Gunnar Olaison

Natural course of Crohn's disease after ileocolic resection: endoscopically visualised ileal ulcers preceding symptoms.

Forty two Crohns disease patients were followed up after ileocolic resection with regard to symptoms and endoscopic appearance of the ileocolic anastomosis. Twenty eight patients resected because of colonic neoplasm served as controls. In all the Crohns disease patients the ileal resection margin was disease free macroscopically at operation. In addition, intraoperative ileoscopy was performed in 13 and no sign of residual inflammation in the neoterminal ileum was seen. Endoscopy soon after surgery often showed preanastomotic ileal ulceration before symptoms appeared, whereas no anastomotic lesions were observed in the controls. Thus, 22 of 30 Crohns disease patients examined had ulceration of the anastomotic area after three months, but only 10 had developed symptoms indicating relapse (73 v 33%). Corresponding figures in the 30 patients examined after one year were 93 v 37%, and in 14 patients after three years they were 100 and 86% respectively. The inflammatory lesions in all cases were preanastomotic, in the neoterminal ileum, and showed time related progression from aphthae to larger ulcers and stricture. The study suggests that endoscopically observed inflammatory lesions that appear soon after ileocolic resection for Crohns disease signify new inflammation and not residual, persistent disease or incomplete anastomotic healing. The data further suggest that despite clinical remission after apparently radical intestinal resection, the bowel is permanently inflamed in Crohns disease.

Appendectomy and protection against ulcerative colitis.

BACKGROUND A history of appendectomy is rare in patients with ulcerative colitis. This suggests a protective effect of appendectomy or that appendicitis and ulcerative colitis are alternative inflammatory responses. We sought to characterize this inverse relation further. METHODS We studied a cohort of 212,963 patients who underwent appendectomy before the age of 50 years between 1964 and 1993 and a cohort of matched controls who were identified from the Swedish Inpatient Register and the nationwide census. The cohort was followed until 1995 for any subsequent diagnosis of ulcerative colitis. RESULTS Patients who underwent appendectomy for appendicitis and mesenteric lymphadenitis had a low risk of ulcerative colitis (for patients with perforated appendicitis, the adjusted hazard ratio was 0.58 [95 percent confidence interval, 0.38 to 0.87]; for those with nonperforated appendicitis it was 0.76 [95 percent confidence interval, 0.65 to 0.90]; and for those with mesenteric lymphadenitis it was 0.57 [95 percent confidence interval, 0.36 to 0.89]). In contrast, patients who underwent appendectomy for nonspecific abdominal pain had the same risk of ulcerative colitis as the controls (adjusted hazard ratio, 1.06; 95 percent confidence interval, 0.74 to 1.52). For the patients who had appendicitis, an inverse relation with the risk of ulcerative colitis was found only for those who underwent surgery before the age of 20 years (P<0.001). CONCLUSIONS Appendectomy for an inflammatory condition (appendicitis or lymphadenitis) but not for nonspecific abdominal pain is associated with a low risk of subsequent ulcerative colitis. This inverse relation is limited to patients who undergo surgery before the age of 20 years.

Augmented increase in tight junction permeability by luminal stimuli in the non-inflamed ileum of Crohn's disease

Background: Crohns disease is associated with deranged intestinal permeability in vivo, suggesting dysfunction of tight junctions. The luminal contents are important for development of neoinflammation following resection. Regulation of tight junctions by luminal factors has not previously been studied in Crohns disease. Aims: The aim of the study was to investigate the effects of a luminal stimulus, known to affect tight junctions, on the distal ileum in patients with Crohns disease. Patients: Surgical specimens from the distal ileum of patients with Crohns disease (n=12) were studied, and ileal specimens from colon cancer patients (n=13) served as controls. Methods: Mucosal permeability to 51Cr-EDTA and electrical resistance were studied in Ussing chambers during luminal exposure to sodium caprate (a constituent of milk fat, affecting tight junctions) or to buffer only. The mechanisms involved were studied by mucosal ATP levels, and by electron and confocal microscopy. Results: Baseline permeability was the same in non-inflamed ileum of Crohns disease and controls. Sodium caprate induced a rapid increase in paracellular permeability—that is, increased permeation of 51Cr-EDTA and decreased electrical resistance—which was more pronounced in non-inflamed ileum of Crohns disease, and electron microscopy showed dilatations within the tight junctions. Moreover, sodium caprate induced disassembly of perijunctional filamentous actin was more pronounced in Crohns disease mucosa. Mucosal permeability changes were accompanied by mitochondrial swelling and a fall in epithelial ATP content, suggesting uncoupling of oxidative phosphorylation. Conclusions: The tight junctions in the non-inflamed distal ileum of Crohns disease were more reactive to luminal stimuli, possibly mediated via disturbed cytoskeletal contractility. This could contribute to the development of mucosal neoinflammation in Crohns disease.

Epithelial permeability to proteins in the noninflamed ileum of Crohn's disease?

BACKGROUND & AIMS Crohns disease (CD) is associated with a disturbed intestinal barrier. Permeability studies have focused on inert molecules, but little is known about transepithelial transport of macromolecules with antigenic potential in humans. The aim of this study was to quantify permeation and to characterize passage routes for macromolecules in ileal mucosa in CD. METHODS Noninflamed and inflamed ileal mucosa specimens from patients with CD (n = 12) and ileal specimens from patients with colon cancer (n = 7) were studied regarding transmucosal permeation of ovalbumin, dextran (mol wt, 40,000), and 51Cr-EDTA for 90 minutes in vitro in Ussing chambers. Transepithelial passage routes for fluorescent ovalbumin and dextran 40,000 were investigated by confocal microscopy. RESULTS Noninflamed ileum from CD patients showed increased permeation of ovalbumin compared with ileum from colon cancer patients (P < 0.05). Dextran permeation was equal in the three groups, whereas 51Cr-EDTA permeability was increased in inflamed ileum. Ovalbumin passed both transcellularly and paracellularly, but dextran followed a strictly paracellular route. Both markers were subsequently endocytosed by cells of the lamina propria. CONCLUSIONS Noninflamed ileal mucosa from patients with CD shows increased epithelial permeability to ovalbumin, probably by augmented transcytosis. This increase in antigen load to the lamina propria could be an initiating pathogenic event in CD.

Different intestinal permeability patterns in relatives and spouses of patients with Crohn’s disease: an inherited defect in mucosal defence?

Background A familial defect in intestinal barrier function has been found in Crohn’s disease. Aim To investigate possible genetic and environmental influences on this barrier defect by studying intestinal permeability in both relatives and spouses of patients with Crohn’s disease. Subjects The study included 39 patients with Crohn’s disease, 34 healthy first degree relatives, and 22 spouses. Twenty nine healthy volunteers served as controls. Methods Intestinal permeability was assessed as the lactulose:mannitol ratio in five hour urinary excretion after oral load, both before (baseline) and after ingestion of acetylsalicylic acid. The permeability response represents the difference between the two tests. A ratio above the 95th percentile for controls was classified as abnormal. Results Baseline permeability was higher in patients and spouses than in controls. An abnormal baseline permeability was seen in 36% of the patients, 23% of the spouses, 18% of the relatives, and 3% of the controls. After ingestion of acetylsalicylic acid, permeability increased significantly in all groups. Relatives were similar to patients with regard to permeability after exposure to acetylsalicylic acid, whereas spouses were similar to controls. The proportions with an abnormal permeability response to acetylsalicylic acid were 32% in patients, 14% in spouses, 41% in relatives, and 3% in controls. Conclusion The findings suggest that baseline permeability is determined by environmental factors, whereas permeability provoked by acetylsalicylic acid is a function of the genetically determined state of the mucosal barrier, and support the notion that environmental and hereditary factors interact in the pathogenesis of Crohn’s disease.

Diagnostic value of disease history, clinical presentation, and inflammatory parameters of appendicitis.

The clinical diagnosis of appendicitis needs to be improved, as up to 40% of explorations for suspected appendicitis are unnecessary. The use of body temperature and laboratory examinations as diagnostic aids in the management of these patients is controversial. The diagnostic power of these variables compared to that of the disease history and clinical findings is not well studied. In this study we prospectively assessed and compared the diagnostic value of 21 elements of the history, clinical findings, body temperature, and laboratory examinations in 496 patients with suspected appendicitis. The diagnostic value of each variable was compared from the area under the receiver operating characteristic (ROC) curve and the likelihood ratios (LR). Logistic regression was used to analyze the diagnostic value of a combination of variables and to analyze independent relations. No single variable had sufficiently high discriminating or predicting power to be used as a true diagnostic test. The inflammatory variables (temperature, leukocyte and differential white blood cell (WBC) counts, C-reactive protein) had discriminating and predicting powers similar to those of the clinical findings (direct and rebound abdominal tenderness and guarding). Anorexia, nausea, and right-sided rectal tenderness had no diagnostic value. The leukocyte and differential WBC counts, C-reactive protein, rebound tenderness, guarding, and gender were independent predictors of appendicitis with a combined ROC area of 0. 93 for appendicitis. This showed that inflammatory variables contain important diagnostic information, especially with advanced appendicitis. They should therefore always be included in the diagnostic workup in patients with suspected appendicitis.

Glucocorticoid treatment in ileal Crohn's disease: relief of symptoms but not of endoscopically viewed inflammation.

The effect of prednisolone (20-30 mg daily for six to nine weeks) was studied in eight patients with Crohns disease and recurrent, preanastomotic ileal inflammation, in respect of symptoms, endoscopic findings and phospholipase A2 activity in the ileal mucosa. The Harvey-Bradshaw Crohns disease activity index improved significantly, mainly because of reduced frequency of loose stools and diminution of abdominal pain. Endoscopy revealed no corresponding decrease in ileal inflammation, which in all cases persisted after treatment. The phospholipase A2 activity in the ileal mucosa was not altered by prednisolone. In two of three patients with concomitant colitis colonic inflammation improved. The study confirmed earlier reports of good symptomatic relief from glucocorticoid treatment in Crohns disease of the small bowel, but endoscopy suggests that this improvement was not the result of resolution of small intestinal mucosal inflammation.

Mechanism of Absorption Enhancement in Humans After Rectal Administration of Ampicillin in Suppositories Containing Sodium Caprate

AbstractPurpose. The medium chain fatty acid sodium caprate (C10) is approved as an absorption enhancer but its mechanism of action has not been studied in humans. The aim of this study was to investigate the mechanism of action of C10 in human subjects after rectal administration. Methods. Twelve healthy human subjects were randomised to receive ampicillin suppositories with (AM-C10) or without (AM) C10. Serum and urine samples were collected and analysed for ampicillin by HPLC. Rectal biopsies were taken before and 25 min (approximate time of maximum serum concentration, Cmax, for ampicillin) and 185 min (during the final part of the elimination phase) after rectal administration of the suppositories. The osmolality of the rectal fluid was also measured. Results. AM-C10 administration increased Cmax, area under the serum concentration-time curve (AUC) and urinary recovery of ampicillin 2.6-, 2.3- and 1.8-fold, respectively, compared to AM. Histological examination of the biopsies showed that AM-C10 exposure resulted in reversible mucosal damage that occurred at the same time as the Cmax for ampicillin while AM prolonged mucosal damage. A reversible increase in rectal fluid osmolality was observed with both treatments. Conclusions. AM-ClO-enhanced absorption of ampicillin coincides with non-specific damage to the rectal mucosa. C10 itself as well as the suppository base and the hyperosmolality of the rectal fluid contributed to this effect. However, the histological damage was reversible with AM-C10, suggesting that C10 also has a protective effect on the rectal mucosa.

Endoscopic biopsies in Ussing chambers evaluated for studies of macromolecular permeability in the human colon

Objective Studies of mucosal permeability to protein antigens in humans are limited to in vitro techniques. The use of surgical specimens for such studies has major shortcomings. Endoscopic biopsies in Ussing chambers have been introduced as a means of studying secretion and transepithelial permeability, but have not been evaluated for studies of protein antigen uptake in human intestine. Material and methods Standard forceps biopsies from the sigmoid colon of 24 healthy volunteers were mounted in Ussing chambers with an exposed tissue area of 1.76 mm2. 51Cr-EDTA (paracellular probe) and horseradish peroxidase (HRP; 45 kDa protein antigen) were used as permeability markers. Mucosal permeability, electrophysiology, histology and energy contents of the biopsies were studied over time. To evaluate the ability of the technique to detect permeability changes, the mucosa was modulated with capric acid, a medium-chain fatty acid, known to affect tight junctions. Results In the Ussing chamber the mucosal biopsies were viable for 160 min with stable levels of ATP and lactate, and only minor changes in morphology. Steady-state permeability with low variability was seen for both markers during the 30–90 min period. Exposure to capric acid induced a rapid decrease in short-circuit current (Isc) and a slower reversible decrease in transepithelial resistance (TER), as well as an increased permeability to 51Cr-EDTA and HRP. Conclusions Endoscopic biopsies of human colon are viable in Ussing chambers and are reliable tools for studies of mucosal permeability to protein antigens. The technique offers a broad potential for studies of mucosal function in the pathophysiology of human gastrointestinal diseases.

Thiopurine therapy is associated with postoperative intra-abdominal septic complications in abdominal surgery for Crohn's disease.

PURPOSE: Thiopurines are important as maintenance therapy in Crohn’s disease, but there have been concerns whether thiopurines increase the risk for anastomotic complications. The present study was performed to assess whether thiopurines alone, or together with other possible risk factors, are associated with postoperative intra-abdominal septic complications after abdominal surgery for Crohn’s disease. METHODS: Prospectively registered data regarding perioperative factors were collected at a single tertiary referral center from 1989 to 2002. Data from 343 consecutive abdominal operations on patients with Crohn’s disease were entered into a multivariate analysis to evaluate risk factors for intra-abdominal septic complications. All operations involved either anastomoses, strictureplasties, or both; no operations, however, involved proximal diversion. RESULTS: Intra-abdominal septic complications occurred in 26 of 343 operations (8%). Thiopurine therapy was associated with an increased risk of intra-abdominal septic complications (16% with therapy; 6% without therapy; P = 0.044). Together with established risk factors such as preoperative intra-abdominal sepsis (18% with sepsis; 6% without sepsis; P = 0.024) and colo-colonic anastomosis (16% with such anastomosis; 6% with other types of anastomosis; P = 0.031), thiopurine therapy was associated with intra-abdominal septic complications in 24% if any 2 or all 3 risk factors were present compared with 13% if any 1 factor was present, and only 4% in patients if none of these factors were present (P < 0.0001). CONCLUSIONS: Thiopurine therapy is associated with postoperative intra-abdominal septic complications. The risk for intra-abdominal septic complications was related to the number of identified risk factors. This increased risk should be taken into consideration when planning surgery for Crohn’s disease.