Sigrid Elsenbruch

Noninvasive Markers in the Assessment of Intestinal Inflammation in Inflammatory Bowel Diseases: Performance of Fecal Lactoferrin, Calprotectin, and PMN-Elastase, CRP, and Clinical Indices

OBJECTIVES:The aim of this study was to compare the performance of fecal lactoferrin (Lf), calprotectin (Cal), polymorphonuclear neutrophil elastase (PMN-e), as well as serum C-reactive protein (CRP) in patients with inflammatory bowel diseases (IBD) to address (a) whether these markers can differentiate IBD patients with endoscopically assessed inflammation from IBD patients without inflammation and from irritable bowel syndrome (IBS); (b) whether they correlate with endoscopic severity of inflammation; and (c) whether a combination of fecal markers with the respective disease-specific activity indices may increase the diagnostic accuracy with reference to the endoscopic severity of inflammation.METHODS:Fecal levels of Lf, Cal, and PMN-e and serum CRP were assessed in 139 patients undergoing diagnostic ileocolonoscopy (54 IBS patients, 42 ulcerative colitis [UC], 43 Crohns disease [CD]). Disease activity was determined for CU with the colitis activity index (CAI) and for CD with the Crohns disease activity index (CDAI). The performance of each marker with reference to endoscopic inflammatory activity was assessed by computing correlations, and sensitivity and specificity using published as well as adjusted cutoffs. A comprehensive activity index was computed by combining results from fecal markers, serum CRP, and a clinical activity index.RESULTS:UC or CD patients with active inflammation demonstrated significantly higher levels of Lf, Cal, and PMN-e in feces as well as serum-CRP when compared to patients with inactive inflammation as well as patients with IBS (all P < 0.05). Using adjusted cutoffs enabled a marked improvement of all markers with an overall diagnostic accuracy in IBD of 80.0% for Lf, 80.0% for Cal, 74.1% for PMN-e, 64.0% for CRP, and 79.0% for the respective clinical disease scores. Cal showed the highest diagnostic accuracy in CD (81.4%), whereas Lf was superior to the other markers in UC (83.3%). The comprehensive activity index yielded a further improvement of sensitivity and specificity, with a diagnostic accuracy of 95.3% for UC patients.CONCLUSION:The fecal markers Lf, Cal, and PMN-e are able to differentiate active IBD from inactive IBD as well as from IBS. None of these three stool markers is consistently superior in its ability to reflect endoscopic inflammation, but all three are superior to CRP in their diagnostic accuracy. A combination of the stool markers with the CRP and a disease-specific activity index in a categorical comprehensive activity index can increase the diagnostic accuracy with reference to the endoscopic inflammation in UC.

Affective disturbances modulate the neural processing of visceral pain stimuli in irritable bowel syndrome: an fMRI study

Objective To address the role of anxiety and depression symptoms in altered pain processing in irritable bowel syndrome (IBS). Design In this functional magnetic resonance imaging study, the blood oxygen level-dependent (BOLD) response to rectal distensions delivered at previously determined individual discomfort thresholds was assessed. Patients 15 female patients with irritable bowel syndrome (IBS) and with normal rectal pain thresholds, and 12 healthy women. Measures The correlation of anxiety and depression symptoms, measured with the Hospital Anxiety and Depression Scale (HADS), with subjective pain ratings and the BOLD response during distension-induced brain activation were analysed within IBS. Group differences in pain-induced brain activation with and without controlling for HADS scores were evaluated. Results Patients with IBS experienced significantly more pain and discomfort upon rectal distensions in the scanner, despite unaltered rectal sensory thresholds. Anxiety and depression scores were associated with these subjective stimulus ratings, but not with rectal sensory thresholds. Anxiety symptoms in IBS were significantly associated with pain-induced activation of the anterior midcingulate cortex and pregenual anterior cingulate cortex. Depression scores correlated with activation of the prefrontal cortex (PFC) and cerebellar areas within IBS. Group comparisons with the two-sample t test revealed significant activation in the IBS versus controls contrast in the anterior insular cortex and PFC. Inclusion of anxiety and depression scores, respectively, as confounding variables led to a loss of significant group differences. Conclusions Altered central processing of visceral stimuli in IBS is at least in part mediated by symptoms of anxiety and depression, which may modulate the affective–motivational aspects of the pain response.

Comparison of 4 neutrophil-derived proteins in feces as indicators of disease activity in ulcerative colitis

Background: To evaluate the diagnostic use of fecal concentrations of lactoferrin (Lf), calprotectin (Cal), polymorphonuclear neutrophil‐elastase (PMN‐e), and lysozyme (Lys) as indicators of disease activity in patients with active and inactive ulcerative colitis (UC). Methods: A total of 76 fecal specimens were collected from 31 patients with UC in times of active and inactive status of disease. Disease activity was determined with the colitis activity index (CAI; Rachmilewitz index), which includes a combination of laboratory parameters and clinical symptoms, with a score of at least 6 indicating active disease. Fecal Lf, Cal, PMN‐e, and Lys were measured and reported as micrograms per milliliter feces. Levels of more than 7.25, more than 6.00, at least 0.062, and at least 0.6 for Lf, Cal, PMN‐e, and Lys, respectively, were considered elevated as specified by the manufacturers. Results: Based on the CAI classification, 25 of the samples were from patients with active disease status and 51 were from patients with inactive status. Lf, PMN‐e, and Cal but not Lys showed increased levels in samples from patients in active disease compared with those in remission (median for Lf: 28.12 ± 110.86 versus 179.54 ± 334.09, P < 0.001; median for Cal: 15.13 ± 30.27 versus 116.23 ± 182.29, P < 0.001; median for PMN‐e: 0.21 ± 0.44 versus 1.02 ± 0.89, P < 0.001; median for Lys: 1.54 ± 2.39 versus 3.75 ± 5.39, P > 0.05). All 4 parameters correlated with the CAI (Lf: r = 0.441, P < 0.001; Cal: r = 0.505, P < 0.001; PMN‐e: r = 0.604, P < 0.001; Lys: r = 0.295, P < 0.05). Introducing a composite index based on Lf, Cal, and PMN‐e, the specificity was 72.5% and the sensitivity 88% compared with the CAI. Conclusions: Among the neutrophil‐derived proteins in feces, PMN‐e, Cal, and Lf represent useful markers of disease activity in patients with UC. Using all 3 markers in a composite index may be an additional noninvasive tool for the management of ambulant patients with UC.

Diarrhea- and constipation-predominant IBS patients differ in postprandial autonomic and cortisol responses.

OBJECTIVE:As the primary link between brain and gut, autonomic and endocrine dysfunction may play a role in the pathophysiology of the irritable bowel syndrome (IBS). The aim of this study was to assess autonomic, endocrine, and symptomatic responses to food intake in diarrhea-predominant and constipation-predominant IBS patients, compared to normals.METHODS:Twelve women with diarrhea-predominant or alternating IBS (IBS-D), 12 women with constipation predominant IBS (IBS-C), and 20 healthy women participated. GI symptoms, saliva cortisol concentration, heart rate, and heart rate variability were assessed at baseline and after a meal. Spectral analysis of heart rate variability was used as a measure of the sympathovagal regulation of the heart rate.RESULTS:Both groups of IBS patients showed a significant postprandial increase in GI symptoms. IBS-D showed a significant increase in the low frequency/high frequency band ratio and a decrease in the high frequency band power during the first postmeal period, which was significantly different, not only from controls, but also from IBS-C. IBS-D also showed a significant postprandial increase in cortisol, which was not evident in controls or IBS-C. There was a significant correlation between the vagal response and the postprandial increase in GI symptoms in IBS-D (r = 0.6, p < 0.05).CONCLUSIONS:These findings support the notion that the IBS symptom groups are characterized by different physiological responses to visceral stimuli, and point to a role of autonomic pathways in IBS symptomatology.

Patients With Irritable Bowel Syndrome Have Altered Emotional Modulation of Neural Responses to Visceral Stimuli

BACKGROUND & AIMS In patients with irritable bowel syndrome (IBS), pain amplification and hypervigilance might result from altered affective-motivational modulation of the pain response. We investigated the effects of emotional context on the behavioral and neural response to visceral stimuli in IBS patients. METHODS We used functional magnetic resonance imaging (fMRI) to assess the blood oxygen level-dependent response to nonpainful and painful rectal distensions in 15 female IBS patients and 12 healthy women. Distensions were delivered during psychologic stress or relaxation; data were compared with those in a neutral condition (control). Group and context-dependent differences in the processing of visceral stimulation were assessed at behavioral and the neuronal levels. Secondary analyses of group differences were performed using anxiety scores as a covariate because of higher anxiety symptoms among patients with IBS. RESULTS During rectal stimulation, IBS patients demonstrated more pronounced stress-induced modulation of neural activation in multiple brain regions, including the insula, midcingulate cortex, and ventrolateral prefrontal cortex. In response to relaxation, IBS patients demonstrated reduced modulation of distension-induced activation in the insula. During relaxation, the difference observed between groups could be accounted for by higher anxiety symptoms in patients with IBS; differential effects of stress in the insula and prefrontal regions were not attributable to anxiety. CONCLUSIONS IBS patients appear to have disrupted emotional modulation of neural responses to visceral stimuli, possibly reflecting the neural basis for altered visceral interoception by stress and negative emotions.

Effects of Mind-Body Therapy on Quality of Life and Neuroendocrine and Cellular Immune Functions in Patients with Ulcerative Colitis

Background: The aim of this study was to investigate the effects of mind-body therapy on neuroendocrine and cellular immune measures, health-related quality of life and disease activity in patients with ulcerative colitis (UC) in remission. Methods: Thirty UC patients in remission or with low disease activity were randomly assigned to an intervention group (n = 15) or a usual-care waiting control group (n = 15). Intervention consisted of a structured 60-hour training program over 10 weeks which included stress management training, moderate exercise, Mediterranean diet, behavioral techniques and self-care strategies. Quality of life, perceived stress and disease activity were assessed with standardized questionnaires (IBDQ, SF-36, PSS, CAI). In addition, the distribution of circulating lymphocytes and lymphocyte subsets as well as the β-adrenergic modulation of TNF-α production in vitro were analyzed. Urine catecholamines and plasma cortisol, prolactin and growth hormone were measured pre- and postinterventionally, and were compared with a healthy control group (n = 10). Results: In response to therapy, patients in the intervention group showed significantly greater improvement in the SF-36 scale Mental Health and the Psychological Health Sum score compared with changes observed in the usual-care waiting control group. Patients in the intervention group showed significantly greater improvement on the IBDQ scale Bowel Symptoms compared with the control group. However, no significant group differences in circulating lymphocyte subsets or endocrine parameters were observed in response to therapy. In addition, no significant effects of intervention on either the basal levels of TNF-α or the suppressive action of the β-adrenergic agonist isoproterenol on TNF-α production were observed. Conclusion: Mind-body therapy may improve quality of life in patients with UC in remission, while no effects of therapy on clinical or physiological parameters were found, which may at least in part be related to selective patient recruitment.

Prevalence and implications of anxiety in polycystic ovary syndrome: results of an internet-based survey in Germany

BACKGROUND Comparatively little attention has been paid to the symptoms of anxiety in polycystic ovary syndrome (PCOS), although anxiety disorders constitute the most common psychiatric diagnoses among endocrine patients and in the general population. Therefore, our goal was to address the prevalence, determinants and implications of anxiety alone or anxiety in combination with depression in German women with PCOS. METHODS In this nation-wide, internet-based survey, anxiety and depression (Hospital Anxiety and Depression Scale, HADS) and quality of life (SF-12) were assessed together with sociodemographic information and clinical PCOS symptoms in 448 PCOS women. RESULTS Of the patients, 34% showed clinically relevant HADS anxiety scores and 21% had clinically relevant HADS depression scores. Quality of life was significantly impaired in PCOS women with anxiety (P < 0.001), in particular, in women with comorbid anxiety and depression (P < 0.001). The risk for clinically relevant HADS anxiety scores was significantly enhanced in PCOS women with acne (odds ratio (OR) = 1.52; 95% confidence interval (CI) = 1.03-2.52) and an unfulfilled wish to conceive (OR = 1.50; 95% CI = 1.01-2.23). CONCLUSIONS PCOS women may be at an increased risk for clinically relevant anxiety, and comorbid anxiety and depression is also very common. Anxiety contributes to impaired quality of life in PCOS. Given the high prevalence and the serious implications, and the availability of effective treatment options given proper diagnosis, clinicians should be more aware of anxiety disorders in women with PCOS.

Perfectionism and the cortisol response to psychosocial stress in men.

Objective: To test the hypothesis that perfectionism is an important moderator of the neuroendocrine stress response, with higher perfectionism predicting increased neuroendocrine activation. Methods: A total of 50 middle-aged men underwent an acute standardized psychosocial stress task (Trier Social Stress Test). Perfectionism, cognitive appraisal of the stressful situation, trait anxiety, and various personality characteristics were assessed with questionnaires. Salivary cortisol, plasma epinephrine and norepinephrine, blood pressure, and heart rate were analyzed before and after stress. Circadian profiles of cortisol secretion during the day and in response to awakening were analyzed to assess basal activity of the hypothalamus-pituitary-adrenal (HPA) axis. Multiple regression analyses were conducted to identify predictors of the neuroendocrine stress response. Results: Perfectionism was significantly associated with area under the total response curve with respect to increase (AUCi) of cortisol (r = 0.322, p = .046), but not with AUCi of norepinephrine (r = −0.217, p = .152) or AUCi of epinephrine (r = 0.116, p = .477). Hence, AUCi of cortisol was the main criterion. As possible predictors, trait anxiety, neuroticism, vital exhaustion, secondary appraisal, depression, and openness were considered. Regression analyses demonstrated that only perfectionism (&bgr; = 0.45, p = .002) and secondary appraisal (&bgr; = 0.50, p = .001) were independent predictors of AUCi of cortisol, the final model explaining 45% of the total variance in cortisol response (R2 = 0.45, “shrunken” R2 [sR2] = 0.38); perfectionism alone accounted for 18% of this variance (&Dgr;R2 = 0.18, sR2 = 0.19). Conclusion: The typical cognitions, and presumably the associated emotions, of perfectionists seem to contribute independently to stress-induced bodily responses, including HPA axis activation, in response to psychosocial stress. HPA = hypothalamic-pituitary-adrenal; TSST = Trier Social Stress Test; AUC = area under the curve; HR = heart rate; BP = blood pressure; PASA = primary appraisal secondary appraisal; MPS = Frost Multidimensional Perfectionism Scale; CMD = concern over mistakes and doubts.

Disturbed stress responses in women with polycystic ovary syndrome

BACKGROUND We analyzed the neuroendocrine and immune cell responses to psychosocial stress in PCOS patients compared to BMI-matched healthy controls. METHODS Responses to public speaking stress were analyzed in 32 PCOS patients and 32 BMI-matched healthy controls. At baseline, during, and 10- and 45-min after stress, state anxiety, cardiovascular responses, cortisol, ACTH, as well as circulating leukocyte subpopulations were analyzed, together with hsCRP and serum IL-6 concentrations. RESULTS In response to public speaking stress, both groups showed significant but comparable increases in state anxiety, and blood pressure (all p<0.001; time effects). The ACTH and cortisol stress responses were significantly enhanced in PCOS (both p<0.05; interaction effect). In addition, heart rate was significantly higher in PCOS (p<0.05; group effect). PCOS patients displayed a reduced upregulation of IL-6 levels in response to stress (p<0.05; interaction effect). Baseline levels of circulating leukocyte subpopulations, IL-6 and hsCRP concentrations did not differ between BMI-matched controls and PCOS patients. PCOS patients were characterized by markedly increased psychological distress. CONCLUSIONS PCOS patients showed enhanced HPA-axis and heart rate reactivity as well as a reduced upregulation of IL-6 in response to stress. The altered stress reactivity in PCOS patients may constitute a link between depression, overweight, and the cardiovascular and diabetes risks associated with the diagnosis.

Neural mechanisms mediating the effects of expectation in visceral placebo analgesia: An fMRI study in healthy placebo responders and nonresponders

Summary In this placebo analgesia study, the expectation of pain relief reduced perceived painfulness of visceral stimuli, which was associated with activity changes in thalamus, and prefrontal and somatosensory cortices. Abstract This functional magnetic resonance imaging study analysed the behavioural and neural responses during expectation‐mediated placebo analgesia in a rectal pain model in healthy subjects. In N = 36 healthy subjects, the blood oxygen level–dependent (BOLD) response during cued anticipation and painful rectal stimulation was measured. Using a within‐subject design, placebo analgesia was induced by changing expectations regarding the probability of receiving an analgesic drug to 0%, 50%, and 100%. Placebo responders were identified by median split based on pain reduction (0% to 100% conditions), and changes in neural activation correlating with pain reduction in the 0% and 100% conditions were assessed in a regions‐of‐interest analysis. Expectation of pain relief resulted in overall reductions in pain and urge to defecate, and this response was significantly more pronounced in responders. Within responders, pain reduction correlated with reduced activation of dorsolateral and ventrolateral prefrontal cortices, somatosensory cortex, and thalamus during cued anticipation (paired t tests on the contrast 0% > 100%); during painful stimulation, pain reduction correlated with reduced activation of the thalamus. Compared with nonresponders, responders demonstrated greater placebo‐induced decreases in activation of dorsolateral prefrontal cortex during anticipation and in somatosensory cortex, posterior cingulate cortex, and thalamus during pain. In conclusion, the expectation of pain relief can substantially change perceived painfulness of visceral stimuli, which is associated with activity changes in the thalamus, prefrontal, and somatosensory cortices. Placebo analgesia constitutes a paradigm to elucidate psychological components of the pain response relevant to the pathophysiology and treatment of chronic abdominal pain.