Weight and Body Composition Compartments do Not Predict Therapeutic Thiopurine Metabolite Levels in Inflammatory Bowel Disease.

OBJECTIVES: Thiopurine drugs are the most commonly used steroid-sparing therapies in moderate-to-severe inflammatory bowel disease (IBD). Their complex metabolism and their narrow therapeutic windows means that optimal dosing is difficult. However, weight-based dosing is the norm. Similar antimetabolites are dosed by body composition parameters. In IBD, treatment response and toxicity has been shown to correlate with thiopurine metabolite levels. We sought to determine whether weight or body composition parameters predicted therapeutic 6-thioguanine nucleotide (6TGN) or toxic 6-methylmercaptopurine (6MMP) levels. METHODS: This single-center retrospective cohort study identified 66 IBD patients who had body composition analysis and thiopurine metabolite levels tested. Statistical analysis was performed using Spearman correlation, Kruskal-Wallis, Mann-Whitney, and unpaired t tests and receiver-operator operating characteristic curves. A P value of <0.05 was considered significant. RESULTS: No correlation was identified between 6TGN and any body composition parameters, absolute drug dose or drug dose/kg of fat mass, fat-free mass (FFM), subcutaneous adipose tissue area, or visceral adipose tissue area. However, 6MMP correlated with azathioprine dose, thiopurine dose/kg of body weight, and with several body composition parameters. CONCLUSIONS: No relationship was found between therapeutic metabolite levels and weight or body composition compartments. Higher thiopurine doses, especially in relation to FFM, are associated with higher levels of potentially hepatotoxic 6MMP and shunting toward this metabolite. Conventional weight-based dosing to attain therapeutic metabolite levels appears unreliable and may be replaced by metabolite level testing.

Vitamin D deficiency impacts on expression of toll-like receptor-2 and cytokine profile: a pilot study.

BACKGROUND: Vitamin D is believed to play an important role outside the endocrine system in the regulation of the immune system, and in cellular proliferation and differentiation. The aim of the study was to investigate the impact of vitamin D levels on innate immunity. METHODS: Participants for this prospective, longitudinal study were recruited amongst otherwise healthy staff of a large hospital in Victoria, Australia. Those fulfilling the inclusion criteria, including a vitamin D level of <50 nmol/L, were supplemented. Using flow cytometry, expression of the innate immune receptors TLR2, TLR4 and CD86 was measured on peripheral blood mononuclear cells (PBMCs) collected prior to vitamin D treatment and then at 1 and 3 months. Additonally, PBMCs at each timepoint were stimulated with specific TLR ligands and resultant supernatants were assayed for the cytokines TNFα, IL-6, IFN-α and IP-10. RESULTS: In participants whose vitamin D level was >100 nmol/L post supplementation (n=11), TLR2 expression on PBMCs increased significantly, with no change noted in TLR4 or CD86 expression. Stimulation of vitamin D deficient samples with TLR ligands produced a number of proinflammatory cytokines, which were significantly reduced upon vitamin D normalisation. In patients whose levels returned to a deficient level at 3 months despite ongoing low-level supplementation, an increase in the pro-inflamamtory state returned. This suggests that vitamin D may play an important role in ensuring an appropriate baseline pro-inflammatory state. CONCLUSIONS: This ex-vivo pilot study adds clinical evidence supporting a possibly important role for vitamin D in innate immunity. If confirmed, this unique clinical study has potentially significant implications for the treatment of a variety of inflammatory conditions, where achieving optimal vitamin D levels may help reduce inflammation.

Waist-to-height ratio as a predictor of serum testosterone in ageing men with symptoms of androgen deficiency.

The decline in serum testosterone in ageing men may be mediated in part by obesity; however, it is uncertain which measure of adiposity is most closely associated with testosterone levels. We have examined the relationships of age, adiposity and testosterone levels in ageing men with symptoms consistent with hypoandrogenism but who were otherwise in good health. We conducted a cross-sectional study of non-smoking men aged ≥ 54 years recruited from the community and who were free of cancer or serious medical illness. Height (Ht), weight and waist circumference (WC) were measured, and body mass index (BMI) and waist-to-height (WHt) ratio were calculated. Two morning blood samples were collected for measurement of total testosterone (TT), sex hormone binding globulin (SHBG) and luteinizing hormone (LH). Free testosterone (cFT) was calculated. Multivariate linear regression analysis was performed to assess their relationship with measures of adiposity. Two hundred and seven men aged 54-86 years were studied. On univariate analysis WHt ratio was more strongly correlated with TT and cFT than either WC or BMI. Furthermore, in models of TT and cFT, the addition of Ht to WC resulted in an increase in the magnitude of the regression coefficients for both WC (inverse correlate) and Ht (positive correlate), with the contributions of both WC and Ht both being significant (P<0.05 for all). In conclusion, WHt ratio is the best anthropometric predictor of both TT and cFT in this group of healthy but symptomatic ageing men.