Effect of concurrent vitamin A and iodine deficiencies on the thyroid-pituitary axis in rats

OBJECTIVE: Deficiencies of vitamin A and iodine are common in many developing countries. Vitamin A deficiency (VAD) may adversely affect thyroid metabolism. The study aim was to investigate the effects of concurrent vitamin A and iodine deficiencies on the thyroid-pituitary axis in rats. DESIGN: Weanling rats (n = 56) were fed diets deficient in vitamin A (VAD group), iodine (ID group), vitamin A and iodine (VAD + ID group), or sufficient in both vitamin A and iodine (control) for 30 days in a pair-fed design. Serum retinol (SR), thyroid hormones (FT(4), TT(4), FT(3), and TT(3)), serum thyrotropin (TSH), pituitary TSHbeta mRNA expression levels, and thyroid weights were determined at the end of the depletion period. MAIN OUTCOME: Compared to the control and ID groups, SR concentrations were about 35% lower in the VAD and VAD + ID groups (p < 0.001), indicating moderate VA deficiency. Comparing the VAD and control groups, there were no significant differences in TSH, TSHbeta mRNA, thyroid weight, or thyroid hormone levels. Compared to the control group, serum TSH, TSHbeta mRNA, and thyroid weight were higher (p < 0.05), and FT4 and TT4 were lower (p < 0.001), in the VAD + ID and ID groups. Compared to the ID group, TSH, TSHbeta mRNA, and thyroid weight were higher (p < 0.01) and FT(4) and TT(4) were lower (p < 0.001) in the VAD + ID group. There were no significant differences in TT3 or FT3 concentrations among groups. CONCLUSION: Moderate VAD alone has no measurable effect on the pituitary-thyroid axis. Concurrent ID and VAD produce more severe primary hypothyroidism than ID alone

An RBP4 promoter polymorphism increases risk of type 2 diabetes

Aims/hypothesis: Retinol-binding protein 4 (RBP4), originally known for retinol transport, was recently identified as an adipokine affecting insulin resistance. The RBP4 -803GA promoter polymorphism influences binding of hepatic nuclear factor 1α and is associated with type 2 diabetes in case-control studies. We hypothesised that the RBP4 -803GA polymorphism increases type 2 diabetes risk at a population-based level. In addition, information on retinol intake and plasma vitamin A levels enabled us to explore the possible underlying mechanism. Methods: In the Rotterdam Study, a prospective, population-based, follow-up study, the -803GA polymorphism was genotyped. In Cox proportional hazards models, associations of the -803GA polymorphism and retinol intake with type 2 diabetes risk were examined. Moreover, the interaction of the polymorphism with retinol intake on type 2 diabetes risk was assessed. In a subgroup of participants the association of the polymorphism and vitamin A plasma levels was investigated. Results: Homozygous carriers of the -803A allele had increased risk of type 2 diabetes (HR 1.83; 95% CI 1.26-2.66). Retinol intake was not associated with type 2 diabetes risk and showed no interaction with the RBP4 -803GA polymorphism. Furthermore, there was no significant association of the polymorphism with plasma vitamin A levels. Conclusions/interpretation: Our results provide evidence that homozygosity for the RBP4 -803A allele is associated with increased risk of type 2 diabetes in the Rotterdam population. This relationship was not clearly explained by retinol intake and vitamin A plasma levels. Therefore, we cannot differentiate between a retinol-dependent or -independent mechanism of this RBP4 variant

Time course of the increase in 4β-hydroxycholesterol concentration during carbamazepine treatment of paediatric patients with epilepsy

Cholesterol is a vital compound that can undergo cytochrome P450 (CYP) mediated conversion into steroid hormones, bile acids and oxysterols. CYP enzymes are present in all human tissues and mediate the metabolism of several endogenous and exogenous compounds such as steroids and drugs. Vitamin D status has been shown to be important for several biological processes such as drug metabolism, modulation of the immune system and bone health. Enzymes in subfamily CYP3A (CYP3A4, CYP3A5, CYP3A7 and CYP3A43) are present in liver and intestine. They metabolize about 50% of all prescribed drugs. Genetic factors, age, sex, ethnicity and environmental factors influence the activity and expression of CYP3A enzymes. These factors combined cause wide inter-patient variability in CYP3A mediated drug response. There are a number of clinical markers to assess the CYP3A activity, e.g. plasma midazolam clearance, quinine metabolic ratio and 4β- hydroxycholesterol/cholesterol ratio. In the present study the plasma levels of 4β- hydroxycholesterol and the 4β-hydroxycholesterol/cholesterol ratio has been evaluated as markers of CYP3A activity during enzyme induction by a number of drugs (carbamazepine in Papers I and III, rifampicin in Papers IV-V and efavirenz in Paper V) and by pregnancy (Paper III). The association between CYP3A activity and vitamin D status has also been studied (Paper IV-V). In Paper I, carbamazepine treatment in children with epilepsy doubled the plasma levels of 4β-hydroxycholesterol within two weeks of treatment. The increase was 5 to 10-fold within eight weeks treatment. In Paper III, pregnancy increased the 4β- hydroxycholesterol/cholesterol ratio and the plasma levels of cholesterol. Newborn children had the same CYP3A activity as adults as indicated by similar 4β-hydroxycholesterol/ cholesterol ratios. Carbamazepine treatment during pregnancy further increased the CYP3A activity in one mother and her child. In Papers IV-V, rifampicin-mediated CYP3A induction did not affect the plasma levels of 25-hydroxyvitamin D in healthy volunteers or in tuberculosis-HIV co-infected patients. In tuberculosis-HIV co-infected patients there was a significant negative correlation between the plasma levels of 25- hydroxyvitamin D and the 4β-hydroxycholesterol/cholesterol ratio already at initiation of treatment (Paper V). Efavirenz treatment caused a transient decrease in the plasma levels of 25-hydroxyvitamin D in HIV-infected patients (Paper V). To summarize, 4β-hydroxycholesterol and the 4β-hydroxycholesterol/cholesterol ratio are useful as markers of CYP3A induction. 4β-Hydroxycholesterol is a non-invasive endogenous clinical marker that is easy to use also in children and vulnerable patient groups. The blood samples can be taken at any time of the day regardless of food intake