Intestinal permeability in patients with Crohn's disease and their first degree relatives.

It has been reported that intestinal permeability to polyethylene glycol 400 is increased in patients with Crohn's disease and their apparently unaffected first degree relatives. Because of the implications that these findings have for the aetiology of Crohn's disease these studies were repeated. Patients with Crohn's disease (n = 28) and 32 first degree relatives from 11 families underwent a polyethylene glycol 400 (PEG400) intestinal permeability test and a hyperosmotic (1500 mosmol/l) absorption/permeability test using 3-0-methyl-D-glucose, D-xylose, L-rhamnose, lactulose, and 51chromium labelled ethylenediamine-tetraacetate. The five hour urine excretion of polyethylene glycol 400 did not differ significantly between controls (n = 25) and first degree relatives, 25.5 (3.3)% v 24.6% (4)% (mean(SD)) p greater than 0.1, respectively. Patients with small bowel involvement excreted significantly less (p less than 0.01) polyethylene glycol 400 (16.3 (4.6)% than controls while those with Crohn's colitis did not (26.4 (3.9)% p greater than 0.1). The permeation of the monosaccharides in patients with Crohn's disease and their first degree relatives did not differ from normal subjects. The permeation of lactulose and 51chromium ethylenediaminetetraacetate was not significantly altered in first degree relatives but was significantly increased in the patients, as was the lactulose/L-rhamnose urine excretion ratio which is a specific measure of small intestinal permeability. These studies show normal absorption and permeability in first degree relatives of patients with Crohn's disease. A genetically determined abnormality of intestinal permeability is not likely to be an important aetiological factor in Crohn's disease.     

Intestinal permeability in gastrointestinal disorders

This study examined intestinal permeability in gastrointestinal disorders by measuring urinary recovery following oral administration of [99mTc]DTPA in 117 subjects. The mean percent of the ingested dose excreted in a 24-hr urine sample was 2.8 +/- 1.6% in 11 healthy controls, 10.8 +/- 10.2% (P less than 0.001) in 21 ulcerative colitis patients, 8.0 +/- 4.7% (P less than 0.001) in 35 Crohn's disease patients, 5.1 +/- 2.9% (P less than 0.01) in 17 patients with heterogeneous digestive disease diagnoses, and 3.2 +/- 4.7% (P greater than 0.05) in 33 patients with hepatobiliary diagnoses. Among ambulatory patients, Crohn's disease subjects, but not ulcerative colitis patients, had greater urinary recovery than the controls (P less than 0.05). The Crohn's disease activity index correlated positively with the radionuclide recovery in Crohn's subjects (r = 0.455, P less than 0.02). In a heterogeneous sample of subjects simultaneous ingestion of [99mTc]DTPA and [51Cr]EDTA produced urinary levels that were correlated positively (r = 0.556, P less than 0.001). Increased absorption of [99mTc]DTPA relative to [51Cr]EDTA, however, was noted in ulcerative colitis patients (P less than 0.05). In conclusion, increased intestinal permeability has been demonstrated by utilizing [99mTc]DTPA in Crohn's disease and ulcerative colitis patients. Although this observation appears to be a nonspecific indicator of injury, the test provides a simple objective means of establishing disease activity, which possibly may be utilized for therapeutic and investigative studies.     

Assessment of pulmonary epithelial permeability in interstitial lung diseases]

The pulmonary epithelial permeability of 99mTc-DTPA (diethylene triamine penta acetate) was assessed in patients with interstitial lung diseases including radiation pneumonitis, idiopathic interstitial pneumonia/pulmonary fibrosis, sarcoidosis, unclassified interstitial pneumonia, and in healthy subjects. Pulmonary epithelial permeability was estimated by the rate constant (kep) of inhaled 99mTc-DTPA clearance from the lungs. Healthy nonsmokers had a mean kep value of 0.82 +/- 0.26% min, and their kep values were constant irrespective of age or sex. Of healthy smokers, 53% showed an increase in kep. This increase correlated with their cigarette consumption per day, but was reversible after cessation of smoking. The provocative concentration of histamine to decrease FEV 1.0 by more than 20% caused an increase in epithelial permeability. However, its effect on permeability was transient, limited, and not dose-dependent. During lung inflation by continuous external negative pressure or by positive end-expiratory pressure, pulmonary 99mTc-DTPA clearance was increased, suggesting changes in epithelial permeability. The patients with diffuse interstitial lung diseases also showed increased permeability compared with healthy nonsmokers. In the patients with pre-existing radiation pneumonitis, the mean kep value obtained from the area with infiltration on chest X-ray films was significantly higher than that from the opposite lung. In the prospective study, 3 of 11 patients developed radiation pneumonitis during the course of radiation therapy. The mean kep value obtained in the 3 patients who developed radiation pneumonitis increased just before onset, and further increased when the disease manifested clinically. We believe that 99mTc-DTPA aerosol inhalation is a sensitive test for the detection of inflammatory changes in the bronchioalveolar epithelium.     

The effect of airway deposition on the assessment of lung injury by 99mTc-DTPA clearance--lung injury in interstitial lung diseases assessed by using the duplicated 99mTc-DTPA aerosol inhalation method

The 99mTc-DTPA aerosol inhalation method permits detection of pulmonary epithelial damage. We investigated one of several problems, airway deposition of inhaled aerosol, on the assessment of pulmonary epithelial permeability in healthy nonsmokers and patients with interstitial lung diseases. We used the rate constant of pulmonary 99mTc-DTPA clearance curve, k, as a parameter of the epithelial permeability. The alveolar-peripheral airway deposition of aerosol was estimated by the duplicated inhalation method, which we newly developed. The mean k in patients with interstitial lung diseases (2.52 +/- 0.72%/min, n = 8; p less than 0.01) was significantly greater than that in healthy nonsmokers (0.92 +/- 0.20%/min, n = 4). The alveolar-peripheral airway deposition was similar in both healthy nonsmokers and interstitial lung diseases (73.5 +/- 7.8% and 75.5 +/- 9.2%, respectively). The mean k corrected for alveolar-peripheral airway deposition (corrected k; kc) was higher in patients with interstitial lung diseases (4.08 +/- 1.63%/min; p less than 0.01) as compared with healthy nonsmokers (1.36 +/- 0.47%/min). The mean k was significantly greater than the mean kc in both groups (p less than 0.01, p less than 0.01). However, there was a significant correlation between the k and kc obtained among the subjects (r = 0.951; p less than 0.01). We, therefore, conclude that correction for alveolar-peripheral airway deposition was not necessary to distinguish the patients with interstitial lung diseases from the healthy nonsmokers using 99mTc-DTPA aerosol inhalation method although the correction was significant in the individual subjects.     

Small-bowel permeability in collagenous colitis

OBJECTIVE: Collagenous colitis (CC) is a chronic inflammatory bowel disease that affects the colon. However, some patients with CC present with accompanying pathologic small-bowel manifestations such as coeliac disease, defects in bile acid absorption and histopathologic changes in small-intestinal biopsies, indicating that CC is a pan-intestinal disease. In small-intestinal disease, the intestinal barrier function may be impaired, and the permeability of the small intestine altered. The purpose of this research was to study small-bowel function in patients with CC as expressed by intestinal permeability. MATERIAL AND METHODS: Ten patients with CC and chronic diarrhoea participated in the study. Coeliac disease was excluded by small-bowel biopsy and/or serology. Intestinal permeability was assessed as urinary excretion (ratios) 2, 4 and 6 h after ingestion of 14C-labelled mannitol (14C-mannitol) and 99mTc-labelled diethylenetriamine-pentaacetic acid (99mTc-DTPA). Data were compared with the results from healthy controls. RESULTS: No difference was found between groups in urinary excretion of 14C-mannitol and 99mTc-DTPA after 2, 4 or 6 h, respectively. Likewise, no significant differences in the 99mTc-DTPA/14C-mannitol ratios between patients and controls were detected after 2 h: 0.030 (0.008-0.130) versus 0.020 (0.007-0.030), p = 0.19, after 4 h: 0.040 (0.009-0.180) versus 0.020 (0.008-0.040), p = 0.14 or after 6 h: 0.040 (0.012-0.180) versus 0.020 (0.010-0.040), p = 0.17. CONCLUSIONS: No alterations in intestinal permeability in patients with CC could be demonstrated. Impairment of the integrity of the mucosa of the small bowel and the presence of a general dysfunction of the small intestine in patients with CC seem unlikely.     

Increased intestinal permeability in patients with Crohn's disease and their relatives. A possible etiologic factor

The cause of Crohn's disease is unknown, although alterations in intestinal permeability may play a primary role. Because we were interested in permeability changes that occur before the onset of intestinal inflammation, we took advantage of the known genetic predisposition to this disease and studied not only patients with Crohn's disease, but their clinically unaffected relatives as well. Intestinal permeability was assessed using the marker polyethylene glycol-400 ingested with a standard meal. We found that 17 normal volunteers absorbed 215 +/- 29.6 mg (mean +/- SE), whereas 11 patients with Crohn's disease absorbed 514 +/- 94.7 mg and their 32 healthy relatives absorbed 566 +/- 62.4 mg. The twofold increase in permeability of patients and their relatives (p less than 0.005 compared with controls) indicates that the intestinal defect in the ability to exclude larger sized molecules is not secondary to clinically recognized intestinal inflammation, but is a primary defect that may be an etiologic factor in this disease.     

Ozone exposure increases respiratory epithelial permeability in humans

Ozone is a respiratory irritant that has been shown to cause an increase in the permeability of the respiratory epithelium in animals. We used inhaled aerosolized 99mTc-labeled diethylene triamine pentacetic acid (99mTc-DTPA) to investigate whether human respiratory epithelial permeability is similarly affected by exposure to ozone. In a randomized, crossover double-blinded study, 8 healthy, nonsmoking young men were exposed for 2 h to purified air and 0.4 ppm ozone while performing intermittent high intensity treadmill exercise (minute ventilation = 66.8 L/min). SRaw and FVC were measured before and at the end of exposures. Seventy-five minutes after the exposures, the pulmonary clearance of 99mTc-DTPA was measured by sequential posterior lung imaging with a computer-assisted gamma camera. Ozone exposure caused respiratory symptoms in all 8 subjects and was associated with a 14 +/- 2.8% (mean +/- SEM) decrement in FVC (p less than 0.001) and a 71 +/- 22% increase in SRaw (p = 0.04). Compared with the air exposure day, 7 of the 8 subjects showed increased 99mTc-DTPA clearance after the ozone exposure, with the mean value increasing from 0.59 +/- 0.08 to 1.75 +/- 0.43%/min (p = 0.03). These data show that ozone exposure sufficient to produce decrements in the pulmonary function of human subjects also causes an increase in 99mTc-DTPA clearance.     

Technetium 99mTc-DTPA clearance in the evaluation of pulmonary involvement in patients with diabetes mellitus

Systemic thickening of capillary endothelial basement membrane underlies the chronic complications of human diabetic microangiopathy. Since 99mTc-DTPA aerosol scintigraphy is a sensitive, non-invasive test of membrane permeability, we decided to study the effect of diabetes on the permeability of lung epithelium in diabetic patients using this test. Fifty (NIDDM) patients, aged 40-70 years, with or without complications, and who were non-smokers, were subjected to evaluation using 99mTc-DTPA aerosol. At the same time, pulmonary function tests, including carbon monoxide diffusion capacity, were done. Normal non-smoking subjects with no history of cardio-respiratory disease, who underwent 99mTc-DTPA and pulmonary function tests, served as controls. The risk factors which included age, sex, degree of control and presence of complications were noted. Twenty-nine (58%) of the patients had abnormal 99mTc-DTPA clearance. Thirty-four percent of the patients with complications and 24% of those without complications had abnormal clearance. Complications recorded included retinopathy, neuropathy and nephropathy. Fifty-five percent of patients with abnormal 99mTc-DTPA had suffered from diabetes for longer than 10 years. Sixty-two percent of patients with poor glycaemic control had abnormal 99mTc-DTPA. Diffusion capacity was not significantly affected in patients with complicated diabetes. Our preliminary results suggest that 99mTc-DTPA is a potentially sensitive test in assessing the degree of lung affection in diabetic patients. No significant correlation exists between diffusion capacity and 99mTc-DTPA. The risk factors did not affect the 99mTc-DTPA clearance, probably due to the small sample size.     

Non-invasive evaluation of activity in inflammatory bowel disease by power Doppler sonography

BACKGROUND: To study the vascularization in the diseased bowel wall by power Doppler sonography in patients with inflammatory bowel disease. PATIENTS AND METHODS: The diseased bowel wall was investigated in 99 patients with inflammatory bowel disease (60 patients with Crohn's disease and 39 patients with ulcerative colitis) either with active disease or in remission by B-mode and power Doppler sonography. Disease activity was determined by clinical indices. Twenty healthy age and sex matched individuals served as controls. RESULTS: Bowel wall was thickened in active Crohn's disease (mean 7 mm, range 4-14) and ulcerative colitis (mean 5 mm, range 2-15) as compared to healthy controls (mean 2 mm, range 1-3), p < 0.001. In contrast to healthy controls blood vessels were detected in the bowel wall in 100 % of patients with active Crohn's disease and 91 % with active ulcerative colitis. Vascularization was significant decreased in patients with quiescent versus active disease in ulcerative colitis (p < 0.05), while in Crohn's disease there was no significance between active and remission phase. CONCLUSIONS: Thickened and hypervascularized bowel wall are characteristic findings in inflammatory bowel disease. A combination of B-mode and power Doppler sonography offers an additional noninvasive procedure for the determination of activity in patients with inflammatory bowel disease.     

Effect of leukotriene receptor antagonists on vascular permeability during endotoxic shock

Evidence has accumulated that sulfidopeptide leukotrienes are significant pathogenic mediators of certain hematologic and hemodynamic sequelae of endotoxic shock. In the present study, the effects of a selective LTD4/E4 receptor antagonist, LY171883 (LY), or a selective LTD4 receptor antagonist, SKF-104353 (SKF), were assessed on splanchnic and pulmonary localization of 99mTechnetium-labeled human serum albumin (99mTc-HSA) in acute endotoxic shock in the rat. Dynamic gamma camera imaging of heart (H), midabdominal (GI), and lung regions of interest generated time activity curves for baseline and at 5-35 min after Salmonella enteritidis endotoxin (10 mg/kg, i.v.). Slopes of GI/H and lung/H activity (permeability index, GI/H or lung/H X 10(-3)/min) provided indices of intestinal and lung localization. Rats received LY (30 mg/kg, i.v.), LY vehicle (LY Veh), SKF (10 mg/kg), or SKF vehicle (SK Veh) 10 min prior to endotoxin or endotoxin vehicle. In rats receiving the LY Veh and endotoxin (n = 8) or SKF Veh and endotoxin (n = 12), the splanchnic permeability indices to 99mTc-HSA were increased 11.2-fold and 5.1-fold, respectively (P less than 0.05) compared to vehicle control groups not given endotoxin (n = 5). Pulmonary permeability index for 99mTc-HSA was increased (P less than 0.05) to a lesser extent (3.2-fold) by endotoxin compared to vehicle controls. Pretreatment with SKF reduced the mesenteric permeability index to control levels (P less than 0.05) during the 5-35 min time interval post-endotoxin. LY reduced the mesenteric permeability index by 70%. Pulmonary relative permeability to 99mTc-HSA was not affected by LY pretreatment. Both splanchnic and lung relative permeability to the isotope was transient; at 135-225 min post-endotoxin, splanchnic localization of 99mTc-HSA (n = 4) was not significantly different from vehicle controls in these vascular beds. Relative localization of 99mTc-labeled red blood cells (RBC) in the splanchnic or lung region was not significantly altered by endotoxin (n = 7) or LY pretreatment (n = 6) compared to vehicle controls (n = 6). In additional studies, small intestinal luminal content of 99mTc-HSA and 111Indium (In)-labeled RBC were determined after i.v. administration of the isotopes, in a 4 cm segment of the upper small bowel. Radioactivity in the luminal lavage was normalized to activity in blood of the same animal. Endotoxin at 2 hr induced a 2.3-fold increase transluminal leakage of 99mTc-HSA (n = 5; P less than 0.03) compared to LY Veh (n = 5) or control (n = 5) rats.(ABSTRACT TRUNCATED AT 400 WORDS)     

Superoxide production by Crohn''s disease neutrophils.

Neutrophil superoxide anion production was measured in healthy subjects and in patients with quiescent and active Crohn's disease using superoxide dismutase inhibitable cytochrome C reduction. Three stimuli were used: phorbol 12-myristate 13-acetate (PMA1), phorbol 20-oxo-20-deoxy 12-myristate 13-acetate (PMA2), and Candida albicans in serum. Normal neutrophils produced significantly more superoxide anion than Crohn's disease neutrophils with both PMA1 (mean (SD) 9.6 (2.2) v 8.6 (1.8) nmol/10(6) cells/5 minutes, p = 0.04) and PMA2 (1.8 (0.8) v 0.8 (0.77) nmol/10(6) cells/5 minutes, p = 0.00004). With C albicans in serum, normal and Crohn's disease neutrophils produced similar amounts of superoxide anion (4.4 (1.5) v 4.3 (1.7) nmol/10(6) cells/30 minutes, not significant). Results were independent of disease activity. Superoxide anion production by PMA-stimulated Crohn's disease neutrophils is significantly lower than by normal neutrophils.     

Hemostasis in Crohn's disease: low factor XIII levels in active disease

Massive gastrointestinal hemorrhage sometimes occurs in Crohn's disease. To examine the possible role of acquired disorders of hemostasis contributing to such events, several laboratory indicators of hemostasis (APT time, Normotest, platelet count, bleeding time, fibrinogen, factor VIII activity, vWF:Ag, factor X, factor XIII, antithrombin III, fibrinopeptide A, and B beta(15-42] were studied in 10 patients with active Crohn's disease (Crohn's disease activity index (CDAI) greater than 150) and 10 patients with quiescent disease (CDAI less than 150). Marked thrombocytosis was seen in three patients with active disease. Factor VIII activity and fibrinogen levels were significantly elevated in patients with Crohn's disease (p less than 0.001), and the factor VIII activity levels were significantly higher (p less than 0.05) in the patients with active disease than in those with quiescent disease. Factor XIII levels were significantly lower (p less than 0.02) in patients with active disease. Three of the patients with active disease had factor XIII levels below the lower reference limit. The two patients with the lowest levels had hemorrhagic diarrhea and spontaneous bleeding from the rectal mucosa. Fibrinopeptide A and B beta(15-42) levels were significantly elevated in both groups. The other coagulation analyses were essentially normal in both patient groups. The results suggest that factor XIII deficiency acquired through gastrointestinal leakage may contribute to gastrointestinal hemorrhage in some patients with active Crohn's disease.     

Bronchial and alveolar absorption of inhaled 99mTc-DTPA

The clearance rate of 99mTc-DTPA deposited in the lung by inhalation has been used as an index to measure lung epithelial permeability. To determine if differences exist between alveolar and bronchial absorption of 99mTc-DTPA we measured regional clearance rates in 4 beagle dogs for 30 min after preferential bronchial and alveolar deposition. Alveolar deposition was maximized by inhalation for 2 min of small 99mTc-DTPA particles (activity median aerodynamic diameter, AMAD = 0.5 micron; geometric standard deviation, GSD = 1.6) with deep slow ventilation (VT = 350 ml; f = 9 min-1), and bronchial deposition was increased by inhalation of large particles (AMAD = 4.1 microns, GSD = 2.3) with rapid shallow ventilation (VT = 50 ml; f = 65 min-1). Respective clearance rates from basal regions, which represent mainly alveolar absorption, were: for small particles, 2.29% min-1; for large particles, 1.57% min-1 (p = 0.10). Apical regions, which contain relatively more bronchial surface than do the basal regions, showed the following clearance rates: for small particles, 1.76% min-1; for large particles, 1.31% min-1 (p less than 0.05). These results indicate that in vivo alveolar absorption of 99mTc-DTPA is more rapid than bronchial absorption. Control or verification of the site of deposition of the tracer in the lung is of importance for the interpretation of the results of the 99mTc-DTPA lung permeability assay.     

A comparison of 99mTc-DTPA and 113mIn-DTPA aerosol clearances in humans. Effects of smoking, hyperinflation, and in vitro oxidation

As an index of permeability of the alveolar epithelium, the clearance of an inhaled aerosol of 99mTc-DTPA is increased in several disease states. However, the usefulness of the test to assess the severity of disease is limited because healthy smokers also have abnormally rapid rates of clearance. Because the stability of the 99mTc-DTPA bond might be a contributory factor, we tested the affinity of 99mTc for DTPA in vitro, and in groups of healthy smokers (n = 13) and nonsmokers (n = 7) we measured the clearances of 99mTc-DTPA and 113mIn-DTPA, which have a similar molecular shape and charge. In vitro, sodium hypochlorite or hydrogen peroxide released as much as 98% of free 99mTc from the 99mTc-DTPA complex. When incubated with human neutrophils stimulated with phorbol myristate acetate, between 4 and 7% of free 99mTc-DTPA was released after 30 min, and 12% was released after 60 min. In vivo, the clearances of both 99mTc-DTPA and 113mIn-DTPA in the smokers (n = 13) were faster than in the nonsmokers (n = 7) (p less than 0.05). Within the smokers, the mean 99mTc-DTPA clearance (T1/2 25 +/- 4 min) was faster than the mean 113mIn-DTPA clearance (34 +/- 6 min), (p less than 0.05). For nonsmokers, the difference was smaller (T1/2 99mTc-DTPA, 56 +/- 6; T1/2 113mIn-DTPA, 62 +/- 6) and not significant. During hyperinflation, smokers (n = 8) and nonsmokers (n = 8) both demonstrated an increase in 113mIn-DTPA clearance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Improved Localizing Method of Radiopill in Measurement of Entire Gastrointestinal pH Profiles: Colonic Luminal pH in Normal Subjects and Patients with Crohn's Disease

Objective: To measure gastrointestinal (GI) pH profiles in patients with Crohn's disease with an improved pH radiotelemetry method. Methods: A computer-assisted method was developed to exactly localize a pH sensitive radiotelemetry capsule (radiopill) in the GI tract from the stomach to the cecum by detecting distinct changes in transmitted pH signals sampled at I-sec intervals. The combined usage of a radiodirectional probe facilitated localization of the radiopill in the colon. With this improved method, GI pH profile's in four patients (male/female, 3/1: age range, 21–34 yr) with Crohn's disease that involved the left colon (active disease: 3: disease at quiescent state. 1) were measured and compared with those in four gender- and age-matched control subjects (controls). Results: Gastric and small intestinal luminal pH profiles in Crohn's disease were similar to those in the controls. In contrast, colonic luminal pH profiles in both right (uninvolved) and left (involved) colon in active or quiescent Crohn's disease showed more coarse fluctuations with a significantly low value than those seen in the controls. The minimum colonic pH registered in the four patients was 0.6, 1.2, 3.2, and 5.3 pH unit respectively. The overall mean luminal pH (±SD) in the right colon was 5.3 ± 0.3 for the patients versus 6.8 ± 0.2 for the controls ( p < 0.01) and that in the left colon was 5.3 ± 0.7 versus 7.2 ± 0.3 ( p < 0.01), respectively. Conclusion: This study first demonstrates that an extremely acidic colonic environment occurs in either active or inactive Crohn's disease.     

Reversibility of Increased Intestinal Permeability to 51Cr-EDTA in Patients with Gastrointestinal Inflammatory Diseases

Intestinal permeability in adults with inflammatory gastrointestinal diseases was investigated by measuring the 24-h urinary excretion of orally administered 51Cr-EDTA. Eighty controls along with 100 patients with Crohn's disease, 46 patients with ulcerative colitis, 20 patients with gluten-sensitive enteropathy, and 18 patients with other diseases were studied. In controls, the median 24-h excretion was 1.34%/24 h of the oral dose. Patients with Crohn's disease (median 2.96%/24 h), ulcerative colitis (median 2.12%/24 h), and untreated gluten-sensitive enteropathy (median 3.56%/24 h) had significantly elevated urinary excretion of the probe compared to controls (p less than 0.0001). Increased 24-h urinary excretion of 51Cr-EDTA had a high association with intestinal inflammation (p less than 0.0001). Test specificity and sensitivity were 96% and 57%, respectively. A positive test has a 96% probability of correctly diagnosing the presence of intestinal inflammation, whereas a negative test has a 50% probability of predicting the absence of disease.     

Dissociation between the functional activity and immunoreactive concentration of C1 esterase inhibitor in active and quiescent Crohn's disease

The plasma immunoreactive concentration and the functional activity of C1 esterase inhibitor (C1INH) were measured in 17 samples from 15 patients with Crohn's disease (CD) and 10 samples from healthy volunteers. C1INH activity was measured by the chromogen substrate method and the immunoreactive concentration by the single radial immunodiffusion method. The functional activity was 95.7 +/- 4.6% in the controls. In CD it was 60.8 +/- 7.5% in the active stage (CDAI greater than 100) and 113.4 +/- 4.9% in the quiescent stage (CDAI less than or equal to 100). There were significant differences between the controls and both the active and quiescent stages (p less than 0.05). The activity was significantly lower in the active than in the quiescent stages (p less than 0.01). However, the difference in the immunoreactive concentration of C1INH in the active and quiescent stages was not significant; it was 27.8 +/- 3.5 mg/dl in the active stage and 33.7 +/- 2.0 mg/dl in the quiescent stage. This difference in the pattern of change between the immunoreactive concentration and the functional activity of C1INH might arise from the mode of C1INH action, with stoichiometric binding to substrates, giving rise to irreversible complexes. These results showed the functional consumption of C1INH in active CD, which may be an aggravating factor in the pathogenesis of the inflammatory process in the patient.     

Zinc supplementation tightens "leaky gut" in Crohn's disease

OBJECTIVES: Small intestinal permeability is often increased in patients with Crohn's disease and may be pathogenic for clinical relapses. No effective prophylactic treatment is available for these patients. The aim of this study was to ascertain whether zinc supplementation may improve intestinal permeability. METHODS: We studied 12 patients with quiescent Crohn's disease who had been in remission for at least 3 months and had increased intestinal permeability on two separate occasions within the last 2 months. Patients received oral zinc sulfate supplements (110 mg three times a day) for 8 weeks and were followed-up for 12 months thereafter to monitor relapses. RESULTS: We found that the lactulose/mannitol ratio was significantly higher before supplementation than after (0.041 +/- 0.003 versus 0.026 +/- 0.005). During follow-up, 10 patients had normal intestinal permeability and did not relapse; of the remaining two who had increased intestinal permeability, one relapsed. CONCLUSIONS: Our findings show that zinc supplementation can resolve permeability alterations in patients with Crohn's disease in remission. Improving intestinal barrier function may contribute to reduce the risk of relapse in Crohn's disease.     

Intestinal permeability before and after ibuprofen in families of children with Crohn's disease.

BACKGROUND: Members of a subset of first-degree relatives of adults with Crohn's disease have been shown to have an increased baseline intestinal permeability and/or an exaggerated increase in intestinal permeability after the administration of acetylsalicylic acid. PURPOSE: To determine intestinal permeability in unaffected first-degree relatives of children with Crohn's disease before and after the administration of an ibuprofen challenge. METHODS: Lactulose-mannitol ratios, a measure of intestinal permeability, were determined in 14 healthy control families (41 subjects) and 14 families with a child with Crohn's disease (36 relatives, 14 probands) before and after ingestion of ibuprofen. An upper reference limit was defined using the control group as mean +/- 2 SD. RESULTS: The proportion of healthy, first-degree relatives with an exaggerated response to ibuprofen (20%, 95% CI 7% to 33%) was significantly higher than controls (P = 0.003). The exaggerated response was more common among siblings than among parents of pediatric probands. CONCLUSIONS: Members of a subset of first-degree relatives of children with Crohn's disease have an exaggerated increase in intestinal permeability after ibuprofen ingestion. These findings are compatible with there being a genetic link between abnormalities of intestinal permeability and Crohn's disease.     

T-cell activation in Crohn's disease. Increased levels of soluble interleukin-2 receptor in serum and in supernatants of stimulated peripheral blood mononuclear cells

Serum levels of soluble interleukin-2 receptor were determined in 29 patients with active and quiescent Crohn's disease. In addition, the ability of peripheral blood mononuclear cells of 23 of these patients to generate soluble interleukin-2 receptor following mitogenic stimulation was studied in vitro. Serum soluble interleukin-2 receptor concentrations of patients with active Crohn's disease (n = 19) were significantly elevated (757 +/- 438 U/ml) compared with levels in patients with inactive disease (n = 10; 412 +/- 120 U/ml) and healthy control individuals (n = 40; 375 +/- 102 U/ml; p less than 0.003 and p less than 0.0005, respectively). Serial determinations of serum soluble interleukin-2 receptor concentration in a follow-up of 11 hospitalized patients treated for highly active disease showed a decrease from 1252 +/- 494 U/ml to 527 +/- 193 U/ml (p less than 0.004) that corresponded to clinical improvement, as assessed by Crohn's disease activity index and a reduction of inflammatory parameters. In vitro phytohemagglutinin stimulation of peripheral blood mononuclear cells derived from patients with Crohn's disease resulted in elevated soluble interleukin-2 receptor production not only in patients with active disease (3987 +/- 2439 U/ml), but also in patients with inactive disease (3297 +/- 2282 U/ml), compared with the amount of soluble interleukin-2 receptor produced by mononuclear cells of healthy individuals (1523 +/- 1152 U/ml; p less than 0.005 and p less than 0.02, respectively). In addition, cultivation of mononuclear cells without mitogen resulted in higher soluble interleukin-2 receptor production in patients with active disease than in patients with inactive disease (p less than 0.02). However, patients suffering from active ulcerative colitis also had significantly increased serum levels of soluble interleukin-2 receptor (1080 +/- 400 U/ml) compared with the levels in patients with chronic disease (455 +/- 140 U/ml; p less than 0.0025). In addition, peripheral blood mononuclear cells derived from patients with ulcerative colitis produced significantly more soluble interleukin-2 receptor upon mitogenic stimulation with phytohemagglutinin (2314 +/- 936 U/ml), than cells from healthy controls (1523 +/- 1152 U/ml; p less than 0.05). The finding of elevated soluble interleukin-2 receptor serum levels in patients with active Crohn's disease and its increased production by mononuclear cells of patients with both active and inactive disease is a further example of an alteration of the immune system in this condition; however, this alteration can also be found in other inflammatory bowel diseases.