Pharmacodynamic mechanisms behind a refractory state in inflammatory bowel disease.

BACKGROUND AND AIMS: Biological therapy for inflammatory bowel disease is efficient in many cases but not all. The underlying molecular mechanisms behind non-response to biological therapy in inflammatory bowel disease are poorly described. Therefore, we aimed to characterize the mucosal cytokine transcript profile in non-immunogenic, non-responder patients with adequate trough level. MATERIAL AND METHODS: Patients with ulcerative colitis (UC) (n = 21) and Crohn's disease (CD) (n = 12) with non-response to biological therapy (anti-tumor necrosis factor (TNF) or vedolizumab) were included. Reference groups were A: untreated patients with UC or CD at debut of disease who had severe 1-year outcome, B: patients with UC or CD treated to endoscopic remission with biological agents, and C: healthy normal controls. Mucosal transcripts of TNF, interleukin (IL)17 and IL23 were measured by reverse transcription real-time quantitative polymerase chain reaction. Results Of the non-responders, 2 out of 12 CD and 1 out of 21 UC patients needed surgery during follow-up. Of the remaining non-responding patients, 8 out of 10 CD and 12 out of 20 UC patients switched biologic treatment. The remaining 2 CD and 8 UC patients continued treatment with the same biological agent with the addition of steroids, immunomodulators (AZA/MTX) and /or local steroids/5ASA. Twelve (8 UC/4 CD) out of 20 IBD patients were still non-responders after changing biological therapy to either anti-TNF (2), vedolizumab (9) or ustekinumab (1). The transcripts of IL17, IL23 and TNF were significantly upregulated in the non-response group compared to normal controls and patients in remission. In UC, 24% of the non-responders had normal mucosal TNF transcript indicating a non-TNF mediated inflammation. No obvious differences in gene expression were observed between primary and secondary non-responders, nor between anti-TNF and vedolizumab non-responders. CONCLUSIONS: Mucosal transcripts of IL17 and IL23 are highly associated with non-response to biological therapy, whereas some UC patients may also have a non-TNF mediated inflammatory pathway.

Discovery and validation of mucosal TNF expression combined with histological score - a biomarker for personalized treatment in ulcerative colitis.

BACKGROUND: There are no accurate markers that can predict clinical outcome in ulcerative colitis at time of diagnosis. The aim of this study was to explore a comprehensive data set to identify and validate predictors of clinical outcome in the first year following diagnosis. METHODS: Treatment naive-patients with ulcerative colitis were included at time of initial diagnosis from 2004 to 2014, followed by a validation study from 2014 to 2018. Patients were treated according to clinical guidelines following a standard step-up regime. Patients were categorized according to the treatment level necessary to achieve clinical remission: mild, moderate and severe. The biopsies were assessed by Robarts histopathology index (RHI) and TNF gene transcripts. RESULTS: We included 66 patients in the calibration cohort and 89 patients in the validation. Mucosal TNF transcripts showed high test reliability for predicting severe outcome in UC. When combined with histological activity (RHI) scores the test improved its diagnostic reliability. Based on the cut-off values of mucosal TNF and RHI scores from the calibration cohort, the combined test had still high reliability in the validation cohort (specificity 0.99, sensitivity 0.44, PPV 0.89, NPV 0.87) and a diagnostic odds-ratio (DOR) of 54. CONCLUSIONS: The combined test using TNF transcript and histological score at debut of UC can predict severe outcome and the need for anti-TNF therapy with a high level of precision. These validated data may be of great clinical utility and contribute to a personalized medical approach with the possibility of top-down treatment for selected patients.

Diurnal secretion of ghrelin, growth hormone, insulin binding proteins, and prolactin in normal weight and overweight subjects with and without the night eating syndrome.

The regulatory peptide ghrelin has been proposed to help mediate both hunger and sleep. The neuroendocrine circadian patterns in the night eating syndrome (NES) have been distinguished by an attenuated nocturnal rise in the plasma concentrations of melatonin and leptin and a greater increase in the concentrations of cortisol. In this study we wanted to test the hypothesis that night eaters have disturbances in the circadian levels of ghrelin, growth hormone (GH) and associated regulatory peptides. In 12 female night eaters (6 normal weight and 6 overweight), and 25 healthy controls (12 normal weight and 13 overweight), blood was sampled over a 24-hour period. Four meals were served from 8 AM to 8 PM, and blood samples were drawn every second hour for determination of plasma ghrelin concentrations and GH by radioimmunoassay (RIA). Analysis of serum GH, IGF-1, IGFBP-3 and prolactin were performed by ELISA. In healthy normal weight subjects there was a slight but non significant nocturnal increase of ghrelin, whereas a more or less flat curve was observed for healthy overweight, NES normal weight and NES overweight patients. The RMANOVA analysis showed a significant independent lowering effect of overweight on the grand mean of ghrelin. No direct effects on NES normal weight and overweight subjects were found, but a near-significant interaction was found between healthy overweight and overweight NES subjects. There were independent significant lowering effects of overweight and NES on the serum GH levels. During the time course no changes in the serum levels of IGF-1 or IGFB-3 were observed. Independent significant lowering effects of overweight and NES on the levels of IGF-1 were detected, whereas a near significant reduction in the global levels of IGFBP-3 was observed in both NES groups. Finally, significant nocturnal changes were observed for serum levels of prolactin in all four subgroups. Grand mean levels tended to be higher in NES subjects whereas the opposite was observed in healthy overweight (ns). We conclude that in both NES groups and in healthy overweight subjects more or less attenuated ghrelin and GH secretions were observed, whereas divergent secretions were observed for prolactin.

Hepatic steatosis, detected by hepatorenal index in ultrasonography, as a predictor of insulin resistance in obese subjects.

BACKGROUND: The metabolic syndrome is a worldwide health issue, with non-alcoholic fatty liver disease (liver steatosis) being one of its features, particularly closely related to insulin resistance. This study aims to investigate whether quantification of hepatic steatosis by abdominal ultrasonography, using hepatorenal index, is a feasible tool for the prediction of insulin resistance, and thus the metabolic syndrome. METHODS: Patients were recruited from the Centre of Obesity at the University Hospital of North Norway, and among participants from the Sixth Tromsø Study. Homeostasis Model Assessment of Insulin Resistance (HOMA1-IR) was measured, body mass index (BMI, kg/m(2)) calculated, and hepatorenal index (HRI), i.e. the ratio of liver to kidney optical densities, was measured by transabdominal ultrasonography. Receiver operating characteristic (ROC) analyses were performed, detecting insulin resistance at HOMA1-IR cut-off values >2.3 and >2.5. RESULTS: Ninety participants were included in the study, of which 46 (51 %) had BMI ≥30 and 27 (30 %) had BMI ≥35. Overall, HRI at level 1.17 had sensitivity 0.90 and specificity 0.70 for predicting insulin resistance (HOMA1-IR >2.3) in all participants. For participants with BMI ≥30, HRI at level 1.17 had sensitivity 0.94 and specificity 0.70, and for BMI ≥35, HRI at level 1.17 had sensitivity 0.93 and specificity 0.75 for predicting HOMA1-IR >2.3. Setting the HRI limit at 1.42 gave low sensitivities and high specificities in all BMI groups. In the analysis predicting HOMA1-IR >2.5, sensitivity values were almost the same as in the analysis predicting HOMA1-IR >2.3, but specificity values were lower in this analysis. CONCLUSION: Detection and quantification of hepatic steatosis by ultrasound and the hepatorenal index is a feasible screening tool for identifying patients with low risk of having insulin resistance (IR, HRI <1.17), patients at risk of having IR (HRI 1.17-1.41) and patients with likely IR (HRI ≥1.42), especially in obese individuals.

Dietary supplementation with bean extract improves lipid profile in overweight and obese subjects.

The aim of this study was to evaluate the long-term effects of a dietary supplementation of bean extract on serum lipids, nutritional parameters, and fat excretion in feces.Sixty-two overweight and obese (body mass index > 25 kg/m(2)) volunteers were randomized to receive the dietary supplement (n = 31, supplement group) or the placebo (n = 31, placebo group). There were 41 women and 21 men, ages 22 to 66 years. Two capsules of a dietary supplement or a placebo were administered three times daily for 3 mo. The supplement group was then invited to participate in an open-label study for 9 mo. Twenty-four subjects (7 men and 17 women) were randomized to receive two or four capsules of the supplement three times daily. Lipids and nutritional blood parameters were measured at baseline, after 3 mo, and at 12 mo. Excretion of fat in feces was measured. At 3 mo, reduction in serum concentration of cholesterol was found in the supplement group but not in the placebo group. High-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triacylglycerols in serum did not change in either group. In the 9-mo open-label study, no further reduction in serum cholesterol was observed. Low-density lipoprotein and the ratio of low- to high-density lipoprotein decreased, whereas triacylglycerols remained unchanged. Serum vitamin B12 and folic acid decreased but remained within the normal range. Ferritin and albumin in serum remained unchanged. No differences were observed in serum lipids and nutritional parameters between groups. The bean extract significantly increased fat excretion in feces. In conclusion, this dietary supplementation improved lipoprotein profile and enhanced fat excretion in feces in overweight and obese subjects.

Bulimia nervosa--a primary defect in the hypothalamic-pituitary-adrenal axis?

Bulimia nervosa has been associated with impaired satiety, decreased resting metabolic rate and abnormal neuroendocrine regulation. The aim of this study was to investigate the diurnal cortisol secretion and the pituitary-adrenal response to corticotropin-releasing hormone (CRH) in subjects suffering from bulimia nervosa. Eight female subjects with remitted bulimia nervosa, ages 24-56, and 8 sex- and weight-matched controls volunteered to participate. After an overnight fast they were admitted to the Clinical Research Center for 24 hour recording of plasma cortisol secretion. Blood were drawn every 2nd hour from 8 AM. After another overnight fast, the subjects performed a 120-min CRH test (100 microg i.v.), drawn for measurements of adrenocorticotropin releasing hormone (ACTH) and cortisol. Compared to the control group (CG), the diurnal cortisol secretions in the bulimic group (BG) decreased at time points 6 AM to 2 PM. In the CRH test, the ACTH response was significantly stronger in the BG than in the CG. Similar observations were found for cortisol, although not at significant levels. Remitted bulimic patients exhibit a neuroendocrine pattern of decreased HPA axis activity with a hyperreactivity to CRH. This may indicate a complex and so far poorly understood neuroendocrine dysregulation of HPA axis associated with the disease.

Hypothalamic-pituitary-adrenal axis in the night eating syndrome.

The typical neuroendocrine characteristics of the night eating syndrome have previously been described as changes in the circadian rhythm by an attenuation in the nocturnal rise of the plasma concentrations of melatonin and leptin and an increased circadian secretion of cortisol. The aim of this study was to test the hypothesis that night eaters have an overexpressed hypothalamic-pituitary-adrenal axis with an attenuated response to stress. Five female subjects with the night-eating syndrome and five sex-, age-, and weight-matched controls performed a 120-min corticotropin-releasing hormone (CRH) test (100 microg iv). Blood samples were drawn intravenously for measurements of the plasma concentrations of ACTH and cortisol. The results showed that, in night eaters compared with controls, the CRH-induced ACTH and cortisol response was significantly decreased to 47 and 71%, respectively. In conclusion, disturbances in the hypothalamic-pituitary-adrenal axis with an attenuated ACTH and cortisol response to CRH were found in subjects with night-eating syndrome.