double-blind multicentre study with two parallel groups: placebo enema in the morning and budesonide enema in the evening (i.e. 2 mg/day) or budesonide enema b.i.d. (i.e. 4 mg/day) until remission (absence of clinical symptoms and endoscopic healing) or at most 8 weeks. Patients in remission were randomized to either budesonide enema or placebo enema twice weekly for 24 weeks or until relapse. Results: The remission rates at 4 weeks were 33% for o.d. and 41% for b.i.d. regimens (NS) and correspondingly 51% and 54% at 8 weeks (NS). The b.i.d. group had an increased frequency of impaired adrenal function, 32% versus 4.8% ( P = 0.001). The relapse rates during maintenance treatment with budesonide enema and placebo were 15% versus 24% after 8 weeks, 31% versus 27% after 16 weeks and 41% versus 51% after 24 weeks (NS). Conclusion: Budesonide enema 2 mg o.d. appears to be the optimal dosage in active distal UC. We could not show that budesonide enema twice weekly is sufficient to maintain remission.

Detection of inflammatory markers in stools from patients with irritable bowel syndrome and collagenous colitis

Objective. Irritable bowel syndrome (IBS) and collagenous colitis (CC) share chronically recurring symptoms of altered bowel habits associated with abdominal pain or discomfort. The aims of the present study were to investigate whether inflammatory markers could be detected in faeces from patients with IBS and CC, and to elucidate whether such analyses could be used as non-invasive tools to distinguish between these disorders. Material and methods. Stool samples were obtained from 18 patients with CC, 46 patients with IBS and 20 healthy controls (HC). Eosinophil protein X (EPX), myeloperoxidase (MPO), tryptase, interleukin-1 beta (IL-1β) and tumour necrosis factor alpha (TNFα) were measured in supernatants from processed faeces using immunoassays. Results. EPX levels were enhanced in faeces from CC patients (median 3.8 µg/g (0.47–16.2)) compared to patients with IBS (0.44 µg/g (0.25–1.8)), p<0.001, and HC (0.46 µg/g (0.21–1.3)), p<0.001. In addition, MPO was increased in CC patients (11.7 µg/g (2.0–124)) compared to IBS patients (1.7 µg/g (0.81–5.2)), p<0.01, and HC (2.5 µg/g (1.1–6.3)), p<0.05. Tryptase was found in 9/18 patients with CC, 6/46 with IBS and 1/19 HC. IL-1β was only enhanced in 2/11 CC patients and TNFα was not detected in any sample. Conclusions. Increased levels of EPX, MPO and tryptase were observed in stools from collagenous colitis patients, whereas the levels in IBS patients did not differ from healthy controls. Our data suggest that faecal markers could be used as part of the clinical work-up to determine which patients should be biopsied and evaluated for collagenous colitis.

Fecal calprotectin one year after ileocaecal resection for Crohn's disease — A comparison with findings at ileocolonoscopy

BACKGROUND AND AIMS Ileocaecal resection for Crohns disease is commonly performed. The severity of endoscopic lesions in the anastomotic area one year postoperatively is considered to reflect the subsequent clinical course. Fecal calprotectin (FC) has been shown to correlate with the findings at ileocolonoscopy in Crohns disease. The objectives of this study were to assess whether the concentration of FC reflects the endoscopic findings one year after ileocaecal resection and to evaluate the variation of FC in individual patients during 6months prior to the ileocolonoscopy. METHODS Thirty patients with Crohns disease and ileocaecal resection performed within one year were included. Stool samples were delivered monthly until an ileocolonoscopy was performed one year postoperatively. RESULTS One year after surgery the median values of FC were not significantly different between the patients in endoscopic remission (n=17) and the patients with an endoscopic recurrence (189 (75-364) vs 227 (120-1066)μg/g; p=0.25). However, most patients with low values were in remission and all patients with high (>600μg/g) calprotectin values had recurrent disease. The variability of the FC concentration was most pronounced in patients with diarrhea. CONCLUSIONS We found no statistical difference in the concentrations of calprotectin between patients in endoscopic remission and patients with a recurrent disease one year after ileocaecal resection for Crohns disease. However, among the minority of patients with low or high values, FC indicated remission and recurrence, respectively. There was significant variation of the fecal calprotectin concentrations over time, which affects the utility of calprotectin in clinical practice.

Normal or increased bile acid uptake in isolated mucosa from patients with bile acid malabsorption

Introduction Bile acid malabsorption as reflected by an abnormal 75Se-labelled homocholic acid-taurine (75SeHCAT) test is associated with diarrhoea, but the mechanisms and cause-and-effect relations are unclear. Objectives Primarily, to determine whether there is a reduced active bile acid uptake in the terminal ileum in patients with bile acid malabsorption. Secondarily, to study the linkage between bile acid malabsorption and hepatic bile acid synthesis. Methods Ileal biopsies were taken from patients with diarrhoea and from controls with normal bowel habits. Maximal active bile acid uptake was assessed in ileal biopsies using a previously validated technique based on uptake of 14C-labelled taurocholate. To monitor the hepatic synthesis, 7&agr;-hydroxy-4-cholesten-3-one, a bile acid precursor, was assayed in blood. The 75SeHCAT-retention test was used to diagnose bile acid malabsorption. Results The taurocholate uptake in specimens from diarrhoea patients was higher compared with the controls [median, 7.7 (n=53) vs 6.1 μmol/g per min (n=17)] (P<0.01) but no difference was seen between those with bile acid malabsorption (n=18) versus diarrhoea with a normal 75SeHCAT test (n=23). The 75SeHCAT values and 7&agr;-hydroxy-4-cholesten-3-one were inversely correlated. Conclusions The data do not support bile acid malabsorption being due to a reduced active bile acid uptake capacity in the terminal ileum.