Serum laminin and collagen IV in inflammatory bowel disease.

BACKGROUND: / AIMS: Laminin and collagen IV have been proposed as extracellular matrix serum markers. Because fibrosis is a major complication of inflammatory bowel disease, serum concentrations of laminin and collagen IV were measured in patients with ulcerative colitis (UC) and Crohn's disease (CD) and compared with inflammatory and healthy controls. METHODS: Laminin and collagen IV serum concentrations were measured in 170 patients with inflammatory bowel disease (86 UC and 84 CD), in 23 patients with other causes of intestinal inflammation, and in 80 matched healthy controls using commercially available enzyme linked immunosorbent assays. Laminin and collagen IV concentrations were correlated with disease activity, type, localisation, and treatment. RESULTS: Mean (SD) serum laminin concentrations were 281.0 (110.1) ng/ml in patients with UC, 275.6 (106.7) ng/ml in patients with CD, 192.0 (17.8) ng/ml in healthy controls, and 198.5 (32.5) ng/ml in inflammatory controls. Mean (SD) serum collagen IV concentrations were 72.8 (22.9) ng/ml in patients with UC, 71.0 (18.2) in patients with CD, 79.8 (12.2) ng/ml in healthy controls, and 88.9 (24.6) ng/ml in inflammatory controls. There was a significant difference among the four groups (p < 0.0001) for both markers. There was a strong correlation between serum laminin, but not collagen IV, and disease activity in both diseases. No significant association was found between these markers and disease localisation or disease type. CONCLUSIONS: Serum concentrations of laminin are increased, whereas serum concentrations of collagen IV are decreased, in patients with inflammatory bowel disease. They may be useful surrogate markers for sustained inflammation and tissue remodelling.

Complete regression of primary gastric plasmacytoma following Helicobacter pylori eradication.

We describe the first case of a primary gastric plasmacytoma stage I completely regressed following Helicobacter pylori (H.pylori) eradication. The patient, a 61-year-old man, had a long history of chronic gastritis and gastric ulcers with recurrent gastrointestinal hemorrhage. Diagnosis of H.pylori infection was based on the positive urease breath test, the elevated titers of serum anti- H.pylori antibodies, and the detection of the bacterium in gastric mucosa biopsy specimens. Diagnosis of gastric plasmacytoma was based on the findings of histopathology, immunocytochemistry and in situ hybridization. Eradication of H.pylori with antibiotics was followed by disappearance of endoscopic and histopathologic features of the gastric tumor 3 months after the completion of the treatment. No relapse has been documented 20 months after the initial diagnosis of plasmacytoma. A possible causal relationship between the tumor and the underlying H.pylori infection is discussed.

Diminutive polyps of large bowel should be an early target for endoscopic treatment.

BACKGROUND AND AIMS: Aim of the present study is to ascertain the importance of diminutive colorectal polyps and define the need for removal according to their characteristics and malignant potential. PATIENTS AND METHODS: A total of 4,723 patients who underwent colonoscopy were evaluated and 624 patients with 826 polyps were recorded. There were 352 patients with 443 diminutive polyps, studied according to their distribution. Of these, 371 were removed, histologically examined and correlated to patient characteristics and occurrence of synchronous neoplasms. RESULTS: Of the right colon polyps, 81/115 were diminutive, versus 362/711 of the left colon (p<0.0001). Adenomas were more common in patients over 50 years of age, (p<0.0001). In all colonic segments, diminutive adenomas prevailed over hyperplastic polyps, whereas the proportion of diminutive adenomas predominated in the right colon (p=0.0015). Adenomas were classified as tubular 39%, tubulovillous 55.7% and villous 5.3%. The degree of dysplasia was mild in 45.5%, moderate in 51% and severe in 3.5%. The prevalence of synchronous neoplasms was 37.4%. They were more frequently found in males over 50 years of age and in patients with diminutive adenomas compared to those with diminutive hyperplastic polyps (p=0.0078). CONCLUSIONS: The majority of right colon polyps are diminutive. The proportion of diminutive adenomas is higher in patients over 50 years and in the right vs left colon. Diminutive polyps should be removed taking into account the high prevalence of adenomas with a villous component and their significant degree of dysplasia.

Retractile mesenteritis presenting as fever of unknown origin and autoimmune haemolytic anaemia.

Retractile mesenteritis is an extremely rare disease characterised by a non-specific inflammatory and fibrotic process of the mesenteric adipose tissue, which is usually accompanied by pain and a variety of other abdominal symptoms. We describe here the case of a patient with retractile mesenteritis presenting with prolonged high-grade fever and autoimmune haemolytic anaemia without abdominal symptoms. The patient's illness was complicated by chylous ascites. Diagnosis was suspected by computed tomography and confirmed histologically following exploratory laparotomy. The patient was treated with prednisone and azathioprine, and he had a rapid improvement in anaemia and fever relief, but no substantial change in the mesenteric lesions. Our case adds autoimmune haemolytic anaemia to the wide spectrum of manifestations of retractile mesenteritis and implies the possible involvement of immune mechanisms in the pathogenesis of the 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 Crohn's 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.

Elevated thrombopoietin serum levels in patients with inflammatory bowel disease.

OBJECTIVES: Elevated platelet count is a well recognized marker of inflammatory bowel disease (IBD) activity. Thrombopoietin (TPO) is a critical cytokine in the physiological regulation of thrombopoiesis. The aim of this study was to investigate the serum levels of endogenous TPO in patients with IBD, the relationship between platelet counts and TPO levels, and the correlation of TPO with the clinical characteristics of the patients. METHODS: TPO levels in 40 patients with Crohn's disease (CD), 63 patients with ulcerative colitis (UC), and in 42 healthy blood donors were assessed by ELISA. Platelet and white blood cell counts as well as C-reactive protein, and erythrocyte sedimentation rate were measured. RESULTS: TPO levels were significantly elevated in patients with CD (mean 124.3 +/- SD 58.0 pg/ml, p < 0.0001) and in patients with UC (mean 152.2 +/- SD 142.3 pg/ml, p < 0.0001), compared to controls (mean 53.4 +/- SD 45.7 pg/ml). TPO levels remained significantly elevated in remission (mean 144.7 +/- SD 131.1 pg/ml, p < 0.0001 compared to controls). Platelets were significantly elevated only in active CD, being normal in inactive disease as well as in all patients with UC. There was no significant correlation between TPO levels and various clinical characteristics of patients with IBD. No significant correlation was found between TPO levels and either platelet counts or white blood cell counts, erythrocyte sedimentation rate, and C-reactive protein. CONCLUSIONS: TPO levels are increased in IBD, irrespective of disease activity, platelet counts, and clinical characteristics of the patients. These observations indicate that TPO, apart from being a platelet producer, might have additional functions, probably related to the procoagulant state of IBD.

Appendectomy, tonsillectomy, and risk of inflammatory bowel disease: case-controlled study in Crete.

PURPOSE: Appendectomy has been suggested as a possible protective factor in ulcerative colitis and as a risk factor in Crohn's disease. Tonsillectomy has also been associated with Crohn's 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 Crohn's 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 Pearson's 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 Crohn's 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 Crohn's disease was 2.2 (95 percent confidence interval, 0.94-5.12). Odds ratio for development of ulcerative colitis or Crohn's 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 Crohn's disease both appendectomy and tonsillectomy have positive associations. Well-established 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 Crohn's disease.

Autoimmune hemolytic anemia and positive Coombs test associated with ulcerative colitis.

OBJECTIVES: To estimate the frequency of autoimmune hemolytic anemia and Coombs positivity without overt hemolysis in ulcerative colitis, to determine possible subsets of patients with ulcerative colitis susceptible to this complication, and to assess the efficacy of the applied therapeutic modalities. METHODS: Three hundred and two patients with ulcerative colitis treated at the University Hospital of Heraklion, Crete, over a 6-yr period were included. Within this group, a subgroup of 152 patients were studied prospectively for the presence of a positive direct Coombs test. RESULTS: Autoimmune hemolytic anemia was diagnosed in five of 302 patients with ulcerative colitis (1.7%). One more patient developed Coombs-positive hemolytic anemia, attributed to sulfasalazine. A positive Coombs test without evidence of hemolysis was found in three of 152 patients (2%). The mean age of all Coombs-positive patients was 50.5 yr, and there was a definitive male preponderance (male: female, 2:1). Autoimmune hemolytic anemia occurred during active colitis in all cases. The mean time between the onset of colitis and the diagnosis of autoimmune hemolytic anemia was 17 months. Three of five patients with autoimmune hemolytic anemia (60%) and seven of nine of all Coombs-positive patients (77.7%) had total colitis. All patients with autoimmune hemolytic anemia were treated initially with large doses of corticosteroids. Three of five (60%) had good hematological responses. One patient responded to the addition of azathioprine, and one underwent splenectomy and proctocolectomy. CONCLUSIONS: In this study, the frequency with which autoimmune hemolytic anemia was associated with ulcerative colitis was higher than in previous reports. The complication occurred early in the course of colitis and was related to activity and extent of the disease. In contrast to others studies, we found a preponderance of males. Although corticosteroids and/or immunosuppressive therapy was successful in most of our cases, one patient required surgery.

Genetic markers may predict disease behavior in patients with ulcerative colitis.

BACKGROUND & AIMS: Recent studies have suggested that HLA DRB1*0103 and allele 2 of the interleukin 1 receptor antagonist (IL-1RA) gene predict severe and extensive ulcerative colitis, respectively. The aim of this study was to test these hypotheses in patients undergoing surgery for their colitis. METHODS: HLA DRB1 and DQB1 genotyping was performed in 99 patients and 472 controls. Genotyping for polymorphisms of genes encoding tumor necrosis factor alpha and IL-1RA was performed in 107 patients and 89 controls. Measurement of antineutrophil cytoplasmic antibody (ANCA) was performed in 72 patients and 58 healthy subjects by fixed neutrophil enzyme-linked immunosorbent assay and indirect immunofluorescence. RESULTS: The DRB1*0103 allele was increased in patients (14.1% vs. 3.2% in controls; P < 1 x 10[-5]). This association was greatest in patients with extensive disease (15.8%; P < 0.0001) or extraintestinal manifestations (22.8%; P < 0.0001): mouth ulcers (25.8%; P < 0.0001), arthritis (27.2%; P < 0.0001), and uveitis (35.7%; P < 0.0001). The DRB1*04 alleles were reduced in patients (P = 0.005). Differences were noted between extensive and distal disease in the frequency of allele 2 of IL-1RA (10.9% in distal vs. 28.6% in extensive; P = 0.01) and allele 2 homozygosity. ANCA was detected in 76.4% of patients. Carriage of IL-1RA allele 2 and tumor necrosis factor 2 allele was increased in ANCA-positive patients. CONCLUSIONS: Genetic markers may predict disease behavior in ulcerative colitis.

Cytokine gene polymorphisms in inflammatory bowel disease.

BACKGROUND: Concordance rates in siblings and twins provide strong evidence that genetic susceptibility is important in the pathogenesis of inflammatory bowel disease. The number and identity of susceptibility genes is largely uncertain. Cytokine genes are attractive candidate loci. AIMS: To study allelic frequencies of polymorphisms of the interleukin-1 receptor antagonist (IL-1RA) gene and the tumour necrosis factor alpha gene in patients with inflammatory bowel disease. SUBJECTS: One hundred and twenty nine North European caucasoid patients with ulcerative colitis, 120 patients with Crohn's disease, and 89 healthy controls. METHODS: Genotyping was performed by polymerase chain reaction. A variable number of tandem repeats (VNTR) in the IL-1RA gene and a single base pair polymorphism in the TNF alpha gene promoter region (TNF-308) were analysed. RESULTS: No significant differences in IL-1RA VNTR allelic frequencies were noted between Crohn's disease (allele 1: 72.6%, allele 2: 24.7%, allele 3: 2.6%), ulcerative colitis (72.6%, 24.3%, 3.1%, respectively), and controls (76.9%, 20.8% and 2.3%). Some 42.4% of patients with ulcerative colitis and 43.4% patients with Crohn's disease were carriers of allele 2, compared with 34.8% healthy subjects. The TNF2 allele was modestly reduced in Crohn's disease (13.2%), compared with healthy subjects (21.3%; p = 0.04), and ulcerative colitis (21.6%). CONCLUSIONS: The associations demonstrated are modest: these polymorphisms are unlikely to be important determinants of overall disease susceptibility.

A prospective epidemiologic study of Crohn's disease in Heraklion, Crete. Incidence over a 5-year period.

BACKGROUND: There has been an impression from published work that Crohn's disease is less common in southern than in northern Europe. A low incidence of Crohn's disease has been observed in Greece, but conclusive data are still lacking. METHOD: A 5-year prospective and population-based epidemiologic study of Crohn's disease was carried out in a well-defined area of Crete. RESULTS: The mean annual incidence of the disease for the years 1990-94 was 3.0 per 10(5) inhabitants. During the study period the incidence increased from 1.9/10(5) in 1990 to 3.8/10(5) in 1994. The male to female ratio was 2.4:1. The age group 25-34 years had the highest age-adjusted incidence (6.3/10(5)). The incidence of Crohn's disease was also found to be higher in smokers, in urban areas, and in people with high educational level. CONCLUSION: Crohn's disease is common in Heraklion, Crete. The findings of the study are discussed in relation to those of other European countries.