Tomas Koller

Colorectal cancer screening in patients with ulcerative and Crohn's colitis with use of colonoscopy, chromoendoscopy and confocal endomicroscopy.

Background Patients with ulcerative colitis and Crohns colitis have increased risk of colorectal cancer. Current screening endoscopy protocols based on white light endoscopy (WLE) and random biopsies are laborious and of uncertain sensitivity. Novel endoscopic techniques include chromoendoscopy (CE) and confocal laser endomicroscopy (CLE). Aim The aim was to compare WLE and CE for the detection of intraepithelial neoplasia (IEN). Furthermore, we analysed the sensitivity and specificity of CE and CLE for the diagnosis of IEN. Methods The cohort consisted of 30 patients examined by WLE, CE with 0.4% indigocarmine, and by a CLE system Pentax EC-3870CIFK during one examination. Additional 15 patients were examined by conventional protocol only. Random biopsies and biopsies from all suspicious lesions were taken. We compared the number of IENs detected by WLE and CE and analysed the predictive values of CE and CLE for the histology diagnosis. Results There were 1584 random biopsies (35.2 per patient) taken. There were 78 targeted biopsies (1.7 per patient) taken in 24 of 45 patients examined by WLE and an additional 36 biopsies in 16 of 30 patients examined by CE (1.17 additional per patient). There were no IENs found on random biopsies versus six low-grade or high-grade IENs in four patients (two detected by WLE, four additional by CE) from targeted biopsies, P=0.02. A total of 100 suspicious lesions were detected and analysed by CE and histology. CLE could not examine 32 of 100 lesions (two of 30 flat vs. 30 of 70 pedunculated lesions, P=0.0002, odds ratio 10.5). The sensitivity of CE/CLE for low-grade or high-grade IEN was 100/100%, the specificity 96.8/98.4%, positive predictive value was 62.5/66.7% and negative predictive value was 100/100%. Conclusion Targeted biopsies are superior to random biopsies in the screening of IEN in patients with inflammatory bowel disease. CE increases the diagnostic yield of WLE. In our study CLE did not provide additional clinical benefits.

Cholelithiasis and markers of nonalcoholic fatty liver disease in patients with metabolic risk factors

Abstract Cholelithiasis and nonalcoholic fatty liver disease (NAFLD) share the same risk factors. The aim of our study was to explore the relationship between these two conditions and to indentify independent predictors of both diseases in a cohort of patients with metabolic risk factors. Consecutive patients with metabolic risk factors referred to the outpatient clinic during a one-year period were included. Cholelithiasis was defined by the presence of gallstones on abdominal ultrasound examination at inclusion or previously performed cholecystectomy. NAFLD was defined by the presence of at least one surrogate marker such as elevated alanine aminotransferase and/or gamma-glutamyl transpeptidase and/or ultrasound signs of fatty liver. Other common liver diseases were thoroughly excluded. The prevalence of cholelithiasis among patients with and without NAFLD was determined and clinical and laboratory parameters were identified as predictors of NAFLD by multivariate logistic regression. In total, 482 consecutive patients were included: mean age 61 years; 61% were women; 52% of patients had more than 2 metabolic risk factors (obesity, type 2 diabetes, hypertension, hypertriglyceridemia, or low HDL cholesterol). NAFLD and cholelithiasis were present in 41% and 34% of all patients, respectively. Significantly higher prevalence of cholelithiasis was found among patients with NAFLD compared with patients without NAFLD (47% vs. 26%, respectively; p < 0.0001). In multivariate logistic regression model, type 2 diabetes (odds ratio (OR) = 1.99), BMI above 25 kg/m2 (OR = 1.78), and cholelithiasis (OR = 1.77) were identified as independent predictors of NAFLD. Fifty six percent of patients with cholelithiasis had NAFLD compared with 33% of patients without cholelithiasis (p < 0.0001). Multivariate logistic regression identified age above 50 years (OR = 3.46), NAFLD (OR = 1.92), triglycerides above 1.7 mmol/l (OR = 1.91), BMI above 25 kg/m2 (OR = 1.84), and total cholesterol concentration (OR = 0.711) as independent predictors of cholelithiasis. In conclusion, patients with metabolic risk factors and cholelithiasis suffer significantly more often from NAFLD compared with the reference group. Cholelithiasis represents an independent risk factor of NAFLD in addition to metabolic risk factors and could be regarded as an additional risk factor of liver damage in patients with NAFLD. Furthermore, NAFLD is an independent risk factor for cholelithiasis and might represent a pathogenetic link between the metabolic syndrome and cholelithiasis.

Higher vitamin D serum concentration increases health related quality of life in patients with inflammatory bowel diseases.

AIM To investigate the effect of vitamin D (VD) concentrations and VD supplementation on health related quality of life in inflammatory bowel disease (IBD) patients. METHODS A cohort of 220 IBD patients including 141 Crohns disease (CD) and 79 ulcerative colitis (UC) patients was followed-up at a tertiary IBD center. A subgroup of the cohort (n = 26) took VD supplements for > 3 mo. Health related quality of life was assessed using the short IBD questionnaire (sIBDQ). VD serum concentration and sIBDQ score were assessed between August and October 2012 (summer/autumn period) and between February and April 2013 (winter/spring period). The mean VD serum concentration and its correlation with disease activity of CD were determined for each season separately. In a subgroup of patients, the effects of VD supplementation on winter VD serum concentration, change in VD serum concentration from summer to winter, and winter sIBDQ score were analyzed. RESULTS During the summer/autumn and the winter/spring period, 28% and 42% of IBD patients were VD-deficient (< 20 ng/mL), respectively. In the winter/spring period, there was a significant correlation between sIBDQ score and VD serum concentration in UC patients (r = 0.35, P = 0.02), with a trend towards significance in CD patients (r = 0.17, P = 0.06). In the winter/spring period, VD-insufficient patients (< 30 ng/mL) had a significantly lower mean sIBDQ score than VD-sufficient patients; this was true of both UC (48.3 ± 2.3 vs 56.7 ± 3.4, P = 0.04) and CD (55.7 ± 1.25 vs 60.8 ± 2.14, P = 0.04) patients. In all analyzed scenarios (UC/CD, the summer/autumn period and the winter/spring period), health related quality of life was the highest in patients with VD serum concentrations of 50-59 ng/mL. Supplementation with a median of 800 IU/d VD day did not influence VD serum concentration or the sIBDQ score. CONCLUSION VD serum concentration correlated with health related quality of life in UC and CD patients during the winter/spring period.

The prevalence and risk factors for osteoporosis in patients with inflammatory bowel disease.

AIM Osteoporosis is a known chronic complication of inflammatory bowel diseases (IBD). The aim of our study was to describe the prevalence of reduced bone mineral density (BMD) in IBD patients and to identify crucial risk factors for osteoporosis. METHODS The cohort consisted of 76 IBD patients, 40 with Crohns disease (CD) and 36 with ulcerative colitis (UC). Clinical characteristics of every patient were recorded, i.e. age, sex, duration of the disease, clinical behavior, location of disease according to Montreal classification, surgeries, steroid medication, sIBDQ, and smoking habits. We examined the serum 25-hydroxyl vitamin D3 (25-OHD3) in each patient. The BMD was determined by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and femoral neck. RESULTS Osteoporosis was documented in 10 IBD patients (13.2 %), while osteopenia in 35 of them (46.1 %). Patients with CD have significantly lower femoral Z score than patients with UC. Femoral Z score was strongly associated with disease duration, and in CD patients suffering from stricturing form, with ileic or ileocolic location and history of proctocolectomy or total colectomy. Patients with osteoporosis had a significantly lower level of 25-OHD3 than patients with normal BMD. CONCLUSION Patients with long disease duration and those suffering from stricturing form of CD with ileic/ileocolic location and history of proctocolectomy/total colectomy are at higher risk of developing osteoporosis than other IBD patients. The high proportion of osteopenia/osteoporosis in our study underlines the importance of BMD measurement in all IBD patients as a base for initiating the appropriate treatment (Tab. 1, Fig. 3, Ref. 63).

Whipple's disease-generalized stage.

Whipple’s disease is a chronic inflammatory systemic disorder in which all organs can be invaded by the rod-shaped bacterium Tropheryma whipplei. It is a rare disease and frequently misdiagnosed, though there is no valid estimate of its actual incidence and prevalence. Only about 1,000–1,500 cases have been reported. The clinical course of untreated Whipple’s disease can include three stages: (1) a non-specific prodromal stage which includes migratory polyarthralgias; (2) a classic abdominal manifestation which involves weight loss, weakness, chronic diarrhea, and abdominal pain; and (3) a generalized stage characterized by steatorhea, cachexia, lymphadenopathy, hyper-pigmentation, and cardiovascular, pulmonary, and neurological dysfunction. The authors describe a case of a 39-year-old male patient with about a year’s history of generalized adenopathy, inappetence, weight loss, progressive weakness, subfebrilities, and convulsive abdominal pain. Following primary exclusion of a tumor disease, a lymph node biopsy demonstrated a typical picture of a granulomatous inflammation—Whipple’s lymphadenitis with partial exemption of the Gram reaction, and stain features corresponding to T. whipplei, which is regarded as the etiological agent causing this disorder. Further tests confirmed the generalized form of the disorder, affecting the lymphatic tissues, gastrointestinal system, respiratory system, and nervous system, with sensory and motor polyneuropathy. HLA-B27 antigen, which is frequent among those with Whipple’s disease, was also present. Following treatment for three months with antibiotics a significant reduction of the changes typical of Whipple’s disease was found upon follow-up biopsy, hence we assume the applied therapy was successful. In our case study we emphasize the atypical course of the disease with dominant generalized lymphadenopathy and only mild gastrointestinal symptoms.

Combination therapy with an immunomodulator and anti-TNFα agent improves bone mineral density in IBD patients

OBJECTIVE There is a high prevalence of low bone mineral density (BMD) among patients with inflammatory bowel disease (IBD) although there is a lack of clinical data on the impact of IBD specific medications and recommended vitamin D (VD) and calcium (Ca) supplements on it. DESIGN The cohort consisted of 150 IBD patients. The average change in BMD at the lumbar spine per year (∆BMDL/year) was calculated and the impact of clinical characteristics, medications and VD and Ca supplements was analysed. RESULTS The prevalence of osteopenia was 69/150 (46%) and osteoporosis was identified in 15/150 (10%) patients at baseline. The presence of osteoporosis was associated with the disease duration OR=1.07 per year of disease duration (95% CI=1.01-1.14), p=0.03. The average ∆BMDL/year was 0.010 g/cm(2)/year. Among patients with no IS the ∆BMDL/year was -0.001±0.010 g/cm(2)/year, with AZA -0.001±0.013 g/cm(2)/year, with anti-TNFα 0.003±0.006 g/cm(2)/year and with COMBO 0.027±0.004 g/cm(2)/year; p<0.05 COMBO vs any other subgroup. ∆BMDL/year among patients treated with CS was -0.031±0.012 g/cm(2)/year versus CS free patients 0.013±0.004 g/cm(2)/year; p<0.001. There was no effect of VD/Ca supplementation on BMDL. CONCLUSIONS The prevalence of low BMD was 55%. Duration of disease was the only independent predictor of low BMD. The BMDL was reduced by high cumulative dose of CS and improved by combined anti-TNFα/AZA therapy. The supplementation with recommended doses of VD and Ca had no effect on BMDL.

Thyroid-stimulating hormone concentration as an independent risk factor of venous thromboembolism regardless of thyroid function.

INTRODUCTION Thyroid dysfunction has been recognised as playing a role in the coagulation cascade, but the clinical implications of this phenomenon are unclear. The aim of our study was to assess the predictive power of TSH measurement on the presence or absence of venous thromboembolism (VTE). MATERIAL AND METHODS From January 2009 to August 2012, all consecutive patients hospitalised for suspected VTE were included in the study. VTE was confirmed either by pulmonary angiography or compressive ultrasound. We investigated the predictive power of TSH concentration on the risk of VTE in univariate and multivariate analysis including the existing risk factors (age, D-dimer). RESULTS A total of 232 patients were eligible for final analysis, with a median age of 70 years (IQR 58-80) and male-to-female ratio of 124:108. VTE was confirmed in 124 patients (53.4%). TSH concentration was significantly higher in cases with VTE (median 2.17 vs. 1.76 mIU/L, p = 0.0104), but free T4 concentrations were not found to be significantly different. Receiver operating curve analysis identified the cut-off of TSH > 2.686 mIU/L as a predictor of VTE with the prevalence of VTE 47.1 vs. 66.7% below and above this cut-off, p = 0.011. Multivariate logistic regression identified five independent predictors of VTE: male gender (odds ratio, OR = 2.22), D-dimer > 0.5 mg/L OR = 16.42), CRP > 5 g/L (OR = 9.178), TSH > 2.686 mIU/L (OR = 2.269), and age (OR = 0.9767/year). CONCLUSIONS Among patients with suspected venous thromboembolism TSH concentration was found to be an independent predictor of VTE in addition to gender, D-dimer, C-reactive protein (CRP), and age.

The impact of thiopurine-S-methyltransferase genotype on the adverse drug reactions to azathioprine in patients with inflammatory bowel diseases.

BACKGROUND AND AIMS The thiopurine drugs, azathioprine (AZA) and 6-mercaptopurine, are established in the treatment of inflammatory bowel diseases (IBD). Polymorphisms in thiopurine S-methyltransferase (TPMT) gene have been associated with adverse drug reactions (ADRs) to AZA. METHODS The aim of this study was to evaluate TPMT polymorphisms and AZA-related toxicity in a Slovak cohort of 220 IBD patients treated with AZA. In every patient, the dose and duration of AZA therapy, concomitant 5-aminosalicylate (5-ASA) medication, frequency, type, time to onset, dose of ADR and concomitant 5-ASA at the onset of ADR were recorded. Each patient was also genotyped for the presence of variant TPMT alleles (*2,*3A,*3B,*3C). Frequency, type and circumstances of ADRs were compared according to TPMT status. RESULTS Of the 220 patients, 205 (93.2 %) were wild-type (TPMT*1/*1), one (0.5%) carried a TPMT*1/*3C allele, 13 (5.9 %) carried TPMT *1/*3A allele and one was homozygous for TMPT *3A allele. No TPMT *2 mutation was found. The incidence of adverse drug reactions was 62/205 (30.2 %) in the wild-type group as compared to 13/15 (86.7 %) in the TPMT mutation group, p=2.10-5. Leukopenia (WBC< 3.0*10^9/L) occurred in 21/205 (10.2 %) patients with wild type TPMT versus 11/15 (73.3 %) patients with TPMT mutations, p=0.000001. There was no significant difference between TMPT groups in gastrointestinal or other ADRs. No impact of 5-ASA on the incidence and severity of AZA adverse drug reactions was observed. CONCLUSION The incidence of leukopenia in TPMT mutant patients was significantly higher and more severe as compared to TPMT wild type patients. We observed no impact of concomitant 5-ASA therapy on AZA induced toxicity (Tab. 4, Fig. 2, Ref. 37).

Vitamin D deficiency - a possible link between osteoporosis and metabolic syndrome.

OBJECTIVES The aim of our study was to evaluate the relationship between bone mineral density (examined by DXA - dual energy x-ray absorptiometry), vitamin D3 levels and the signs of metabolic syndrome. METHODS We examined 55 subjects (37 women, 18 men, age median 67.8 years) with no history of osteoporosis, suffering from metabolic syndrome (defined as abdominal obesity and more than 2 of other components - arterial hypertension, dyslipidemia and diabetes mellitus or impaired glucose tolerance, according to IDF, 2006). RESULTS Osteoporosis (T-score less than - 2.5) was found in 32.7 % (15 women and 3 men) and osteopenia (T-score between - 1.5 and - 2.5) in 29 % (13 women and 3 men) of patients. We observed a negative correlation between BMI and fat percentage (examined by DXA) and vitamin D3 levels. Low concentration of vitamin D3 was found in 90 % of patients with median 19.36 ug/l (64 % measured in winter, 36 % in summer, no relationship between vitamin D3 levels and season). We also observed a negative correlation between the low concentration of vitamin D3 and presence of diabetes mellitus as a part of metabolic syndrome. CONCLUSION The link between osteoporosis and metabolic syndrome could influence the therapeutic approach in both disorders and vitamin D supplementation may play an important role in prevention of these severe conditions (Tab. 5, Fig. 1, Ref. 29).

Noninvasive scoring algorithm to identify significant liver fibrosis among treatment-naive chronic hepatitis C patients.

Aims Staging for liver fibrosis is recommended in the management of hepatitis C as an argument for treatment priority. Our aim was to construct a noninvasive algorithm to predict the significant liver fibrosis (SLF) using common biochemical markers and compare it with some existing models. Methods The study group included 104 consecutive cases; SLF was defined as Ishak fibrosis stage greater than 2. The patient population was assigned randomly to the training and the validation groups of 52 cases each. The training group was used to construct the algorithm from parameters with the best predictive value. Each parameter was assigned a score that was added to the noninvasive fibrosis score (NFS). The accuracy of NFS in predicting SLF was tested in the validation group and compared with APRI, FIB4, and Forns models. Results Our algorithm used age, alkaline phosphatase, ferritin, APRI, &agr;2 macroglobulin, and insulin and the NFS ranged from −4 to 5. The probability of SLF was 2.6 versus 77.1% in NFS<0 and NFS>0, leaving NFS=0 in a gray zone (29.8% of cases). The area under the receiver operating curve was 0.895 and 0.886, with a specificity, sensitivity, and diagnostic accuracy of 85.1, 92.3, and 87.5% versus 77.8, 100, and 87.9% for the training and the validation group. In comparison, the area under the receiver operating curve for APRI=0.810, FIB4=0.781, and Forns=0.703 with a diagnostic accuracy of 83.9, 72.3, and 62% and gray zone cases in 46.15, 37.5, and 44.2%. Conclusion We devised an algorithm to calculate the NFS to predict SLF with good accuracy, fewer cases in the gray zone, and a straightforward clinical interpretation. NFS could be used for the initial evaluation of the treatment priority.