Integrating the Patient Perspective to Validate a Measure of Disease Severity in Inflammatory Bowel Disease: Online Survey of Patients and Their Physicians.

BACKGROUND: The patient perspective is essential for assessing disease severity, but it is not always adequately considered. We describe how a comprehensive clinical disease severity index (DSI) for inflammatory bowel disease (IBD) correlates with patient global self-assessment (PGSA). METHODS: In an individually linked parallel online survey, physicians provided the DSI, and patients provided self-assessed severity using a global question and visual analog scale (0-100) (PGSA). Mean DSI values by PGSA were calculated with 95% confidence intervals. Pearson correlation (r) and the intraclass correlation coefficient were calculated for PGSA vs DSI. Positive predictive values for identifying severe disease with PGSA categories as a reference were based on a threshold >22 points. RESULTS: The primary analysis included 89 pairs (46 Crohn's disease [CD], 43 ulcerative colitis [UC]) with strict criteria and 147 pairs when less stringent. Common reasons for exclusion were missing values for albumin or colonoscopy. Mean DSI values showed no clear trend with increasing PGSA in CD but good discrimination between moderate, severe, and very severe PGSA in UC. For PGSA on the visual analog scale, r was 0.54 for CD and 0.59 for UC (difference in means: CD 27.7, UC 13.8; intraclass correlation coefficient: CD 0.48, UC 0.58). A high DSI predicted severe disease in 76.2% of CD and 65.2% of UC. CONCLUSIONS: The DSI showed good discrimination for patient-reported disease severity in UC but performed unsatisfactorily in CD. Correlations were moderate. Further refinement of the DSI is suggested to better reflect the patient perspective.

The performance of an inflammatory bowel disease severity score was compared with self-perceived severity based on an individually linked online survey of patients and their physicians. Agreement and prediction of severe disease were moderate and should be improved by integrating the patients' perspective.

[Preoperative fluid fasting : Establishment of a liberal fluid regimen using fasting cards]. / Präoperative Flüssigkeitskarenz : Etablierung eines liberalen Flüssigkeitsregimes mittels Nüchternheitskarten.

BACKGROUND: Preoperative fasting times for clear liquids surpass by far the recommendations of the specialist societies. The aim of this study was to introduce a liberal regimen for preoperative fasting of clear liquids using fasting cards as a training tool and to evaluate the implementation. MATERIAL AND METHODS: We developed a liberalized regimen of preoperative clear fluid fasting times, which allows patients to drink water, apple juice, tea and coffee until being called to the operating theatre. Each patient receives a bed-side fasting card with written information specifying fasting times for solid food and liquids. Patients who are allowed to drink water, apple juice, tea and coffee until the call to the operating theatre receive a blue fasting card. Patients with coexisting diseases or conditions that can affect gastric emptying or who need longer fasting times because of the surgical procedure get a yellow fasting card on which fasting times for fluids and solids can be documented individually. Patients who need to be nil per os (for example patients with ileus or bowel obstruction, emergency care) receive a red fasting card. On the back of the card the information is written in English, Turkish, Russian and Arabic. After a period of 8 months all surgical ward managers were asked to complete a questionnaire to assess the implementation of the new fasting regimen. RESULTS: The response rate of the questionnaire was 100%. Without exception all interviewees would recommend the use of our liberalized fasting regimen. Almost all would also support the implementation of fasting cards. Out of 11 wards 9 found that patients were more relaxed and asked for intravenous fluids less often while waiting for surgery. The multilingual nature of the cards makes it easier to deal with patients who do not speak German. All ward managers consistently approved the new regimen in the event they themselves would need an operation. In order to make the fasting cards also usable in the future for rescue centers and functional units, such as endoscopy, echo or cardiac catheters, the reasons for fasting on the blue and yellow cards have been extended to operation or examination and on the red card to illness, operation or upcoming examination. CONCLUSION: Patients should be allowed to drink water and hypotonic clear fluids until shortly before an operation to avoid complications of overly long fasting times. Fasting cards help to implement this by providing easy to understand information for patients and healthcare workers. This concept should be clearly structured, transparent for everyone, written down and brought to the attention of the patient without a language barrier.

Discriminatory potential of C-reactive protein, cytokines, and fecal markers in infectious gastroenteritis in adults.

This study evaluates potential markers in blood and stools for their ability to distinguish bacterial from viral gastroenteritis. A total of 108 patients were prospectively recruited, of which 27 showed bacterial, 30 viral, and 51 no detectable pathogen, respectively. Cytokines, C-reactive protein (CRP), and white blood cells as well as the 2 fecal markers lactoferrin and calprotectin were determined. Statistics comprised Kruskal-Wallis test and U test in addition to an assessment of receiver operating characteristic. Interferon γ (IFNγ) levels were significantly increased in the viral group compared to the bacterial and nonspecific group. For the bacterial group, both fecal markers lactoferrin and calprotectin as well as CRP were significantly higher in comparison to the other 2 groups. To differentiate between bacterial and viral gastroenteritis, CRP, serum IFNγ, and the fecal proteins lactoferrin and calprotectin may be useful. A corresponding algorithm should be evaluated prospectively.

Prospective noninvasive analysis of hepatic fibrosis in patients with Crohn's disease: correlation of transient elastography and laboratory-based markers.

BACKGROUND AND AIMS: Hepatobiliary disorders, associated either with extraintestinal manifestations or with consequences of treatment, are prevalent among patients with inflammatory bowel disease (IBD). This study aimed to prospectively assess the potential of noninvasive markers for the evaluation of liver fibrosis in patients with Crohn's disease. METHODS: A total of 114 patients were recruited. Established markers of fibrosis, namely, aspartate transaminase-to-platelet ratio index (APRI), fibrotest, Forns, sonography, and transient elastography were performed and correlated with disease parameters. In addition to descriptive statistical analysis, Pearson's correlation coefficients were determined. The t-test and the Mann-Whitney U-test were applied and univariate and multivariate data analyses were performed. RESULTS: Ultrasound indicated hepatic steatosis in 33 patients, hepatomegaly in 10, and cirrhosis in two. Liver stiffness as quantified by transient elastography was determined to be 5.06±2.33 kPa (2.6-21.5). Results of noninvasive liver fibrosis markers were as follows: fibrotest,-1.65±0.94; APRI, 0.33±0.22; and Forns, 3.11±2.00. Correlation coefficients were found to be fibrotest/transient elastography: r=0.35291; APRI/transient elastography: r=0.38442; Forns/transient elastography: r=0.33949; fibrotest/APRI: r=0.52937; fibrotest/Forns: r=0.42413; and APRI/Forns: r=0.56491. Correlation of inflammatory markers and noninvasive liver fibrosis tests, respectively, was generally negative, whereas correlation of parameters indicating liver damage and liver fibrosis tests, respectively, was generally positive. CONCLUSION: In a center-based, unselected cohort of patients with Crohn's disease, the positive correlations between laboratory-based markers of fibrosis and transient elastography were highly significant. A study correlating noninvasive and invasive tools for the assessment of liver fibrosis in IBD is reasonable.

Double-contrast micro-CT colonoscopy in live mice.

PURPOSE: Models of colon cancer in small rodents are of particular interest as they most closely simulate the development and growth of colonic cancer in humans. Micro-computed tomography has been used for detection of polyps in murine models of colon cancer. The study was performed to evaluate whether a novel high-speed continuous-rotation, single-breath-hold scanning protocol in combination with double-contrasting of the colon can be successfully applied for colonoscopy of live mice at acquisition times of 40 s. METHODS: C57BL/6JApcMin/+ mice were intubated and ventilated. After double-contrasting the colon with barium and air, mice underwent continuous rotation micro-CT (mean resolution 41 × 41 × 53 µm) during a single-breath-hold period of 40 s. Sensitivity to detect colon polyps by four blinded radiologists was analysed. Number and location of polyps were verified in the excised colon. Radiation dose was measured using a thermoluminescence dosimeter placed within the distal colon. RESULTS: In six of seven mice, a total of 12 polyps were detected in the explanted colon (one mouse without polyps). One tumor (8.3%) was located in the proximal third, seven tumors (58.1%) and four tumors (33.2%) were located in the middle and in the distal third of the colon, respectively. Mean tumor volume was 6.5 ± 3.6 mm(3). Sensitivity to detect colon polyps was 0.85 ± 0.1. Mean radiation dose was 0.241 ± 0.002 Gy. CONCLUSION: Using a high-speed continuous rotation micro-CT protocol, double-contrast single-breath-hold colonoscopy in mice is feasible and yields sufficient contrast to visualize the proximal colonic folds and to detect colonic polyps in vivo.

Comparison of magnetic resonance imaging and video capsule enteroscopy in diagnosing small-bowel pathology: localization-dependent diagnostic yield.

OBJECTIVE: New technology has considerably advanced the diagnosis of small-bowel pathology. However, its significance in clinical algorithms has not yet been fully assessed. The aim of the present analysis was to compare the diagnostic utility and yield of video-capsule enteroscopy (VCE) to that of magnetic resonance imaging (MRI) in patients with suspected or established Crohn's disease (Group I), obscure gastrointestinal blood loss (Group II), or suspected tumors (Group III). MATERIAL AND METHODS: Forty-six out of 182 patients who underwent both modalities were included: 21 in Group I, 20 in Group II, and five in Group III. Pathology was assessed in three predetermined sections of the small bowel (upper, middle, and lower). The McNemar and Wilcoxon tests were used for statistical analysis. RESULTS: In Group I, lesions were found by VCE in nine of the 21 patients and by MRI in six. In five patients, both modalities showed pathology. In Group II, pathological changes were detected in 11 of the 20 patients by VCE and in eight patients by MRI. In five cases, pathology was found with both modalities. In Group III, neither modality showed small-bowel pathology. For the patient groups combined, diagnostic yield was 43% with VCE and 30% with MRI. The diagnostic yield of VCE was superior to that of MRI in the upper small bowel in both Groups I and II. CONCLUSION: VCE is superior to MRI for the detection of lesions related to Crohn's disease or obscure gastrointestinal bleeding in the upper small bowel.

Neohepatocytes from alcoholics and controls express hepatocyte markers and display reduced fibrogenic TGF-ß/Smad3 signaling: advantage for cell transplantation?

BACKGROUND: Liver transplantation is the only definitive treatment for end stage liver disease. Donor organ scarcity raises a growing interest in new therapeutic options. Recently, we have shown that injection of monocyte-derived NeoHepatocytes can increase survival in rats with extended liver resection. In order to apply this technology in humans with chronic liver diseases in an autologous setting, we generated NeoHepatocytes from patients with alcoholic liver disease and healthy controls and compared those to human hepatocytes. METHODS: We generated NeoHepatocytes from alcoholics with Child A and B cirrhosis and healthy controls. Hepatocytes marker expression and transforming growth factor (TGF)-beta signaling was investigated by RT-PCR, Western blot, immunofluorescent staining, and adenoviral reporter assays. Glucose and urea was measured photometrically. Phase I and II enzyme activities were measured using fluorogenic substrates. Neutral lipids were visualized by Oil Red O staining. RESULTS: There was no significant difference in generation and yield of NeoHepatocytes from alcoholics and controls. Hepatocyte markers, e.g., cytokeratin18 and alcohol dehydrogenase 1, increased significantly throughout differentiation. Glucose and urea production did not differ between alcoholics and controls and was comparable to human hepatocytes. During differentiation, phase I and II enzyme activities increased, however remained significantly lower than in human hepatocytes. Fat accumulation was induced by treatment with insulin, TGF-beta and ethanol only in differentiated cells and hepatocytes. TGF-beta signaling, via Smad transcription factors, critically required for progression of chronic liver disease, was comparable among the investigated cell types, merely expression of Smad1 and -3 was reduced (approximately 30 and approximately 60%) in monocytes, programmable cells of monocytic origin, and NeoHepatocytes. Subsequently, expression of TGF-beta regulated pro-fibrogenic genes, e.g., connective tissue growth factor and fibronectin was reduced. CONCLUSIONS: Generation of NeoHepatocytes from alcoholics, displaying several features of human hepatocytes, offers new perspectives for cell therapeutic approaches, as cells can be obtained repeatedly in a noninvasive manner. Furthermore, the autologous setting reduces the need for immunosuppressants, which may support recovery of patients which are declined for liver transplantation.

Significant differences between Crohn's disease and ulcerative colitis regarding the impact of body mass index and initial disease activity on responsiveness to azathioprine: results from a European multicenter study in 1,176 patients.

In a survey comprising 1,176 patients with inflammatory bowel disease (IBD) we recently showed that azathioprine (AZA) beyond 4 years is beneficial in ulcerative colitis (UC) patients and in a subset of Crohn's disease (CD) patients. Here, we show for the first time that azathioprine responsiveness depends on body mass index (BMI). The relationship is reciprocal in UC and CD, with a better outcome in UC patients with a BMI<25 and in CD patients with a BMI>25. These observations are particularly interesting considering the evolving concept of a relationship between fatty metabolism and immune regulation. Additionally, we show that CD patients, but not UC patients, respond better to AZA when it is started in clinical remission. This observation may support data favouring a "hit hard and early" regime in CD. Finally, we were able to demonstrate a decrease in the incidence of CD-related complications requiring surgery through treatment with AZA.

Interleukin 18 promoter variants (-137G>C and -607C>A) in patients with chronic hepatitis C: association with treatment response.

BACKGROUND: Recently, two functional IL18 promoter variants, -607C>A (rs1946518) and -137G>C (rs187238), were associated with viral clearance in patients with hepatitis C. The present study focused on their relevance for treatment response. METHODS: Seven hundred fifty-seven chronically infected European patients and 791 controls were enrolled in the study. IL18 genotyping was performed by allele-specific PCR. Liver histology was available in 67.9%. RESULTS: Genotype and allele frequencies were equally distributed in patients and controls. No significant association with various disease characteristics was observed. However, when comparing patients with sustained virological response (SR) and non-SR, statistically significant associations were found for both variants (p = 0.0416 and p = 0.0274, respectively). In viral genotype 1, the -607A allele was positively associated with treatment response (p = 0.0190; OR 1.537; 95% CI, 1.072-2.205) and the -137G allele with a higher rate of nonresponse (p = 0.0302; OR 1.524; 95% CI, 1.040-2.233). CONCLUSIONS: The association of IL18 variants with treatment response in genotype 1 hepatitis C patients implies a predictive and modifying role of these genetic variants.

Interleukin-18 serum levels in inflammatory bowel diseases: correlation with disease activity and inflammatory markers.

BACKGROUND: An imbalance of cytokines is believed to contribute to the immunopathogenesis of inflammatory bowel diseases (IBD). Serum cytokine levels may correlate with disease activity and acute phase reactivity. AIM: To determine the correlation of systemic interleukin-18 (IL-18) levels with disease activity and other markers of inflammation using a crosssectional pilot study in outpatients with IBD. METHODS: Peripheral venous blood was obtained from 84 patients with Crohn's disease (CD) and from 46 patients with ulcerative colitis (UC). Serum levels of C-reactive protein (CRP), IL-8, IFN-gamma, IL-12p70 and IL-18 were assessed by ELISA. Disease activity was expressed by the Crohn's Disease Activity Index (CDAI) and the Clinical Activity Index (CAI), respectively. Statistical analysis comprised correlation coefficients and linear regression analysis. RESULTS: In CD IL-18 and other cytokine concentrations, CRP levels, leukocyte and platelet counts did not correlate with the CDAI. However, IL-18 as well as IL-8 and platelets positively correlated with CRP levels (p <0.001), while IFN-gamma and IL-12p70 did not. In contrast, in UC only the CAI and CRP levels showed a significant positive correlation. COMCLUSIONS: In CD IL-18 lacks significant correlation with the CDAI, as do serum acute phase protein and other cytokine markers of inflammation. As opposed to UC, IL-18 and IL-8 may, however, serve as indicators of acute phase reactivity in CD and should be explored in a larger study.

Prospective evaluation of small bowel preparation with bisacodyl and sodium phosphate for capsule endoscopy.

AIM: To determine the effect of Prepacol, a combination of sodium phosphate and bisacodyl, on transit and quality of capsule endoscopy (CE). METHODS: Fivety two consecutive patients were included in this prospective study. CE was performed following a 12 h fasting period. Twenty six patients were randomized for additional preparation with Prepacol. The quality of CE was assessed separately for the proximal and the distal small bowel by 3 experienced endoscopists on the basis of a graduation which was initially developed with 20 previous CE. RESULTS: Preparation with Prepacol accelerated small bowel transit time (262 +/- 55 min vs 287 +/- 97 min), but had no effect on the quality of CE. Visibility was significantly reduced in the distal compared to the proximal small bowel. CONCLUSION: The significantly reduced visibility of CE in the distal small bowel allocates the need for a good preparation. Since Prepacol has no beneficial effect on CE the modality of preparation and the ideal time of application remains unclear. Further standardized examinations are necessary to identify sufficient preparation procedures and to determine the impact of the volume of the preparation solution.

Endoscopy and magnetic resonance imaging in patients with Crohn's disease: a retrospective single-centre comparative study.

OBJECTIVE: There is ongoing debate about which imaging modality is best for patients with inflammatory bowel diseases. Magnetic resonance imaging (MRI) has been successfully used to evaluate the jejunum and the ileum. Because virtual colonoscopy by MRI requires bowel cleansing and/or rectal filling, endoscopy is preferred for assessment of the colon. However, hydro-MRI without special bowel preparation may be sufficient as a diagnostic tool if specifically targeted in the course of a known disease. The aim of this study was retrospectively to assess the correlation of endoscopy, histology and MRI findings for the terminal ileum and the colon in a cohort of patients with Crohn's disease. MATERIAL AND METHODS: In all, 60 patients with a confirmed diagnosis of Crohn's disease were included in the study. Here, 412 anatomical segments of the colon were analysed by MRI, 401 by endoscopy and 374 by histology. RESULTS: Presence or absence of inflammation was concordantly diagnosed in 310 segments (77.3%). The highest concordance was found for the terminal ileum and, in patients with previous surgery, the anastomosis. Sensitivity and specificity for MRI versus endoscopy, MRI versus histology and endoscopy versus histology were 64.4%/81.1%, 62.1%/86.2% and 78.2%/80.3%, respectively. CONCLUSIONS: In a retrospective analysis of patients with Crohn's disease, hydro-MRI assessment of inflammation in anatomical segments of the colon reaches acceptable concordance rates with endoscopy and histology without prior preparation of the bowel. The data justify a prospective controlled trial.

Long-term effectiveness of azathioprine in IBD beyond 4 years: a European multicenter study in 1176 patients.

In Crohn's disease the optimal duration of azathioprine treatment is still controversial and for ulcerative colitis only limited data are available to support its efficacy. Charts of 1176 patients with IBD from 16 European centers were analyzed. Flare incidences and steroid dosages were assessed for the time before and during treatment and after discontinuation. Within the first 4 years, azathioprine suppressed flare incidence and steroid consumption in both diseases (P < 0.001). While in CD discontinuation after 3-4 years did not lead to reactivation, this was the case in UC. However, continuation beyond 4 years further improved clinical activity in CD and steroid requirement in both diseases (P < 0.001). Discontinuation of azathioprine may thus be considered after 3-4 years in CD patients in complete remission without steroid requirement. In all other CD patients and for UC patients in general, continuation seems beneficial. These results support a novel differential algorithm for long-term azathioprine therapy in IBD.

Severe TNF receptor-associated periodic syndrome due to 2 TNFRSF1A mutations including a new F60V substitution.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is typically characterized by episodic fever, myalgia, skin rash, conjunctivitis, and abdominal cramps. Recently, mutations in the TNFRSF1A gene on chromosome 12p13 encoding tumor necrosis factor receptor type 1 have been linked to this autoinflammatory syndrome. We report the case of a 29-year-old white woman who experienced periodic inflammatory manifestations with fever up to 40 degrees C, leukocytosis, and elevation of C-reactive protein level (>100 mg/L) in conjunction with acute peritonitis of unknown origin since the age of 19 years. The patient had undergone 2 laparotomies with appendectomy and left hemicolectomy. Familial Mediterranean fever was excluded by sequencing of the MEFV gene. In view of the possibility of TRAPS, sequence analysis of the TNFRSF1A gene was also performed. The patient carried a novel T-->G substitution in exon 3, leading to the replacement of phenylalanine by valine at amino acid position 60 (F60V), as well as the common R92Q low-penetrance mutation, encoded by exon 4. Upon the next flare, the patient started corticosteroid therapy, resulting in complete relief and normalization of elevated C-reactive protein levels. To the best of our knowledge, we report the first case of compound heterozygosity for 2 TNFRSF1A gene mutations, including a novel one that causes a severe form of TRAPS that responds to anti-inflammatory treatment. A history of recurrent sterile peritonitis should prompt genotyping for periodic fever syndromes.

Low-dose exposure of intestinal epithelial cells to formaldehyde results in MAP kinase activation and molecular alteration of the focal adhesion protein paxillin.

We investigated the potential pathophysiological role of non-lethal formaldehyde concentrations on human intestinal epithelial HT-29 cells. Expression levels of actin, tubulin and detectable cytokeratin isoforms 5, 13, 18, 19 and 20 were not affected after 24h of exposure to 1mM formaldehyde. By contrast, cellular organization of cytoskeletal constituents was already changed after 60 min. Within 15 min, formaldehyde induced profound tyrosine phosphorylation of the focal adhesion protein paxillin and of proteins at about 120-130 kDa. Concomitantly, phosphorylation of ERK-1/2 and p38 MAP kinase occurred. Paxillin was not only tyrosine phosphorylated but underwent a sustained molecular weight shift representing serine/threonine phosphorylation that was independent of MAP kinase activity and EGF-R-mediated signalling. Our data show that exposure of intestinal epithelial cells to low-dose formaldehyde is followed by rapid and profound signalling events. The data suggest a modifier role of environmental or endogenous formaldehyde for epithelial cell functions.

-137 (G/C) IL-18 promoter polymorphism in patients with inflammatory bowel disease.

OBJECTIVE: There is strong evidence that genetic factors contribute to the susceptibility for inflammatory bowel diseases (IBD). Recently, IL-18 promoter polymorphisms were characterized as risk factors for inflammatory diseases such as sepsis, asthma and adult-onset Still's disease. The aim of this study was to determine whether the -137 (G/C) IL-18 promoter polymorphism was associated with IBD susceptibility. MATERIAL AND METHODS: For association analysis, 470 patients with Crohn's disease (CD), 235 unrelated patients with ulcerative colitis (UC) and 347 controls were enrolled. Furthermore, 233 UC and 470 CD trios were included for segregation analysis. Genotyping was performed by application of the TaqMan MGB biallelic discrimination system. RESULTS: When comparing genotype frequencies of CD and UC patients versus controls, no significant difference was found (p=0.089 and p=0.078, respectively). However, the Cochran-Armitage trend test revealed a rising probability for CD and UC with increasing number of G alleles (p=0.030 and 0.028, respectively) for the case-control analysis. On the contrary, the family-based transmission disequilibrium test (TDT) did not show an association of the G allele with CD or UC in 470 CD and 233 UC trios (p=0.53 and p=0.79, respectively). CONCLUSION: The -137 (G/C) IL-18 promoter polymorphism is not a susceptibility factor for IBD in a German cohort.