Evidence for a Cystic Fibrosis Enteropathy.

BACKGROUND: Previous studies have suggested the existence of enteropathy in cystic fibrosis (CF), which may contribute to intestinal function impairment, a poor nutritional status and decline in lung function. This study evaluated enterocyte damage and intestinal inflammation in CF and studied its associations with nutritional status, CF-related morbidities such as impaired lung function and diabetes, and medication use. METHODS: Sixty-eight CF patients and 107 controls were studied. Levels of serum intestinal-fatty acid binding protein (I-FABP), a specific marker for enterocyte damage, were retrospectively determined. The faecal intestinal inflammation marker calprotectin was prospectively studied. Nutritional status, lung function (FEV1), exocrine pancreatic insufficiency (EPI), CF-related diabetes (CFRD) and use of proton pump inhibitors (PPI) were obtained from the medical charts. RESULTS: Serum I-FABP levels were elevated in CF patients as compared with controls (p<0.001), and correlated negatively with FEV1 predicted value in children (r-.734, p<0.05). Faecal calprotectin level was elevated in 93% of CF patients, and correlated negatively with FEV1 predicted value in adults (r-.484, p<0.05). No correlation was found between calprotectin levels in faeces and sputum. Faecal calprotectin level was significantly associated with the presence of CFRD, EPI, and PPI use. CONCLUSION: This study demonstrated enterocyte damage and intestinal inflammation in CF patients, and provides evidence for an inverse correlation between enteropathy and lung function. The presented associations of enteropathy with important CF-related morbidities further emphasize the clinical relevance.

Blood biomarkers are helpful in the prediction of response to chemoradiation in rectal cancer: a prospective, hypothesis driven study on patients with locally advanced rectal cancer.

PURPOSE/OBJECTIVE: Chemoradiation (CRT) has been shown to lead to downsizing of an important portion of rectal cancers. In order to tailor treatment at an earlier stage during treatment, predictive models are being developed. Adding blood biomarkers may be attractive for prediction, as they can be collected very easily and determined with excellent reproducibility in clinical practice. The hypothesis of this study was that blood biomarkers related to tumor load, hypoxia and inflammation can help to predict response to CRT in rectal cancer. MATERIAL/METHODS: 295 patients with locally advanced rectal cancer who were planned to undergo CRT were prospectively entered into a biobank protocol (NCT01067872). Blood samples were drawn before start of CRT. Nine biomarkers were selected, based on a previously defined hypothesis, and measured in a standardized way by a certified lab: CEA, CA19-9, LDH, CRP, IL-6, IL-8, CA IX, osteopontin and 25-OH-vitamin D. Outcome was analyzed in two ways: pCR vs. non-pCR and responders (defined as ypT0-2N0) vs. non-responders (all other ypTN stages). RESULTS: 276 patients could be analyzed. 20.7% developed a pCR and 47.1% were classified as responders. In univariate analysis CEA (p=0.001) and osteopontin (p=0.012) were significant predictors for pCR. Taking response as outcome CEA (p<0.001), IL-8 (p<0.001) and osteopontin (p=0.004) were significant predictors. In multivariate analysis CEA was the strongest predictor for pCR (OR 0.92, p=0.019) and CEA and IL-8 predicted for response (OR 0.97, p=0.029 and OR 0.94, p=0.036). The model based on biomarkers only had an AUC of 0.65 for pCR and 0.68 for response; the strongest model included clinical data, PET-data and biomarkers and had an AUC of 0.81 for pCR and 0.78 for response. CONCLUSION: CEA and IL-8 were identified as predictive biomarkers for tumor response and PCR after CRT in rectal cancer. Incorporation of these blood biomarkers leads to an additional accuracy of earlier developed prediction models using clinical variables and PET-information. The new model could help to an early adaptation of treatment in rectal cancer patients.

Basal glucose metabolism and peripheral insulin sensitivity in equine pituitary pars intermedia dysfunction.

BACKGROUND: Glucocorticoids are suggested to precipitate laminitis and induce insulin resistance in horses. HYPOTHESIS/OBJECTIVES: To assess insulin sensitivity and the basal amount of glucose metabolized in equine pituitary pars intermedia dysfunction (PPID). ANIMALS AND METHODS: The euglycaemic hyperinsulinaemic clamp (EHC) technique was performed in seven horses with a diagnosis of PPID based on the presence of hypertrichosis and positive dexamethasone suppression-test results comprising one gelding and six mares with a mean age of 21.1 ± 5.8 (SD; range 15-34) years. Results were compared with those from five negative (healthy) controls comprising two geldings and two mares with a mean age of 10.0 ± 2.5 (range 7-13) years and six positive (diseased) controls comprising two geldings and four mares with a mean age of 12.5 ± 4.5 (range 8-21) years examined during the same period. Differences were assessed by means of the Mann-Whitney U test. RESULTS: Mean basal rate of glucose metabolism (9.0 ± 4.2 versus 16.0 ± 5.2 µmol/kg BW/min; p = 0.030) and mean glucose metabolism rate-to-plasma insulin concentration ratio (2.9 ± 1.6 versus 6.2 ± 2.7 × 10(-6); p = 0.048) were significantly lower in PPID horses than in negative controls, respectively. No differences were found between both control groups. CONCLUSIONS AND CLINICAL IMPORTANCE: In horses suffering from PPID it seems important to reduce the insulin resistance, thereby potentially decreasing the risk of laminitis as being a major complication of equine PPID. Plasma glucose concentration following fasting might be considered in the screening of horses for PPID.

High prevalence of morphometric vertebral deformities in patients with inflammatory bowel disease.

BACKGROUND: Earlier studies have documented that the prevalence of decreased bone mineral density (BMD) is elevated in patients with inflammatory bowel disease. The objective of this study was to investigate the prevalence of vertebral deformities in inflammatory bowel disease patients and their relation with BMD and bone turnover. METHODS: One hundred and nine patients with Crohn's disease (CD) and 72 with ulcerative colitis (UC) (age 44.5+/-14.2 years) were studied. BMD of the hip (by dual X-ray absorptiometry) was measured and a lateral single energy densitometry of the spine for assessment of vertebral deformities was performed. Serum markers of bone resorption (carboxy-terminal cross-linked telopeptide of type I collagen) and formation (procollagen type I amino-terminal propeptide) were measured, and determinants of prevalent vertebral deformities were assessed using logistic regression analysis. RESULTS: Vertebral deformities were found in 25% of both CD and UC patients. Comparing patients with and without vertebral deformities, no significant difference was found between Z-scores and T-scores of BMD, or levels of serum carboxy-terminal cross-linked telopeptide of type I collagen and serum procollagen type I amino-terminal propeptide. Using logistic regression analysis the only determinant of any morphometric vertebral deformity was sex. The presence of multiple vertebral deformities was associated with older age and glucocorticoid use. CONCLUSION: The prevalence of morphometric vertebral deformities is high in CD and UC. Male sex, but neither disease activity, bone turnover markers, clinical risk factors, nor BMD predicted their presence. The determinants for having more than one vertebral deformity were age and glucocorticoid use. This implies that in addition to screening for low BMD, morphometric assessment of vertebral deformities is warranted in CD and UC.

Bone turnover and hip bone mineral density in patients with sarcoidosis.

BACKGROUND AND AIM OF THE WORK: Sarcoidosis is a chronic inflammatory T-cell-driven disease that can also affect bone. We evaluated bone remodelling and bone mineral density (BMD) in patients with sarcoidosis and their dependency of disease-related and treatment-related factors. METHODS: In 124 patients BMD of the hip (DXA) and markers of bone resorption (ICTP) and formation (PINP) were evaluated. Furthermore a lateral DXA of the spine for morphometric assessment of vertebral deformities was performed in 87 patients. Potential predictors of bone markers, BMD and determinants of prevalent vertebral deformities were assessed using multiple and logistic regression analysis. RESULTS: The population studied comprised untreated patients (n=51), patients that previously used glucocorticoids (n=31) and patients currently using glucocorticoids (n=42). In all these groups the age- and gender corrected Z-scores of the hip were normal, except in untreated patients, which revealed an increased Z-score at the trochanter (p = 0.004). In all but the patients currently on glucocorticoids the Z-scores for PINP and ICTP were increased (p < 0.05). In patients currently on glucocorticoids the Z-ICTP was also increased (p < 0.05), but the Z-PINP decreased (p < 0.01 compared to untreated patients). In 20.6% of patients one or more morphometric vertebral deformities were found. CONCLUSIONS: Hip BMD is normal in patients with sarcoidosis, despite an increased bone turnover. This may imply that in sarcoidosis mechanisms are involved that compensate for the well-known effects of cytokines in inflammatory diseases on osteoclastogenesis and bone resorption. Nonetheless, vertebral deformities suggestive of fracture were found in a significant number of patients which indicates that patients with sarcoidosis still have a relevant fracture risk.

Hip bone mineral density, bone turnover and risk of fracture in patients on long-term suppressive L-thyroxine therapy for differentiated thyroid carcinoma.

OBJECTIVE: Untreated hyperthyroidism and treatment with high doses of thyroid hormone are associated with osteoporosis. However, their effect on bone turnover, their contribution to bone mineral density (BMD) in the context of other clinical risk factors for osteoporosis and the prevalence of vertebral fractures is not well documented. DESIGN: Cross-sectional study. METHODS: We studied 59 patients receiving L-thyroxine suppressive therapy for differentiated thyroid carcinoma (DTC). BMD of the hip was measured by dual X-ray absorptiometry (DXA) and lateral DXA pictures of the lumbar and thoracic vertebrae were performed. Bone resorption was measured by C-telopeptides of type I collagen (ICTP) and bone formation by procollagen type I N-propeptide (PINP). Clinical risk factors for osteoporosis were evaluated using a questionnaire. RESULTS: Z-scores of BMD were similar as the NHANES (National Health and Nutrition Examination Survey) III reference group in women and men, also after long-term (> 10 years) suppression therapy. Patients in the lowest and highest quartile of BMD showed significant differences in the presence of clinical risk factors. ICTP levels were significantly higher than in age-matched controls, PINP levels were not different. We found four patients with a prevalent vertebral fracture. CONCLUSIONS: We conclude that patients with well-differentiated thyroid carcinoma are not at increased risk of developing low bone mass nor have a higher prevalence of vertebral fracture at least when treated with relatively low doses of L-thyroxine.