Andreas N. Kapsoritakis

Mean Platelet Volume: A Useful Marker of Inflammatory Bowel Disease Activity

OBJECTIVES:We investigated whether the mean platelet volume would be a useful marker in the evaluation of inflammatory bowel disease activity.METHODS:Complete blood count, C-reactive protein, erythrocyte sedimentation rate, serum thrombopoietin and erythropoietin, plasma β-thromboglobulin, and platelet factor 4 were measured in 93 patients with ulcerative colitis, 66 patients with Crohns disease, and 38 healthy blood donors. Disease activity was assessed by the Clinical Colitis Activity Index in patients with ulcerative colitis and by the Crohns Disease Activity Index in patients with Crohns disease.RESULTS:Mean platelet count was increased in patients with active compared to inactive ulcerative colitis (p < 0.05), and in patients with active compared to inactive Crohns disease (p = 0.0002) or healthy controls (p < 0.0001). On the other hand, mean platelet volume was significantly decreased in patients with active compared to inactive ulcerative colitis (p = 0.02) or healthy controls (p < 0.0001), and in patients with active compared to inactive Crohns disease (p = 0.0005) or healthy controls (p < 0.0001). Mean platelet volume was inversely correlated with the white blood cell count (r =−0.17, p = 0.02), C-reactive protein (r =−0.46, p = 0.009) and erythrocyte sedimentation rate (r =−0.28, p = 0.008). No significant correlations were found between mean platelet volume and serum thrombopoietin or erythropoietin levels; however, a strong negative correlation between mean platelet volume and β-thromboglobulin (r =−0.34, p < 0.0001) and platelet factor 4 (r =−0.30, p = 0.0002) was observed.CONCLUSIONS:Mean platelet volume is significantly reduced in active inflammatory bowel disease and is negatively correlated with the known inflammatory bowel disease activity markers and the platelet activation products. We propose that mean platelet volume provides a useful marker of activity in inflammatory bowel disease.

Resistance to activated protein C and low levels of free protein S in Greek patients with inflammatory bowel disease

OBJECTIVE:Patients with inflammatory bowel disease (IBD) frequently suffer from thromboembolic events. A recently identified mechanism for thrombophilia, the poor anticoagulant response to activated protein C, has been suggested as one of the leading risk factors for thrombosis. The aim of this study was to evaluate the frequency of thrombophilic abnormalities, including activated protein C-resistance (APCR), in Greek patients with ulcerative colitis (UC) and Crohns disease (CD).METHODS:Forty-eight patients with UC, 36 with CD, and 61 matched healthy controls (HC) were studied. Cases with presence of lupus anticoagulant, use of anticoagulants or heparin, and pregnancy were excluded. Disease activity in CD was evaluated by use of the Crohns Disease Activity Index (CDAI) score and in UC by the Truelove-Witts grading system. Plasma levels of protein C, free protein S, antithrombin III (AT-III), activated protein C resistance (APCR), and fibrinogen were determined in IBD patients, as well as in HC. All the cases and controls with abnormal APCR were further studied by genetic testing for the factor V Leiden mutation.RESULTS:Mean fibrinogen levels in UC and CD patients were significantly elevated (p < 0.0001), compared with HC. The mean values of free protein S, as well as mean APCR, were significantly lower in UC and CD patients than in the HC (p < 0.0001). Seven (five UC and two CD) of 84 IBD patients (8.3%) and three of the HC (4.9%) had the factor V Leiden mutation. No significant difference was observed for the other thrombophilic parameters. Fibrinogen levels and profound free protein S deficiency were found related to disease activity.CONCLUSIONS:Thrombophilic defects are common in Greek patients with IBD and they could interfere either in the disease manifestation or in the thrombotic complications.

An epidemiological study of acute upper gastrointestinal bleeding in Crete, Greece

Objectives Information about the epidemiology of acute upper gastrointestinal bleeding (UGIB) in southern Europe is very limited and especially in Greece non‐existent. Our study sought to determine the current epidemiology of acute UGIB (incidence, mortality and case fatality) in the prefecture of Heraklion‐Crete. Design/methods From February 1998 to February 1999, we prospectively obtained data on all patients with acute UGIB in the prefecture of Heraklion‐Crete. All patients who were permanent residents of the prefecture of Heraklion, aged 16 years and over with acute UGIB were included in the study. Results During this period, 353 cases of acute UGIB were included in the study. The overall incidence of acute UGIB is 160/100 000 adults per year with a male‐to‐female ratio of 1.7 and a mean age 66.2 ± 17.1 years. The incidence rises from 30 in those aged under 30 years to 609 in those aged over 75 years. The overall population mortality was 9/100 000 adults per year. Overall case fatality during hospitalization was 5.6%. All deaths occurred in patients older than 60 years. One or more comorbid illnesses were noted in 61% of cases. Recent intake of non‐steroidal antiinflammatory drugs (NSAIDs) was reported in 49% of the cases. The most common recorded diagnoses were erosive disease in 108 (30.5%) patients, duodenal ulcer in 97 (27.4%) and gastric ulcer in 75 (21.2%). Rebleeding occurred in 41 patients (12%). Twelve patients (3.3%) had surgery during hospitalization. Conclusions The overall annual incidence of acute UGIB in the prefecture of Heraklion‐Crete is one of the highest reported in Europe and increases appreciably with age. Both population mortality and case fatality are slightly lower compared to those reported in most previous studies.

A REVIEW OF THE POSTULATED MECHANISMS CONCERNING THE ASSOCIATION OF HELICOBACTER PYLORI WITH ISCHEMIC HEART DISEASE

Since its discovery, Helicobacter pylori has been implicated in the pathogenesis of several diseases, both digestive and extradigestive. Interestingly, the majority of the extradigestive‐related literature is focused on two vascular manifestations: stroke and ischemic heart disease. Potential mechanisms for the establishment of a H. pylori‐induced ischemic heart disease have been proposed with regard to chronic inflammation, molecular mimicry, oxidative modifications, endothelial dysfunction, direct effect of the microorganism on atherosclerotic plaques as well as changes regarding traditional or novel risk factors for ischemic heart disease or even platelet‐H. pylori interactions. A positive link between H. pylori infection and ischemic heart disease has been suggested by a series of studies focusing on epidemiologic evidence, dyslipidemic alterations, upregulation of inflammatory markers or homocysteine levels, induction of hypercoagulability, oxidation of low‐density lipoprotein, causation of impaired endothelial function, detection of H. pylori DNA in atherosclerotic plaques, and participation of certain antigens and antibodies in a cross‐reactivity model. There are studies, however, which investigated the relationship between H. pylori and ischemic heart disease with regard to the same parameters and failed to confirm the suggested positive association. Further studies in the direction of interaction between H. pylori and the hosts genotype as well as a quest for evidence towards novel risk factors for ischemic heart disease such as oxidative stress, vascular remodeling, vascular calcification, or vasomotor activity, may reveal a field of great interest, thus contributing to the determination of new potential mechanisms.

Laparoendoscopic rendezvous versus preoperative ERCP and laparoscopic cholecystectomy for the management of cholecysto-choledocholithiasis: interim analysis of a controlled randomized trial.

Background:Although the ideal management of cholecysto-choledocholi-thiasis is controversial, the 2-stage approach [endoscopic retrograde cholangiopancreatography (ERCP), sphincterotomy, and common bile duct (CBD) clearance followed by laparoscopic cholecystectomy] remains the standard way of management worldwide. One-stage approach using the so-called laparoendoscopic rendezvous (LERV) technique offers some advantages, mainly by reducing the hospital stay and the risk of post-ERCP pancreatitis. Objective:To compare the LERV 1-stage approach with the standard 2-stage approach consisting of preoperative ERCP followed by laparoscopic cholecystectomy for the treatment of cholecysto-choledocholithiasis. Setting:Controlled randomized trial, University/Teaching Hospital. Methods:Patients with cholecysto-choledocholithiasis were randomized either to LERV or to the 2-stage approach. Both elective and emergency cases were included in the study. Primary endpoint was to detect difference in overall hospital stay, whereas secondary endpoints were (i) to detect differences in morbidity (especially post-ERCP pancreatitis) and (ii) success of CBD clearance. This is an interim analysis of the first 100 randomized patients. Results:Hospital stay was significantly shorter in the LERV group; median 4 (2–19) days versus 5.5 (3–22) days, P = 0.0004. There was no difference in morbidity and success of CBD clearance between the 2 groups. Post-ERCP amylase value was found significantly lower in the LERV group: median 65 (16–1159) versus 91 (30–1846), P = 0.02. Conclusions:Interim analysis of the results suggests the superiority of the LERV technique in terms of hospital stay and post-ERCP hyperamylasemia.

Calprotectin, Calgranulin C, and Other Members of the S100 Protein Family in Inflammatory Bowel Disease

BackgroundSince their discovery, S100 proteins have been associated with diverse diseases of inflammatory, degenerative, or malignant nature. Due to their participation in inflammation, they have also been studied with regard to inflammatory bowel disease (IBD).MethodTo provide a review of available literature, a PubMed, MEDLINE, and Embase-based literature search was performed, using all available nomenclature for each member of the S100 protein family, along with the terms inflammatory bowel disease, ulcerative colitis, Crohn’s disease, or indeterminate colitis.ResultS100A8/A9, also known as calprotectin, S100A12, or calgranulin C and in a lesser extent S100P, are involved in the pathogenesis, activity, diagnosis, and therapeutic management of IBD. The majority of available literature is focused primarily on S100A8/9, although there is growing evidence on the significance of S100A12. Most studies emphasize the potential merit of S100A8/A9 and S100A12, as markers for differential diagnosis, monitoring of activity, or disease relapse, in IBD. Limitations, regarding the diagnostic utility of these markers, seem to exist and are mainly related to the publication of conflicting results, i.e., for IBD activity, and to the fact that S100A8/A9 and S100A12 are not disease-specific.ConclusionsAlthough the existing data link specific S100 proteins with IBD, there are still several drawbacks in the use of these markers for diagnostic purposes. Thus, it seems that further research is mandatory in order to eliminate the impact of confounding factors but also to detect additional associations between S100 proteins and IBD or novel S100 proteins with a closer correlation with IBD.

Renal manifestations and complications of inflammatory bowel disease

Renal manifestations and complications are not rare in patients with inflammatory bowel disease (IBD) and may present as nephrolithiasis, amyloidosis, tubulointerstitial nephritis, and glomerulonephritis. Symptoms of renal impairment are not always specific and since the underlying bowel disease is preponderant, renal function deterioration may be underestimated. Additionally, medical treatment of patients with IBD such as aminosalicylates, cyclosporine, and tumor necrosis factor‐&agr; inhibitors can cause renal complications, although direct correlation to bowel disease is not always clear. The well‐documented renal manifestations and complications of IBD, as well as the possible renal side effects of new drugs, emphasize the need for periodic evaluation of renal function. New markers of renal function may facilitate early diagnosis and unravel the complex mechanisms responsible for kidney damage. The purpose of this review is to summarize the renal manifestations and complications as well as the markers of renal function utilized in IBD, attempting to shed more light on the pathophysiology of renal damage in IBD. (Inflamm Bowel Dis 2011;)

Appendectomy, tonsillectomy, and risk of inflammatory bowel disease

PURPOSE: Appendectomy has been suggested as a possible protective factor in ulcerative colitis and as a risk factor in Crohns disease. Tonsillectomy has also been associated with Crohns disease. We performed a case-controlled study to investigate these associations in a homogeneous Greek population. METHODS: One hundred thirty-four consecutive cases of ulcerative colitis and 76 cases of Crohns disease were included in the study. For each inflammatory bowel disease patient and a corresponding healthy control subject, matched for gender, age, and educational level, a standard record on various risk factors was completed by interview. The association between disease status and risk factors was assessed by Pearsons chi-squared test and the independent contribution of each risk factor was analyzed by means of logistic regression analysis. RESULTS: Appendectomy had been performed in 11 (8.2 percent) patients with ulcerative colitis, in 18 (13.4 percent) of their matched healthy control cases, in 19 (25.0 percent) patients with Crohns disease, and in 10 (13.2 percent) of their matched healthy control cases. Odds ratio for development of ulcerative colitis after appendectomy was 0.6 (95 percent confidence interval, 0.26–1.27). Odds ratio for Crohns disease was 2.2 (95 percent confidence interval, 0.94–5.12). Odds ratio for development of ulcerative colitis or Crohns disease after tonsillectomy was 0.95 (95 percent confidence interval, 0.49–1.82) and 3.29 (95 percent confidence interval, 1.29–8.37), respectively. The logistic regression analysis showed that appendectomy and tonsillectomy have no independent association with the risk of developing ulcerative colitis, whereas in Crohns disease both appendectomy and tonsillectomy have positive associations. Wellestablished risk factors, such as family history and smoking status, were also verified in this study. CONCLUSIONS: This case-control study, using multivariate logistic regression analysis, showed a less pronounced association between ulcerative colitis and appendectomy than previous reports. Our data also support the conclusion that tonsillectomy is a risk factor for developing Crohns disease.

Angiogenin, angiopoietin-1, angiopoietin-2, and endostatin serum levels in inflammatory bowel disease.

Background: Angiogenesis is a complex process, involving a great number of mediators. It is implicated in the pathogenesis of numerous diseases, holding a critical role in inflammatory bowel disease (IBD). The objective of this study was to assess serum levels of angiogenin, angiopoietin‐1, angiopoietin‐2, and endostatin in IBD patients. Methods: Measurement of all angiogenesis mediators was performed with a commercially available enzyme‐linked immunosorbent assay. Fifty‐two patients with ulcerative colitis (UC), 59 with Crohns disease (CD), and 55 healthy controls (HC) were included in the study. The values were analyzed with regard to disease and patients characteristics. Results: Angiogenin levels were significantly higher in IBD patients compared to HC (P < 0.001) and in UC and CD smoker patients compared to nonsmokers (P = 0.0121 and P = 0.005, respectively). Angiogenin levels were lower in UC patients receiving 5‐aminosalicylate (5‐ASA) alone, compared to those receiving combined therapy (P = 0.0478). Angiopoietin‐1 levels were significantly lower in IBD patients compared to HC (P < 0.0001) and increased in smokers compared to nonsmoker UC patients (P = 0.0085). IBD patients demonstrated increased angiopoietin‐2 levels compared to HC (P = 0.0131), while CD patients with disease restricted to the colon had significantly lower levels compared to other disease locations (P < 0.0001). Higher endostatin levels were recorded in UC patients with extensive colitis. Conclusions: Elevated serum angiogenin and angiopoietin‐2 levels and lower serum angiopoietin‐1 levels were shown in IBD patients, as well as a different pattern of angiogenic factor alterations related to location, treatment, smoking habits and gender. Inflamm Bowel Dis 2011

Resistance to Activated Protein C, Factor V Leiden and the Prothrombin G20210A Variant in Patients with Colorectal Cancer

Objective: The aim of our study was to determine the frequency of resistance to activated protein C (APC), factor V Leiden (FVL) and the prothrombin G20210A variant in patients with colorectal cancer. Methods: 74 patients with colorectal cancer and 192 colonoscopically selected controls were prospectively investigated for the presence of APC resistance, FVL and the prothrombin G20210A variant. APC resistance was measured as the ratio of activated partial thromboplastin times with and without APC (APC sensitivity ratio, APC-SR). The FVL and prothrombin G20210A variant were detected by a polymerase-chain-reaction-based technique. Results: FVL was detected in the heterozygous form in 4 of 74 cancer patients (5.4%) and in 7 of 192 controls (3.6%; p > 0.5, odds ratio: 1.51). After excluding patients and controls with FVL, APC-SR was below 2 in 6 of 70 cancer patients (8.5%) and in 1 of 185 controls (0.5%; p < 0.01, odds ratio: 17.25), and the mean value of APC-SR was significantly lower in cancer patients than the respective level of controls (2.8 vs. 3.7, p < 0.001). The G20210A mutation in the prothrombin gene was found in the heterozygous form in 2 of 74 patients with colorectal cancer (2.7%) and in 5 of 192 colonoscopically control subjects (2.6%; p > 0.5, odds ratio: 1.03). Conclusions: These findings suggest that patients with colorectal cancer have a high frequency of resistance to APC but no significant differences in the frequency of the FVL or G20210A mutation of the prothrombin gene compared to colonoscopically selected controls.