Henrik Hey

Platelets and anticoagulant capacity in patients with inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) are susceptible to thromboembolic complications. Several mechanisms can be responsible, including abnormal regulation of coagulation activity, disturbances of fibrinolysis, inflammatory reactions and thrombocytosis. The aim of this study was to assess hemostatic alterations in these parameters during exacerbation of disease. We studied disease activity in 99 IBD patients receiving anti-inflammatory therapy, in relation to: procoagulant markers, i.e. prothrombin fragment F1 + 2 (F1 + 2), D-dimer and platelet count, anticoagulant markers, i.e. protein C, protein S and antithrombin, and a mediator of inflammation (IL-6). Coagulation activity and platelet count were increased during active disease in IBD patients compared with those in a state of remission. The IL-6 concentrations were positively correlated with disease activity and thrombocytosis in patients with ulcerative colitis, but no association with the anticoagulant capacity could be demonstrated except for a decrease in protein C during high disease activity.

Hyperhomocysteinaemia, Coagulation Pathway Activation and Thrombophilia in Patients with Inflammatory Bowel Disease

Background : The 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C → T polymorphism encoding the thermolabile variant is, when present as homozygote type (TT variant), a known genetic cause of mild hyperhomocysteinaemia (HHCY). This polymorphism has been observed in increased numbers in patients with inflammatory bowel disease (IBD). Coagulation and fibrinolysis are activated in patients with active IBD, but it is not known whether raised plasma homocysteine (HCY) found in patients with IBD significantly contributes to this activation. The aim of this study was to investigate if HHCY or presence of the TT variant significantly induces a hypercoagulable state in IBD patients receiving anti-inflammatory therapy during active disease, and to study if genetic determinants for thromboembolic disease are more frequent in these patients. Methods : The study was designed as a cross-sectional study in an outpatient clinic comprising 106 IBD patients receiving anti-inflammatory therapy. Markers of coagulation were measured in order to elucidate whether patients with HHCY or the MTHFR TT variant were hypercoagulant compared with patients with no impairment of HCY metabolism. In addition, markers of inflammation and acute-phase reactants were measured in order to compare activity during active disease and during remission. Genetic determinants of thromboembolic disease in patients with IBD and in relevant controls were investigated in the expectation of a more frequent occurrence of these markers of thrombophilia if hypercoagulability could be a primary or contributory factor in IBD. Results : No significant difference could be found in coagulation activity, acute-phase reactants or inflammatory markers in IBD patients with the TT variant of the 677C → T polymorphism or high (>15 μmol/L) plasma HCY levels, compared with IBD patients with no impairment of HCY metabolism. In patients with IBD, the coagulation activity was significantly increased during active disease compared with a state of remission. As expected, a significant difference regarding interleukin 6, C-reactive protein and erythrocyte sedimentation rate was present in IBD, comparing active disease with a state of remission. No significant complement activation was present in either of the groups or during active disease. Neither of the allele frequencies of genetic determinants for thrombophilia (coagulation factor V 1691G → A (factor V Leiden) and factor II 20210G → A polymorphisms) in the background population differed significantly from that in IBD patients. Conclusions : This study found no correlation between the MTHFR TT variant or HHCY and a hypercoagulable state in IBD patients receiving anti-inflammatory treatment. This coagulation activity is high during exacerbations of disease, but a considerable reduction is seen in patients on anti-inflammatory therapy compared with non-treated patients. Coagulation activation in IBD is probably a consequence of the inflammatory nature of the disease. That thrombophilia could be a contributory or primary factor in the development of IBD is not supported by the present study, as the frequencies for the genetic determinants for thrombophilia are similar in IBD patients and controls.

Omega-3 fatty acids inhibit an increase of proinflammatory cytokines in patients with active Crohn's disease compared with omega-6 fatty acids

Background : Crohns disease is a chronic inflammatory condition affecting the gastrointestinal tract. Polyunsaturated omega‐3 fatty acids given orally may reduce the secretion of proinflammatory cytokines and hereby downregulate the inflammatory process.

Serum Trefoil Factors in Patients with Inflammatory Bowel Disease

Background: Trefoil factors (TFF1–3) play a critical role in mucosal protection and repair in the gastrointestinal tract. The aims of the present study were to examine associations between serum TFF1–3 and clinical and biochemical markers reflecting disease activity and to examine changes in TFF1–3 in patients with inflammatory bowel disease (IBD) before and during high-dose prednisolone treatment and tapering.Methods: Serum concentrations of TFF1–3 were quantified in 48 ulcerative colitis (UC) and 50 Crohn’s disease (CD) patients with little or moderate activity. Additionally, serum TFF concentrations were determined in patients with severe activity in colon IBD (4 UC and 6 CD) before and during prednisolone treatment with 7 healthy subjects as controls. Results: Median concentrations of TFF1, TFF2, and TFF3 were significantly increased in IBD patients compared with healthy controls (p < 0.01). TFF3 concentrations correlated with clinical and biochemical parameters of disease activity in UC patients. In addition, a trend towards reduction in TFF concentrations during treatment with prednisolone and concomitant clinical and biochemical remission was observed. Conclusions: The present data support the concept that trefoil peptides are upregulated and may play a role in IBD mucosal protection and repair. In UC patients, TFF3 levels were increased in active disease levels correlated with disease activity indices. Due to a large variation, serum TFFs are not a potential marker for disease activity.

Saliva Interleukin-6 in patients with inflammatory bowel disease

Objective. The inflammatory bowel diseases (IBD), Crohns disease (CD) and ulcerative colitis (UC) are chronic inflammatory conditions that affect the gastrointestinal tract. In regulation of this inflammatory process, Interleukin-6 (IL-6) has a major role. Overproduction of IL-6 by immunocompetent cells contributes to development of the inflammatory condition. Elevated levels of IL-6 in saliva could be expected, because the saliva-producing cells are part of the digestive system. Material and methods. IL-6 concentrations in saliva and plasma were studied in patients with CD (n=15), UC (n=7) and reference persons (RP) (n=19) by use of an ELISA method. Results. A significant difference in saliva IL-6 concentration between CD patients (median 16.9 ng/L; p<0.05) and RP (median 6.3 ng/L) was found. A significant difference in plasma IL-6 concentration between CD (median 10.3 ng/L; p<0.001) or UC (median 7.8 ng/L; p<0.001) and RP (median 0.8 ng/L) was observed. In patients with CD, plasma IL-6 correlated significantly with C-reactive protein (CRP) as well as albumin. In patients with UC, saliva IL-6 and plasma IL-6 correlated significantly with AI (activity index) scores as well as albumin. In patients with UC, a significant correlation between the saliva and plasma IL-6 concentrations was found. Conclusions. IL-6 was found in saliva in patients with IBD, documenting the general involvement of the gastrointestinal tract extending to the mouth cavity, and measuring IL-6 may be an additional method for evaluating and monitoring the disease activity.

Insulin-like growth factors (IGFs) and IGF binding proteins in active Crohn's disease treated with ω-3 or ω-6 fatty acids and corticosteroids

Objective. Catabolism and growth impairment are well-known complications of inflammatory bowel disease (IBD). This may be caused by the disease activity itself and/or the medical treatment, and both may lead to changes in the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis. The aim of the present study was to examine the effects of enteral nutrition, Impact Powder®, as adjuvant therapy to corticosteroid treatment on changes in the GH/IGF-I axis in patients with Crohns disease (CD). Material and methods. The patients were randomized to 3-IP (ω-3-fatty acid (FA), 3 g/day) or 6-IP (ω-6-FA, 9 g/day). Changes in total IGF-I (tIGF-I) and total IGF-II (tIGF-II), free IGF-I (fIGF-I), IGF binding proteins (IGFBP-1 and IGFBP-3), IGFBP-3 protease activity and insulin levels were examined in 31 patients with active CD (CDAI: 186–603) during treatment with prednisolone (40 mg for 1 week) and tapering the dose by 5 mg/week. Clinical and biochemical markers of inflammation were studied at day 0, and after 5 and 9 weeks. Results. There were no differences at baseline between the two groups. During the treatment period, tIGF-I, fIGF-I and IGFBP-3 increased significantly in both groups compared to baseline (p<0.05) without differences between the groups. Insulin and IGFBP-1 showed no significant changes throughout the treatment period. Conclusions. There was no difference between 3-IP and 6-IP as adjuvant enteral nutrition on the GH/IGF-I axis. The changes observed in the GH/IGF-I axis are in line with previously published studies and may be explained by corticosteroid treatment; however, we cannot exclude an additional effect of ω3-/ω6 FA as adjuvant enteral nutrition.

Effects of five different alcoholic drinks on patients with Crohn's disease

Objective. Many patients with Crohns disease (CD) complain of abdominal discomfort after alcohol intake. The aim of the present study was to investigate the effect of ethanol and sugar content in five different alcoholic drinks on abdominal discomfort in patients with CD. Material and methods. In a crossover study, two weeks apart, 12 healthy individuals and 20 patients with CD in remission consumed randomly red wine, white wine, Smirnoff Ice, Elephant Beer and pure ethanol. Blood samples were obtained for determination of serum ethanol and plasma glucose at 0, 30, 60, 90, 120 and 180 min. A self-reported pain symptom score was used. Results. There was no difference between CD patients and healthy individuals in the area under the curve (AUC) for the ethanol concentration after intake of the five different drinks. The plasma AUC for glucose in the CD patients after intake of Smirnoff Ice and Elephant beer was significantly increased (p<0.05) in comparison with that in the remaining three alcoholic drinks. Abdominal pain manifestations were significantly more pronounced in CD patients following intake of Smirnoff Ice and Elephant beer, with their higher sugar concentration, compared with intake of the remaining three drinks (p<0.05). Conclusions. The present study shows no difference in alcohol absorption between CD patients and controls. The alcoholic drinks Smirnoff Ice and Elephant beer have an increased effect on self-reported abdominal pain in CD patients, probably due to the high sugar content in these drinks.

Impact of enteral supplements enriched with omega-3 fatty acids and/or omega-6 fatty acids, arginine and ribonucleic acid compounds on leptin levels and nutritional status in active Crohn's disease treated with prednisolone.

Background: Patients with Crohn’s disease (CD) often develop malnutrition due to disease activity. We aimed to assess the effect of two different enteral supplements of Impact® Powder (IP; Novartis, Switzerland) on leptin levels and nutritional status in active CD patients during prednisolone treatment and tapering. Methods: Thirty-one CD patients were randomized to IP Extra (group 1) or IP Standard (group 2). Leptin levels, nutritional, clinical and biochemical markers were studied at inclusion, after 5 and after 9 weeks of the study. Results: Leptin levels, body mass index (BMI) and total cholesterol increased significantly within both groups at week 5 compared to inclusion. Leptin levels correlated with BMI in both groups at inclusion and in group 2 at week 9. In group 1, triglyceride levels remained unchanged, while levels in group 2 increased significantly at week 5 compared to inclusion. Clinical and biochemical markers improved during the study compared to inclusion. Conclusions: Increased leptin levels during the study progress were transient, decreasing due to prednisolone withdrawal at the end of the study. Both formulas used as adjuvant therapy to prednisolone treatment were able to improve nutritional status in CD patients.

Low S-adenosylmethionine concentrations found in patients with severe inflammatory bowel disease.

Abstract Background: S-adenosylmethionine is a methyl donor in many cellular reactions including detoxification of constantly produced hydrogen sulphide in the colon. A reduced capacity to detoxify hydrogen sulphide may be implicated in the pathogenesis of inflammatory bowel disease. S-adenosylmethionine could be low if this assumption is correct. We compared S-adenosylmethionine concentrations in whole blood in patients with severe and moderate inflammatory bowel disease with healthy reference persons. Methods: S-adenosylmethionine concentrations in whole blood were measured using high-pressure liquid chromatography. Patients with Crohns disease (n=21), ulcerative colitis (n=7) and healthy age-matched reference persons (or controls) (n=17) were studied. Results: S-adenosylmethionine concentrations were significantly decreased in patients with severe inflammatory bowel disease (mean 1.10 mg/l) as compared to patients with moderate Crohns disease and ulcerative colitis (mean 1.83 mg/l) and reference persons (mean 1.84 mg/l). Statistically significant inverse correlations were found between S-adenosylmethionine concentration and activity index (p<0.01 and R2=0.86) as well as Crohns disease activity index (p<0.01 and R2=0.50) scores. Conclusions: Low concentrations of S-adenosylmethionine were found in patients with severe inflammatory bowel disease. Future studies will show whether S-adenosylmethionine is a marker for disease activity and a possible tool for investigation of sulphur toxicity as a causative mechanism in inflammatory bowel disease.

Absorption of pivampicillin as related to dose, and tolerability of a 700 mg tablet

To evaluate the absorption and tolerability of a new formulation of pivampicillin administered as a 700 mg tablet, 14 healthy volunteers received single doses of 350, 500 and 700 mg p.o. Maximum serum concentrations (Cmax) of 5.73, 7.05 and 8.61 mg/l were obtained. The corresponding values for the area under the concentration/time curve (AUC) were 12.32, 18.99 and 25.30 mg/lxh. Concomitant intake of food increased the Cmax of the 700 mg tablet to 9.5 mg/l, while the AUC remained unchanged. Co-administration of the 700 mg pivampicillin dose with an antacid reduced the Cmax to 7.45 mg/l and the AUC to 17.92 mg/l × h. The tolerance of the 700 mg tablet was evaluated in a double-blind placebo-controlled study involving 57 patients. Six percent of the patients in each treatment group reported minor adverse reactions. Zur Beurteilung einer neuen Formulierung von Pivampicillin als 700 mg Tablette erhielten 14 gesunde freiwillige Probanden Einzeldosen der Substanz von 350, 500 und 700 mg per os. Die entsprechenden Spitzenspiegel (Cmax) lagen bei 5,73, 7,05 und 8,61 mg/l und die Fläche unter der Konzentrations-Zeitkurve (AUC) bei 12,32, 18,99 und 25,30 mg/l × h. Bei Einnahme der Tablette mit dem Essen erhöhte sich Cmax für die 700 mg Tablette auf 9,5 mg/l bei unveränderter AUC. Wenn Pivampicillin zusammen mit einem Antazidum eingenommen wurde, nahmen Cmax auf 7,45 mg/l und die AUC auf 17,92 mg/l × h ab. In einer placebokontrollierten Doppelblindstudie mit 57 Patienten wurde die Verträglichkeit der 700 mg Tablette geprüft. In jeder Gruppe berichteten 6% der Patienten über leichte Nebenwirkungen.SummaryTo evaluate the absorption and tolerability of a new formulation of pivampicillin administered as a 700 mg tablet, 14 healthy volunteers received single doses of 350, 500 and 700 mg p.o. Maximum serum concentrations (Cmax) of 5.73, 7.05 and 8.61 mg/l were obtained. The corresponding values for the area under the concentration/time curve (AUC) were 12.32, 18.99 and 25.30 mg/lxh. Concomitant intake of food increased the Cmax of the 700 mg tablet to 9.5 mg/l, while the AUC remained unchanged. Co-administration of the 700 mg pivampicillin dose with an antacid reduced the Cmax to 7.45 mg/l and the AUC to 17.92 mg/l × h. The tolerance of the 700 mg tablet was evaluated in a double-blind placebo-controlled study involving 57 patients. Six percent of the patients in each treatment group reported minor adverse reactions.ZusammenfassungZur Beurteilung einer neuen Formulierung von Pivampicillin als 700 mg Tablette erhielten 14 gesunde freiwillige Probanden Einzeldosen der Substanz von 350, 500 und 700 mg per os. Die entsprechenden Spitzenspiegel (Cmax) lagen bei 5,73, 7,05 und 8,61 mg/l und die Fläche unter der Konzentrations-Zeitkurve (AUC) bei 12,32, 18,99 und 25,30 mg/l × h. Bei Einnahme der Tablette mit dem Essen erhöhte sich Cmax für die 700 mg Tablette auf 9,5 mg/l bei unveränderter AUC. Wenn Pivampicillin zusammen mit einem Antazidum eingenommen wurde, nahmen Cmax auf 7,45 mg/l und die AUC auf 17,92 mg/l × h ab. In einer placebokontrollierten Doppelblindstudie mit 57 Patienten wurde die Verträglichkeit der 700 mg Tablette geprüft. In jeder Gruppe berichteten 6% der Patienten über leichte Nebenwirkungen.