Anna D'Odorico

Intestinal Permeability Test as a Predictor of Clinical Course in Crohn's Disease

Objective:The clinical course of Crohns disease is often unpredictable. The aim of this study was to select the most useful parameters able to predict clinical relapses.Methods:One hundred-thirty Crohns disease patients in clinical remission were followed every 4 months for 2 yr or until clinical relapse. Demographic and clinical data were recorded and intestinal permeability (lactulose/mannitol [L/M] test) and biochemical tests (white blood cell count, erythrocyte sedimentation rate, C-reactive protein, α1 acid glycoprotein, and serum iron) were performed at study entry. A subgroup of 54 patients had clinical follow-up and repeated tests every 4 months.Results:Fifty-two patients (40%) relapsed during the 2-yr follow-up. A significant correlation was found between relapse and gender (p= 0.030) but not between relapse and age, extent and type of disease, previous surgery, or therapy. Increased L/M test (p= 0.0001) and decreased serum iron level (p= 0.0057) were associated with clinical relapse. Time-dependent analysis, performed on patients receiving serial evaluation, showed that L/M test alteration was the only variable that could predict a relapse (RR 8.84, 95% confidence interval [CI] 1.41–53.37; p < 0.05).Conclusion:The L/M test identifies Crohns disease patients in apparent remission, but with a high risk of clinical relapse, better than clinical and biochemical indices. Different treatment strategies might be suggested for this subgroup of patients.

Reduced Plasma Antioxidant Concentrations and Increased Oxidative DNA Damage in Inflammatory Bowel Disease

Background: Oxidative stress is believed to play a key role in the pathogenesis of inflammatory bowel disease (IBD)-related intestinal damage. Circulating antioxidants may have a role to play in preventing free radical-mediated tissue injury. Methods: Plasma vitamin A, E and carotenoid concentrations, leukocytic genomic damage and 8-hydroxy-deoxy-guanosine (8-OHdG) concentration were determined in 46 ulcerative colitis (UC) patients, 37 Crohn disease (CD) patients and 386 controls. A 20 ml blood sample was taken from each subject for antioxidant and 8-OHdG measurements. A food frequency questionnaire was administered to a sample of subjects from each group to evaluate daily intake of dietary compounds. Results: Antioxidant concentration was significantly reduced in IBD patients, particularly in those with active disease, with respect to controls ( P < 0.0001). 8-OHdG concentrations were significantly increased in IBD patients compared to controls, independent of disease activity ( P < 0.05). No correlation was found between antioxidant and 8-OHdG concentrations. Carotenoid concentrations were significantly reduced in malnourished IBD patients (0.89 ± 0.14 μmol/l) compared to patients with normal or high body mass index (1.83 ± 0.12 μmol/l; P < 0.05), independent of disease activity or extension. Protein, fruit and vegetable intakes of IBD patients were significantly lower than those of controls. Conclusions: Depletion of antioxidants is likely to be important in the pathophysiology of IBD: UC and CD patients show increased free radical peripheral leukocyte DNA damage and decreased plasma antioxidant defenses. These results indicate the necessity of further studies to establish whether optimal vitamin status may improve the clinical course of UC and CD.BACKGROUND Oxidative stress is believed to play a key role in the pathogenesis of inflammatory bowel disease (IBD)-related intestinal damage. Circulating antioxidants may have a role to play in preventing free radical-mediated tissue injury. METHODS Plasma vitamin A, E and carotenoid concentrations, leukocytic genomic damage and 8-hydroxy-deoxy-guanosine (8-OHdG) concentration were determined in 46 ulcerative colitis (UC) patients, 37 Crohn disease (CD) patients and 386 controls. A 20 ml blood sample was taken from each subject for antioxidant and 8-OHdG measurements. A food frequency questionnaire was administered to a sample of subjects from each group to evaluate daily intake of dietary compounds. RESULTS Antioxidant concentration was significantly reduced in IBD patients, particularly in those with active disease, with respect to controls (P < 0.0001). 8-OHdG concentrations were significantly increased in IBD patients compared to controls, independent of disease activity (P < 0.05). No correlation was found between antioxidant and 8-OHdG concentrations. Carotenoid concentrations were significantly reduced in malnourished IBD patients (0.89 +/- 0.14 micromol/l) compared to patients with normal or high body mass index (1.83 +/- 0.12 micromol/l; P < 0.05), independent of disease activity or extension. Protein, fruit and vegetable intakes of IBD patients were significantly lower than those of controls. CONCLUSIONS Depletion of antioxidants is likely to be important in the pathophysiology of IBD: UC and CD patients show increased free radical peripheral leukocyte DNA damage and decreased plasma antioxidant defenses. These results indicate the necessity of further studies to establish whether optimal vitamin status may improve the clinical course of UC and CD.

High plasma levels of α- and β-carotene are associated with a lower risk of atherosclerosis: Results from the Bruneck study

BACKGROUND AND PURPOSE A large number of studies have contributed to the hypothesis that carotenoids, vitamins A and E are protective against atherosclerosis by acting as antioxidants. The aim of this study was to assess the relationship between plasma levels of carotenoids (alpha- and beta- carotene, lutein, lycopene, zeaxanthin, beta-cryptoxanthin), vitamins A and E, and atherosclerosis in the carotid and femoral arteries. METHODS This prospective and cross sectional study involved a randomly selected population sample of 392 men and women aged 45-65 years. Carotid and femoral artery atherosclerosis was assessed by high-resolution duplex ultrasound. RESULTS alpha- and beta- carotene plasma levels were inversely associated with the prevalence of atherosclerosis in the carotid and femoral arteries (P=0.004) and with the 5-year incidence of atherosclerotic lesions in the carotid arteries (P=0.04). These findings were obtained after adjustment for other cardiovascular risk factors (sex, age, LDL (low density lipoproteins), ferritin, systolic blood pressure, smoking, categories of alcohol consumption, social status, C-reactive protein). Atherosclerosis risk gradually decreased with increasing plasma alpha- and beta-carotene concentrations (P=0.004). No associations were found between vitamin A and E plasma levels and atherosclerosis. CONCLUSIONS This study provides further epidemiological evidence of a protective role of high alpha- and beta- carotene in early atherogenesis.

Neurological complications of celiac disease and autoimmune mechanisms: A prospective study

Humoral immune mechanisms may have a role in the neurological complications of celiac disease (CD). We assessed 71 CD patients for neurologic manifestations and presence of serum antibodies to neural antigens. Sixteen patients (22.5%) were found to have neurological deficits including headache, depression, entrapment syndromes, peripheral neuropathy, and epilepsy. Antibody reactivity to neural antigens was detected in 30/71 (42.2%) patients. There was no clear correlation between anti-neural reactivity and neurologic dysfunction. Follow-up of 62 patients did not reveal change in electrophysiology or antibodies, regardless of diet. However, in 2 patients with neuropathy, symptoms improved or worsened depending on the diet.

Altered Plasma and Mucosal Concentrations of Trace Elements and Antioxidants in Active Ulcerative Colitis

BACKGROUND The production of free radicals is increased in inflammatory bowel disease, and trace elements are crucial components of several antioxidants. Trace elements deficiency may therefore compromise the defense against oxidative damage. The aims of this study were to measure plasma and tissue concentration of trace elements and antioxidants and to relate this to disease activity. METHODS A 10-ml blood sample and six colonic biopsy specimens were obtained from 24 patients with either active ulcerative colitis or in remission and 10 patients with irritable bowel syndrome for measurement of trace elements and trace element-dependent enzymes. RESULTS Patients with moderately active disease had significantly lower plasma iron, selenium, and glutathione peroxidase levels than patients in remission and controls, whereas no significant differences were found between the zinc and copper values of patients and controls. Mucosal concentrations of zinc and metallothionein were reduced, whereas iron and glutathione peroxidase concentrations were increased in patients with endoscopically active disease as compared with controls and patients in remission. CONCLUSIONS Patients with ulcerative colitis have altered plasma and tissue levels of trace elements and antioxidant-related enzymes. The resulting reduced protection against free radicals may contribute to the inflammatory process.

Plasma antioxidant levels in chronic cholestatic liver diseases

A predictable consequence of cholestasis is malabsorption of fat‐soluble factors, (vitamins A, D, E, K) and other free radical scavengers, such as carotenoids. It has been suggested that oxygen‐derived free radicals may be involved in the pathogenesis of chronic liver damage.

Lack of intestinal mucosal toxicity of Triticum monococcum in celiac disease patients

Objective. The treatment of celiac disease is based on lifelong withdrawal of foods containing gluten. Unfortunately, compliance with a gluten-free diet has proved poor in many patients (mainly due to its low palatability), emphasizing the need for cereal varieties that are not toxic for celiac patients. In evolutionary terms, Triticum monococcum is the oldest and most primitive cultivated wheat. The aim of this study was to evaluate the toxicity of T. monococcum on small intestinal mucosa, using an in vitro organ culture system. Material and methods. Distal duodenum biopsies of 12 treated celiac patients and 17 control subjects were cultured for 24 h with T. aestivum (bread) gliadin (1 mg/ml) or with T. monococcum gliadin (1 mg/ml). Biopsies cultured with medium alone served as controls. Each biopsy was used for conventional histological examination and for immunohistochemical detection of CD3 + intraepithelial lymphocytes (IELs) and HLA-DR. Secreted cytokine protein interferon-γ (IFN–γ) was measured in the culture supernatant using an enzyme-linked immunoadsorbent assay. Results. Significant morphological changes, HLA-DR overexpression in the crypt epithelium and an increased number of CD3 + IELs, found after bread gliadin exposure, were not observed in celiac biopsies cultured with T. monococcum gliadin. In contrast, with bread gliadin, there was no significant IFN-γ response after culture with monococcum gliadin. Similarly, biopsies from normal controls did not respond to bread or monococcum gliadin stimulation. Conclusions. These data show a lack of toxicity of T. monococcum gliadin in an in vitro organ culture system, suggesting new dietary opportunities for celiac patients.

Inhibition of gastric acid secretion reduces zinc absorption in man.

Numerous factors seem to affect zinc absorption. Gastric acid secretion has been demonstrated to facilitate iron absorption. The zinc tolerance test (ZTT with ZnSO4 220 mg p.o.) was performed in 11 healthy volunteers to study the effects of administering the acid secretion inhibitor cimetidine (1 g/day p.o. for 3 days) and to evaluate the influence of HCl gastric secretion on zinc absorption in physiological conditions. Zinc absorption was reduced after cimetidine administration (p less than 0.005), suggesting that gastric pH influences zinc absorption. To rule out any direct effect of the drug on zinc absorption in five other healthy adults we further evaluated zinc absorption by using a different H2 antagonist (ranitidine 300 mg/day for 3 days and 300 mg before the test). Cimetidine was also tested in these subjects at half the dosage administered to the first group of subjects. Gastric acidity was monitored at 60-min intervals throughout the test via a nasogastric tube. The areas under the plasma concentration curves for zinc were significantly reduced after ranitidine (p less than 0.01), but not after cimetidine administration. Gastric acid was also reduced after ranitidine, but not after cimetidine (500 mg) administration, suggesting that gastric acid secretion plays a role in the regulation of zinc absorption in man.

Influence of Disease Site and Activity on Peripheral Neutrophil Function in Inflammatory Bowel Disease

Reactive oxygen species, released by phagocytes, are involved in tissue injury in inflammatory bowel diseases. The aim of our study was to evaluate peripheral neutrophil function in patients with ulcerative colitis (N = 66) and Crohns disease (N = 62) with respect to disease activity and extent, using chemiluminometry after three stimuli. Twenty-seven healthy subjects were enrolled as controls. Neutrophils from ulcerative colitis and Crohns disease patients had a significantly higher response than those from controls following phorbol myristate acetate (86.6 ± 6.5, 173.8 ± 11.9, 167.5 ± 12.2 mV, P < 0.0001), formyl-methionyl-leucyl-phenylalanine (39.5 ± 3.4, 41.3 ± 2.7, 58.6 ± 4.7 mV, P < 0.001), and zymosan (142.6 ± 10.4, 223.7 ± 8.9, 231.2 ± 9.5 mV, P < 0.0001) administration. The increased response was observed during both active disease and remission. The highest chemiluminescence values were found in patients with active ulcerative pancolitis and ileal Crohns disease. The activation of circulating neutrophils may indicate persistent intestinal inflammation or may be triggered by luminal factors even in the absence of symptoms.

Neurological complications of celiac disease and autoimmune mechanisms: preliminary data of a prospective study in adult patients.

Abstract: Antibodies to gangliosides and Purkinje cells have been reported in patients with celiac disease (CD) with neuropathy and ataxia, respectively. Whether these antibodies are pathogenic is not clear. The response of neurological symptoms and antibody titers to a gluten‐free diet is still controversial. The objective of our study was to assess whether neurological manifestations in CD patients correlate with antibody titers and a gluten‐free diet.Thirty‐five CD patients (9 males, 26 females, mean age 37.1 ± 12.6 yrs) were followed prospectively. At initial evaluation, 23 were on a gluten‐free diet, 12 were not. At recruitment and during follow‐up, patients underwent neurological and electrophysiological evaluation. IgG, IgM, and IgA anti‐ganglioside antibodies were assayed by ELISA; anti‐neuronal antibodies were assessed by immunohistochemistry and Western blot. Four patients, all males, had electrophysiological evidence of neuropathy; three had been on a gluten‐free diet for several months, and one was newly diagnosed. One had reduced tendon reflexes; another complained of distal paresthesias. With regard to anti‐ganglioside antibodies, three patients had a moderate increase in antibodies without symptoms or signs of neuropathy. No patients had ataxia or cerebellar dysfunction, although in four patients reactivity to neuronal antigens was found. In 17 patients, an electrophysiological follow‐up (mean duration of follow‐up, 9 months) showed no changes. In conclusion, the preliminary results of this prospective study indicate that neuropathy, usually subclinical, may accompany CD. Antibody titers do not seem to correlate with neurological symptoms/signs or diet. Ongoing follow‐up will help confirm these data and clarify the role, if any, of antibodies in neurological involvement in CD.