Andreas Tromm

A polymorphism of the NFKBIA gene is associated with Crohn's disease patients lacking a predisposing allele of the CARD15 gene.

Background and aimsNuclear factor kappa-B (NFκB) plays a crucial role in diseases associated with dysregulated immune response. NFκB inhibitor α downregulates the activity of NFκB.Patients and methodsTo evaluate the contribution of the NFκB inhibitor α gene in Crohns disease single nucleotide polymorphisms in the 3′-UTR and at position −420 in the promoter were studied in 259 patients with Crohns disease genotyped for the variations of the CARD15 gene in comparison to 441 healthy controls. Additionally we screened the coding region of the NFκB inhibitor α gene for polymorphisms by SSCP analysis.ResultsIn comparison to controls the A allele and the AA genotype frequencies of the single nucleotide polymorphisms in the 3′-UTR were significantly increased only in Crohns disease patients without a variation in the CARD15 gene. Similarly, the difference between patients harboring no predisposing CARD15 alleles and patients harboring such a variation was significant.ConclusionThe findings indicate that the phenotype Crohns disease is to be substructured with respect to genetic susceptibility.

Budesonide for the treatment of collagenous colitis: first results of a pilot trial

OBJECTIVES:Collagenous colitis is a chronic watery diarrhea disorder characterized by a subepithelial collagen layer and a lymphoplasmacytic infiltration within the lamina propria. However, no standard treatment has been introduced by controlled clinical trials. Aim of the present pilot trial was to investigate the clinical effects of orally administered budesonide (3 mg t.i.d.) in 7 patients with collagenous colitis. In addition, the histomorphological changes after budesonide treatment were described in a group of 3 patients.METHODS:The study was performed as an open label pilot trial. Study end point was the clinical remission of collagenous colitis defined by stool frequency and stool consistency.RESULTS:The results indicate a rapid and sustained clinical response in all patients. Stool frequency significantly decreased (p < 0.001) from 10.43 ± 5.56 per day (4–20 per day) to 3.3 ± 1.2 (1–5 per day) after 10 days and to 1.86 ± 0.69 per day (1–3 per day) after 10 wk. Moreover stool consistency changed from watery (6 patients) or soft (1 patient) to soft (1 patient) or solid (6 patients). Clinical improvement was achieved within the first 10 days in all patients and maintained after dose reduction. In 3 patients no diarrhea recurred within 7, 12, or 15 months after treatment with budesonide was terminated. In these patients control biopsies were taken and showed a marked regression of both characteristics, the collagen band and the lymphoplasmacytic infiltration.CONCLUSIONS:With respect to the preliminary data from this pilot trial, budesonide with its high topical and low systemic effects seems to be of therapeutic clinical benefit in collagenous colitis. A therapeutic effect could be demonstrated for both therapeutic goals, the clinical response and morphological changes. Further studies on the effects of budesonide on mucosal collagen metabolism and long-term follow-up are warranted.

The IL‐10 gene is not involved in the predisposition to inflammatory bowel disease

Although genetic predisposition for inflammatory bowel disease (IBD) is well established, little is known about the accountable genes. The pathogenesis of IBD is characterized by an imbalanced activation of Th1‐ and Th2‐lymphocytes. IL‐10 represents an anti‐inflammatory cytokine which downregulates the production of Th1‐derived cytokines. To evaluate the role of the IL‐10 gene in IBD, two polymorphisms in the promoter region (G/A at position —1082 and C/A at position —592) were genotyped in 142 patients with Crohns disease (CD), 104 patients with ulcerative colitis (UC), and 400 healthy controls. Significant differences were not apparent, neither in the allele frequencies of either polymorphism, nor in the haplotype frequencies. Screening of the coding region of the IL‐10 gene by polymerase chain reaction — single strand conformation polymorphism (PCR‐SSCP) analysis revealed a rare sequence variation in exon 1 leading to an amino acid exchange (G→A; G15R) in two patients with CD and five healthy controls. Therefore, polymorphisms of the IL‐10 gene are not demonstrably involved in the predisposition of IBD in our cohorts of patients.

The polymorphism at position -174 of the IL-6 gene is not associated with inflammatory bowel disease.

Objective Inflammatory bowel diseases (IBD) are multifactorial disorders, characterized by failure to limit the inflammatory response to luminal antigens. Genetic factors play an important role in the pathogenesis, but little is known about the accountable genes. Increased secretion of pro-inflammatory cytokines appears crucial in the initiation of the inflammatory response. Methods To evaluate the role of the IL-6 gene in IBD, a functionally relevant polymorphism in the promoter region (G/C at position −174) has been genotyped in 169 patients with Crohns disease (CD), 133 patients with ulcerative colitis (UC) and 440 healthy controls by using restriction fragment length polymorphism (RFLP) analysis. Results No significant differences were apparent in the allele, genotype and carrier frequencies between patients and controls. Conclusion High secretion of IL-6 does not seem to play a major role in the genetic predisposition to IBD.

Collagenous colitis: implications for the role of vascular endothelial growth factor in repair mechanisms.

Objectives Collagenous colitis is a chronic inflammatory bowel disease with a band-like subepithelial deposition of immature extracellular matrix. Because the extracellular matrix deposition is potentially reversible, an imbalance between fibrogenesis and fibrolysis with reduced matrix degradation has been suspected. Vascular endothelial growth factor plays a central role in extracellular matrix degradation. Therefore, we investigated the expression of vascular endothelial growth factor in the colonic mucosa of patients with collagenous colitis before and after long-term treatment with oral budesonide. Method A quantitative immunohistochemical method was used to measure the amount of immunoreactive vascular endothelial growth factor, tenascin and leucocyte common antigen within the epithelium and the lamina propria of colonic biopsies by area morphometry. Results Strong immunostaining for vascular endothelial growth factor within the epithelium and the lamina propria, and for tenascin, was seen in patients with collagenous colitis compared with normal controls. The enhanced immunostaining for vascular endothelial growth factor within the lamina propria was accompanied by the accumulation of leucocytes, detected by staining for leucocyte common antigen. After long-term treatment with oral budesonide, the amount of immunostaining for leucocyte-derived vascular endothelial growth factor within the lamina propria decreased significantly to normal levels. In contrast, staining for vascular endothelial growth factor within the epithelium remained significantly increased. Conclusions Our data suggest an important role of vascular endothelial growth factor in counteracting the local imbalance of fibrogenesis and fibrolysis, leading to an accumulation of immature subepithelial matrix in collagenous colitis.

Vascular endothelial growth factor (VEGF) in Crohn's disease: increased production by peripheral blood mononuclear cells and decreased VEGF165 labeling of peripheral CD14+ monocytes.

Recently, increased serum levels of vascularendothelial growth factor (VEGF) have been shown inpatients with inflammatory bowel disease. The origins ofthe circulating VEGF are still not described. Monocytes play an important role in the inflammatoryprocess. VEGF binding to monocytes mediates monocyterecruitment and activation. The present studyinvestigates the VEGF production of peripheral bloodmononuclear cells and the ability of peripheral monocytesto bind VEGF165 in patients with Crohnsdisease. Nineteen patients with Crohns disease and 10healthy volunteers were studied. VEGF165labeling of CD14+ monocytes was measured using two-color flow cytometry.Density of VEGF labeling was expressed as the meanfluorescence intensity (MFI). Furthermore, VEGF levelswere determined in culture supernatants of unstimulated peripheral blood mononuclear cells. VEGF inculture supernatants was measured using a solid-phaseenzyme-linked immunosorbent assay. There was asignificantly decreased VEGF165 labeling ofmonocytes of patients with active Crohns disease (MFI:369.9 ± 121.6, N = 7, P < 0.002) compared topatients with inactive disease (MFI: 457.7 ±74.5, N = 6) and healthy controls (MFI: 542.9 ±96.2, N = 10). Unstimulated peripheral blood mononuclear cellsof patients with active Crohns disease producedsignificantly higher amounts of VEGF (1142.6 ±483.9 pg/ml, N = 12, P < 0.001) compared withperipheral blood mononuclear cells of healthy volunteers(113.4 ± 101.8 pg/ml, N = 10). VEGF production byperipheral blood mononuclear cells of patients withactive disease was significantly increased compared to patients with quiescent disease (261.6± 254.8 pg/ml, N = 7, P < 0.001). Inconclusion, our data describe peripheral bloodmononuclear cells as one of the origins of the elevatedVEGF serum levels in patients with active Crohns disease.Furthermore, a decrease in VEGF165 bindingsites on peripheral monocytes of patients with activeCrohns disease has been shown. The study underlines theimportant role of VEGF in Crohns disease.

Polymyositis of the skeletal muscles as an extraintestinal complication in quiescent ulcerative colitis.

Abstract Myositis of the skeletal muscle is a rare complication of inflammatory bowel disease. We report about a 33-year-old woman with quiescent ulcerative colitis known since 1995. She had suffered from recurring fever and pain in the thighs for about 4 weeks. Electromyography of quadriceps and deltoid muscles revealed myopathic changes. Diagnosis of polymyositis was confirmed by magnetic resonance imaging indicating edematous changes in the distal extremity muscles. The symptoms rapidly responded to high doses of steroids. Review of the literature indicates only a few cases describing an association of ulcerative colitis and myositis, most of them during acute exacerbations of the disease. In contrast, the present patient was in remission. Diagnosis of myositis should be considered in inflammatory bowel disease patients complaining of myalgia or muscular weakness. Magnetic resonance imaging may show specific features and can be used in addition to laboratory investigations and muscle biopsy for diagnosis of polymyositis.

A polymorphism of the bactericidal/permeability increasing protein (BPI) gene is associated with Crohn's disease.

Background: The bactericidal/permeability increasing protein (BPI) is involved in the elimination of gram-negative bacteria. A functionally relevant single nucleotide polymorphism of the BPI gene causes an amino acid exchange (Glu216Lys). Study: To evaluate whether this single nucleotide polymorphism contributes to the predisposition to inflammatory bowel disease, we compared the allele frequencies of 265 patients with Crohns disease, 207 patients with ulcerative colitis, and 608 healthy controls. Results: The Glu/Glu genotype frequency was decreased significantly in Crohns disease patients as compared with controls (P < 0.027). No differences were obvious in patients with ulcerative colitis. Conclusions: Failure of the innate intestinal immune system could be involved in the pathogenesis of Crohns disease via reduced/impaired defense against gram-negative bacteria.

Overlap syndrome between autoimmune hepatitis and primary sclerosing cholangitis in two cases

The overlap syndrome between autoimmune hepatitis and primary sclerosing cholangitis is a rare condition and only few cases have been published, partly associated with ulcerative colitis, but not with Crohns disease. We report an autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome in a female patient with Crohns disease. In addition, a second case of overlap syndrome is reported in a man without inflammatory bowel disease. A 24-year-old woman was referred with a 10-month history of diarrhoea and biochemical changes including elevated serum levels of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase and immunoglobulin G. Enzyme linked immunosorbent assay showed that antinuclear autoantibodies were elevated. Immunofluorescence for perinuclear-staining antineutrophil cytoplasmatic antibodies was positive. Diagnostic criteria of definite autoimmune hepatitis according to the International Autoimmune Hepatitis Group were fulfilled. Liver biopsy simultaneously showed criteria of autoimmune hepatitis and primary sclerosing cholangitis. Endoscopic retrograde cholangiography demonstrated features of primary sclerosing cholangitis. Colonoscopy and colonoscopic biopsies indicated an active Crohns disease affecting the terminal ileum and the ascending and transverse colon. Furthermore, we report the case of a 28-year-old man with known primary sclerosing cholangitis for the previous 6 years, and who developed jaundice and a marked increase of aspartate aminotransferase, alanine aminotransferase and immunoglobulin G, leading to the diagnosis of definite autoimmune hepatitis. A review of the literature revealed only 16 cases of an autoimmune hepatitis/primary sclerosing cholangitis syndrome in patients without inflammatory bowel disease or in association with ulcerative colitis. We report two additional cases, one case showing an association with Crohns disease.

Kyphoskoliose als Ursache einer pulmonalen Hypertonie

Zusammenfassung.Anamnese und klinischer Befund: Ein 61-jähriger Patient stellte sich mit diffusen Oberbauchbeschwerden und den Symptomen einer progredienten Belastungsdyspnoe stationär vor. Klinisch imponierten die Zeichen einer Rechtsherzbelastung und eine ausgeprägte Kyphoskoliose. Therapie und Verlauf: Mittels Einschwemmkatheteruntersuchung konnte eine pulmonale Hypertonie mit Ausschluss einer kardialen Genese diagnostiziert werden. Eine obstruktive Atemwegserkrankung und eine Lungenembolie wurden durch eine Lungenfunktionsanalyse bzw. durch eine Spiralcomputertomographie des Thorax ausgeschlossen. Die Kyphoskoliose blieb somit als alleinige Ursache der pulmonalen Hypertonie bestehen. Da der Patient einer nichtinvasiven Beatmung als Therapie der Wahl ablehnend gegenüberstand, konnte alternativ unter einer medikamentösen Therapie mit Calciumantagonisten und ACE-Hemmern und nachfolgender Sauerstofftherapie der pulmonalvaskuläre Widerstand effektiv gesenkt werden (746 vs. 332 dyn*s*cm−5). Schlussfolgerung: Eine Kyphoskoliose kann eine beträchtliche pulmonalarterielle Widerstandserhöhung hervorrufen. Diese lässt sich durch eine medikamentöse Therapie und eine Sauerstofftherapie effektiv senken.Abstract.History and Clinical Findings: A 61-year-old male patient complained about diffuse upper abdominal pain and a progressive dyspnoe on exertion. Of clinical relevance were signs of congestive heart failure and a distinct kyphoscoliosis. Therapy and Clinical Course: A cardiac catheter examination proved a pulmonary hypertension without cardiac genesis. Both, pulmonary function test and computed tomography of the thorax rule out obstructive bronchial asthma and embolism of the lung. As the sole cause of pulmonary hypertension, kyphoscoliosis was diagnosed. Since the patient refused noninvasive positive pressure ventilation, a medication with calcium entry blocker and ACE blocker was induced, followed by oxygen breathing. This successfully helped to reduce pulmonary resistance (746 vs. 332 dyn*s*cm−5). Conclusion: Kyphoscoliosis can create a considerable increase of pulmonar resistance. Medical treatment and oxygen breathing have proven to be an efficient method to lower that significantly.