Regulation of duodenal mucosal bicarbonate secretion

The present research studied the regulation of duodenal bicarbonate secretion in the anaesthetized guinea-pig, using a model that permitted the study of active transport of bicarbonate. It was determined that dibutyryl 3' ,5'-cyclic adenosine monophosphate, vasoactive intestinal polypeptide, prostaglandin E2, carbachol and theophylline are the chief agonists of duodenal bicarbonate secretion. Vasoactive intestinal polypeptide and prostaglandin E2 act directly via distinct receptors on the duodenal enterocytes, activating adenylate cyclase and protein kinase A in sequence to initiate bicarbonate secretion. In addition, there is good evidence that the inositol phospholipid and protein kinase C cascade is also involved, possibly to a lesser extent, since tetradecanoyl-phorbolacetate and prostaglandin F2a were agonists of bicarbonate secretion. Carbachol, using a m-cholinoceptor pathway, stimulates duodenal bicarbonate secretion by releasing vasoactive intestinal polypeptide. Consistent with this finding is the observation that carbachol has no receptors on duodenal enterocytes. The role of the nicotinic pathway in bicarbonate secretion, however, remains uncertain. Duodenal bicarbonate secretion can be inhibited by somatostatin and acetazolamide. Somatostatin selectively suppresses carbachol-stimulated and VIP-stimulated duodenal bicarbonate secretion, but not PGE2-stimulated bicarbonate secretion. Receptors for somatostatin coupled to adenylate cyclase could not be detected on isolated duodenal enterocytes, which strengthens the hypothesis that carbachol does not act directly on these epithelial cells, but via a second transmitter, vasoactive intestinal polypeptide. Carbonic anhydrase activity is necessary for secretion of bicarbonate, since acetazolamide-inhibition of this enzyme decreased bicarbonate secretion, both basal and stimulated by many different agonists. Carbonic anhydrase serves as a common final step in the generation of bicarbonate in duodenal enterocytes. This enzyme was located in the cytoplasm of cells in the villus as well as the crypt cells, implying that bicarbonate secretion occurs along the length of the villus and crypt. In summary, the present research has shown direct stimulation of duodenal bicarbonate secretion by vasoactive intestinal polypeptide, which participates also in themcholinergic pathway, and by prostaglandin E2. Adenylate cyclase and protein kinase A appear to be the intracellular messengers with the primary function of initiating duodenal bicarbonate secretion. However, there is convincing evidence that the inositol phospholipid and protein kinase C cascade also activates this secretion. Somatostatin selectively stops duodenal bicarbonate secretion. Carbonic anhydrase activity in the crypt and villus is required as the final common step in bicarbonate production

Comparison of the Multiattribute Utility Instruments EQ-5D and SF-6D in a Europe-Wide Population-Based Cohort of Patients with Inflammatory Bowel Disease 10 Years after Diagnosis

Background. The treatment of chronic inflammatory bowel disease (IBD) is costly, and limited resources call for analyses of the cost effectiveness of therapeutic interventions. The present study evaluated the equivalency of the Short Form 6D (SF-6D) and the Euro QoL (EQ-5D), two preference-based HRQoL instruments that are broadly used in cost-effectiveness analyses, in an unselected IBD patient population. Methods. IBD patients from seven European countries were invited to a follow-up visit ten years after their initial diagnosis. Clinical and demographic data were assessed, and the Short Form 36 (SF-36) was employed. Utility scores were obtained by calculating the SF-6D index values from the SF-36 data for comparison with the scores obtained with the EQ-5D questionnaire. Results. The SF-6D and EQ-5D provided good sensitivities for detecting disease activity-dependent utility differences. However, the single-measure intraclass correlation coefficient was 0.58, and the Bland-Altman plot indicated numerous values beyond the limits of agreement. Conclusions. There was poor agreement between the measures retrieved from the EQ-5D and the SF-6D utility instruments. Although both instruments may provide good sensitivity for the detection of disease activity-dependent utility differences, the instruments cannot be used interchangeably. Cost-utility analyses performed with only one utility instrument must be interpreted with caution

How expensive is inflammatory bowel disease? A critical analysis

Economic analysis of chronic diseases is required for proper allocation of resources and understanding cost-effectiveness studies of new therapies. Studies on health care cost of ulcerative colitis (UC) and Crohn’s disease (CD) are reviewed here. These studies were carried out in various countries with disparate health care systems. In the United States, data were often modeled or retrieved from large insurance schemes. Surgery and in-patient hospitalization accounted for over half the outlay on UC and CD. Fistulous disease in CD and parenteral nutrition were very costly. In Canada, overall charges were lower than in the United States, but there too, surgical costs were relatively high. In European studies, economic data were abstracted directly from patients’ files. One pan-European study examined the outlay on UC and CD in a community-based prospective inception cohort followed for 10 years. Overall costs in Europe were lower than in the United States. Surgery, hospitalization, year of follow-up, disease phenotype in CD and ASCA-positivity impacted significantly on costs. In all studies, the cost data were right skewed, aminosalicylates were expensive drugs, and biological agents the most expensive; moreover indirect costs were not calculated. Infliximab raised costs considerably in CD, but there were no long-term follow-up studies, so that the cost-benefit of biological agents remains unknown. In conclusion, costs of managing UC and CD vary by country, surgery, genotype and several other factors. The most important question for further research is whether the biological therapies are cost-effective in the long-term

Cost-Effectiveness and Heterogeneity: Using Finite Mixtures of Disease Activity Models to Identify and Analyze Phenotypes

Heterogeneity in patient populations is an important issue in health economic evaluations, as the cost-effectiveness of an intervention can vary between patient subgroups, and an intervention which is not cost-effective in the overall population may be cost-effective in particular subgroups. Identifying such subgroups is of interest in the allocation of healthcare resources. Our aim was to develop a method for cost-effectiveness analysis in heterogeneous chronic diseases, by identifying subgroups (phenotypes) directly relevant to the cost-effectiveness of an intervention, and by enabling cost-effectiveness analyses of the intervention in each of these phenotypes. We identified phenotypes based on healthcare resource utilization, using finite mixtures of underlying disease activity models: first, an explicit disease activity model, and secondly, a model of aggregated disease activity. They differed with regards to time-dependence, level of detail, and what interventions they could evaluate. We used them for cost-effectiveness analyses of two hypothetical interventions. Allowing for different phenotypes improved model fit, and was a key step towards dealing with heterogeneity. The cost-effectiveness of the interventions varied substantially between phenotypes. Using underlying disease activity models for identifying phenotypes as well as cost-effectiveness analysis appears both feasible and useful in that they guide the decision to introduce an intervention