Antoni Stadnicki

Cutaneous manifestations in patients with inflammatory bowel diseases: Pathophysiology, clinical features, and therapy

Abstract:The skin is one of the most common extraintestinal organ system affected in patients with inflammatory bowel disease (IBD), including both Crohns disease and ulcerative colitis. The skin manifestations associated with IBD are polymorphic and can be classified into 4 categories according to their pathophysiology: (1) specific, (2) reactive, (3) associated, and (4) induced by IBD treatment. Cutaneous manifestations are regarded as specific if they share with IBD the same granulomatous histopathological pattern: perianal or metastatic Crohns disease (commonly presenting with abscesses, fistulas or hidradenitis suppurativa-like features) is the prototype of this setting. Reactive cutaneous manifestations are different from IBD in the histopathology but have close physiopathological links: pyoderma gangrenosum, a neutrophil-mediated autoinflammatory skin disease typically manifesting as painful ulcers, is the paradigm of this group. Among the cutaneous diseases associated with IBD, the most commonly seen are erythema nodosum, a form of panniculitis most commonly involving bilateral pretibial areas, and psoriasis, a T helper 1/T helper 17–mediated erythematous squamous inflammatory disease. Finally, the number of cutaneous adverse reactions because of IBD therapies is progressively increasing. The most frequent drug-induced cutaneous manifestations are psoriasis-like, eczema-like, and lichenoid eruptions, as well as cutaneous lupus erythematosus for biologics, and nonmelanoma skin cancer, mainly basal cell and squamous cell carcinomas for thiopurines.

Ezetimibe – a new approach in hypercholesterolemia management

Ezetimibe is the first agent used in hypercholesterolemia treatment known to lower intestinal cholesterol uptake that is able to inhibit NPC1L1 transport proteins in the brush boarder of enterocytes and macrophages. Furthermore, it demonstrates anti-inflammatory and immunomodulatory properties and influences the expression of certain antigens. The drug is rapidly absorbed from the gastrointestinal tract and is then glucuronidated to form the active metabolite. It also undergoes extensive enterohepatic circulation. Various genetic polymorphisms seem to influence the pharmacokinetics of ezetimibe with different effects. The drug also presents a complex impact on cytochrome P450 enzymes, as it is a metabolism-dependent inhibitor of CYP3A4. Ezetimibe does not demonstrate any clinically significant interactions with statins, fibrates, mipomersen sodium, levothyroxine or lopinavir. However, its effect in conjunction with cyclosporine is not neutral. The use of this cholesterol absorption inhibitor has been shown to be safe and effective among patients after cardiac, renal and liver transplants, as well as in HIV patients.

Transforming growth factor-β1 and its receptors in patients with ulcerative colitis

Transforming growth factor-beta1 (TGF-beta1) plays a role in the pathogenesis of ulcerative colitis (UC) by activating its specific receptors (T beta RI-T beta RIII). We investigated the expression of genes encoding for TGF-beta1 and T beta RI-III using RT-QPCR in patients with active and inactive UC and non-IBD controls. The localization and level of TGF-beta1 protein in intestinal tissue was estimated by immunohistochemistry, and serum TGF-beta1 concentrations were determined using ELISA. We found a significant increase in TGF-beta1 gene expression and increase in the expression of genes encoding receptor T beta RI in patients with active UC when compared with controls. The expression of genes encoding T beta RII was found to be higher in patients with both active and inactive UC when compared to controls. Specific staining for TGF-beta1 in fibroblasts was significantly greater in both active and inactive UC as compared to controls. The serum concentration of TGF-beta1 was significantly higher in patients with active UC when compared with controls as well as in UC patients with left side/total colonic extension when compared with those with disease limited to rectum/rectosigmoid area. However, no correlation between TGF-beta1 serum concentrations and UC activity index was found. Increases in TGF-beta1 gene expression and its protein level, associated with altered TGF-beta1 receptor profile indicate a functional role for TGF-beta1 in intestinal inflammatory/repair processes in UC. Increases in TGF-beta1 serum concentrations correlate with extension of disease.

Intestinal tissue kallikrein-kinin system in inflammatory bowel disease

Tissue kallikrein cleaves kininogens to release kinins. Kinins mediate inflammation by activating constitutive bradykinin receptor-2 (BR2), which are rapidly desensitized, and induced by inflammatory cytokines bradykinin receptor-1 (BR1), resistant to desensitization. Intestinal tissue kallikrein (ITK) may hydrolyze growth factors and peptides, whereas kinins are responsible for capillary permeability, pain, synthesis of cytokines, and adhesion molecule-neutrophil cascade. Our and others results have demonstrated ITK in intestinal goblet cells and its release into interstitial space during inflammation. Kallistatin, an inhibitor of ITK, has been shown in epithelial and goblet cells, and was decreased in inflamed intestine as well as in plasma compared with noninflammatory controls. BR1 was upregulated in patients with inflammatory bowel disease (IBD), and it has expressed in an apical part of enterocytes in inflamed intestine, but in the basal part in normal intestine. ITK and BR1 were visualized in macrophages forming granuloma in Crohns disease. In animal studies BR2 blockade decreased intestinal contraction, but had limited effect on inflammatory lesions. BR1 was found to be upregulated in animal inflamed intestine, in part dependent on tumor necrosis factor alpha (TNF-α). A selective BR1 receptor antagonist decreased morphological and biochemical features of experimental intestinal inflammation. Both BR1 and BR2 mediate epithelial ion transport that leads to secretory diarrhea. The upregulation of BR1 in inflamed intestine provides a structural basis for the kinins function, suggesting that a selective BR1 antagonist may have potential in therapeutic trial of IBD patients.

Intestinal tissue kallikrein–kallistatin profile in inflammatory bowel disease ☆

The profile of tissue kallikrein (TK) and its inhibitor, kallistatin was evaluated in patients with active ulcerative colitis (UC) and Crohns disease (CD). Tissue kallikrein is mainly localized to goblet cells and kallistatin to epithelial cells of human intestine. Intestinal tissue kallikrein (ITK) and kallistatin are significantly decreased in inflamed intestine compared to noninflammatory controls. TK mRNA as well as kallistatin mRNA is significantly decreased in intestinal biopsy samples from UC-active patients compared with controls. The difference in distribution and levels of ITK and kallistatin in protein and mRNA in patients with inflammatory bowel disease (IBD) compared to controls suggest a role in inflammatory state.

Expression, localization and systemic concentration of vascular endothelial growth factor (VEGF) and its receptors in patients with ulcerative colitis.

Vascular endothelial grow factor (VEGF) promotes angiogenesis by activating the specific receptors KDR and Flt-1. We investigate the expression of genes encoding VEGF and its receptors KDR and Flt- 1 by RT-QPCR reaction using Quanti Tect SYBR Green RT-PCR in patients with active and inactive ulcerative colitis (UC) and control subjects. The localization and level of VEGF protein and its receptors protein in intestinal tissue were estimated by immunohistochemistry. VEGF concentration in serum and plasma was determined by ELISA. We found a significant increase of VEGF gene expression and increase expression of genes encoding receptor Flt-1 in patients with active UC when compared with controls, but KDR was present in trace amount. VEGF and Flt-1 proteins were colocalized in enterocytes as well as in endothelium and muscularis layer of the intestine. The specific staining reaction for VEGF protein as well as for Flt-1 protein was significantly higher in active UC compared with controls. Serum level of VEGF was significantly higher in active UC patients as compared with inactive UC patients as well as with controls. The plasma VEGF level was found to be significantly higher in active UC patients as compared with controls. The increase of gene expression as well as protein level for VEGF and its receptor in UC - inflamed colon, and VEGF action via Flt-1 receptor may have a functional role in UC. Increased VEGF levels in both serum and plasma in active UC patients may reflect VEGF overexpression in intestinal inflammatory tissue.

High-resolution Manometry in Patients with Gastroesophageal Reflux Disease Before and After Fundoplication.

Background/Aims The study aimed to determine pre- and post-fundoplication esophagogastric junction (EGJ) pressure and esophageal peristalsis by high-resolution manometry (HRM) in patients with gastroesophageal reflux disease (GERD). Methods Pre-operative and post-operative HRM data from 25 patients with GERD were analyzed using ManoView version 2.0.1. with updated software for Chicago classification and pressure topography. The study involved swallowing water boluses of 10 mL in the upright position. Results Significant increase of mean basal EGJ pressure and minimal basal EGJ pressure was found in post-operative as compared with preoperative patients (P < 0.05 and P < 0.001, respectively). Integrated relaxation pressure (IRP) reached higher values in post-operative patients than in pre-operative patients (P < 0.001). Intra-bolus pressure (IBP) was significantly higher (P < 0.05) and contractile front velocity (CFV) was slower (P < 0.01) in post-operative patients than in pre-operative patients. Moreover significant increase of distal contractile integral (DCI) was found in post-operative patients (P < 0.05). Hiatal hernia was detected by HRM in 11 pre-operative patients. Fifteen out of 25 post-operative patients complained of dysphagia. Conclusions Fundoplication restores the antireflux barrier by reinforcing EGJ basal pressures, repairing hiatal hernias, and enhances peristaltic function of the esophagus by increasing DCI. However slight IRP elevation found in post-fundoplication patients may result in bolus pressurization and motility disorders.

PTU-151 High Resolution Manometry Profile of Hiatal Hernia in Patients before and after Fundoplication

Introduction Current data relating to esophageal motility evaluated by high resolution manometry(HRM) in presence of hiatal hernia(HH) is equivocal. This study was aimed to compare HRM variables in patients with HH before and after fundoplication and to evaluate diagnostic performance of HRM in detecting sliding HH. Methods Sensitivity and specificity of HRM were assessed in 31 patients(20 females; mean age 48.2) with gastroesophageal reflux disease who were qualified for Nissen fundoplication and underwent preoperative HRM. Intraoperative diagnosis of HH was the gold standard. Area under curve(AUC) of receiver operating characteristic(ROC) reflecting diagnostic accuracy of HRM was also computed. Eleven patients(5 females; mean age 52.1) out of 31 were selected who underwent both: HRM before fundoplication(preoperative group) and at least 3 months after surgery(postoperative group). Manometric protocol included 10 consecutive swallows of 10 ml of water. Variables from pre and postoperative group were compared using paired Wilcoxon test. Results 29 patients out of 31 were found to have HH during surgery while 14 patients had manometric criteria for HH(mean HH size was 2.44 cm). Sensitivity and specificity of HRM in detecting HH were 48% and 100% respectively. AUC under ROC curve for HRM was 0.74 indicating limited usefulness of this method; regarding threshold value of 0.8 for clinical practise. HRM profile of HH in preoperative group is characterised by significantly lower minimal basal esophagogastric junction(EGJ) pressure as well as integrated relaxation pressure(IRP) comparing to postoperative group without HH. IRP values were within normal range in both examined groups( < 15 mmHg). Although mean basal EGJ pressure was lower in preoperative than in postoperative group, the difference between groups didn’t reach statistical significance. Neither DCI nor IBP was affected by fundoplication. Data is shown in table. Abstract PTU-151 Table Preoperative median (IQR*) Postoperative median (IQR*) Hiatal hernia by HRM and intraoperative diagnosis (n) 11 0 Mean Basal EGJ pressure (mmHg) 8.3 (2.6, 11.2) 15.8 (9.9,22.8) Minimal Basal EGJ pressure (mmHg) 0.5 (–2.8, 4.1) 6.5 (4.6, 14.8)† IRP (mmHg) 1.5 (–0.7, 3.7) 5.2 (2.1, 11.8)†† IBP (mmHg) 14.1 (9.6, 18.7) 13.9 (7.1, 24.6) DCI (mmHgxsxcm) 1324 (711.6, 2207.7) 1381.7 (648, 2699.7) * interquartile range; † p < 0.01; ††p < 0.001 Conclusion HRM is not reliable tool to diagnose HH. Due to poor sensitivity of HRM in detecting HH, manometric profile of patients with HH versus those without should be evaluated with caution. Surgical correction of HH contributes to higher EGJ relaxation pressure and improvement of antireflux barrier however neither bolus pressurisation nor DCI is affected by fundoplication. Disclosure of Interest None Declared

PTU-152 High Resolution Manometry Pattern of Esophagogastric Junction and Esophageal Motility in Patients before and after Fundoplication

Introduction Until now it has been limited knowledge related to the application of high resolution manometry(HRM) for the evaluation of fundoplication results. The aim of this study is to assess prospectively esophagogastric junction(EGJ) relaxation and resting pressures and esophageal motility by HRM in patients with gastroesophageal reflux disease(GERD) before and after laparoscopic Nissen fundoplication. Methods 25 patients with GERD(15 females; mean age 46.8 ) underwent HRM before(preoperative group) and at least 3 months after surgery(postoperative group). Manometric protocol included 10 consecutive swallows of 10 ml of water. Variables from pre and postoperative group were compared using Wilcoxon test for paired samples and also McNemar’s test was done to evaluate if surgery had influenced values normalisation. Abstract PTU-152 Table Preoperative median (IQR*) Postoperative median (IQR*) p value Mean Basal EGJ pressure (mmHg) 10.0 (5.7 – 15.6) 15.8 (15.2 – 23.7) p < 0.05 Minimal Basal EGJ pressure (mmHg) 1.8 (–1.1 – 6.5) 7.3 (4.6 – 13.9) p < 0.001 IRP (mmHg) 2.0 (0 – 3.3) 6.0 (2.9 –11.4) p < 0.001 Hiatal hernia (n, %) 11 (45%) 0 IBP (mmHg) 10.2 (6.2 – 14.1) 13.9 (11.7 – 20. 8) p < 0.05 DCI (mmHgxsxcm) 859 (430 – 1574) 1008 (725 – 1968) p < 0.05 CFV (cm/s) 4.3 (3.1 – 5.4) 2.9 (2.0 – 4.0) p < 0.01 Double-peaked waves (%) (0 – 22) (0 – 78) p < 0.01 * interquartile range Results In postoperative group mean basal EGJ pressure as well as minimal basal EGJ pressure were significantly higher than in preoperative group. Integrated relaxation pressure(IRP) was also significantly higher in postoperative group as compared with preoperative group. IRP values were within the normal range in both examined groups(<15 mmHg) except one patient in postoperative group. Before fundoplication 11 patients had hiatal hernia, but none after surgery. Significant increase of intrabolus pressure(IBP) and decrease of contractile front velocity(CFV) were found in postoperative group as compared with preoperative group. Distal contractile integral(DCI) was significantly higher in postoperative group, however based on DCI threshold(450mmHgxsxcm) only trend from ineffective to effective esophageal motility was observed(p = 0.07). Also double-peaked waves were more frequent in postoperative than in preoperative group. Early dysphagia was observed in 8 of 25 patients after fundoplication. Data is shown in table. Conclusion HRM is valuable tool for EGJ characteristics in GERD patients before and after fundoplication. Fundoplication establishes antireflux barrier by increasing EGJ resting pressures and correcting hiatal hernia. Even moderate increased of IRP may contribute to motility disorders and bolus pressurisation in some patients after fundoplication. Disclosure of Interest None Declared