Lean body mass is a major determinant of levothyroxine dosage in the treatment of thyroid diseases.

Total body weight is usually employed to calculate the amount of l-T(4) to be administered in patients with thyroid diseases. The aim of this study was to evaluate the effect of body composition on l-T(4) requirements. Body composition was assessed by dual energy x-ray absorptiometry in 75 patients on TSH-suppressive l-T(4) therapy after conventional thyroid ablation for differentiated cancer. The mean daily dose of l-T(4) was lower in normal-weight (127.5 +/- 21.3 mug/d) vs. overweight (139.4 +/- 24.5) and obese (151.3 +/- 29.1) subjects. There was a much stronger association between the l-T(4) dosage and lean body mass (P < 0.001, r = 0.667) compared with fat mass (P = 0.023, r = 0.26). Measurement of regional tissue composition showed peripheral lean mass as the best correlate with the dose of l-T(4) (r = 0.679, P < 0.001) whereas no correlation was observed with peripheral fat mass. In conclusion, individual l-T(4) requirements are dependent on lean body mass. Age- and gender-related differences in l-T(4) needs reflect different proportions of lean mass over the total body weight. An estimate of lean mass may be helpful to shorten the time required to attain a stable dose of l-T(4), particularly in subjects with high body mass index values that may be due either to increased muscular mass or to obesity.

Genetic screening for melanocortin-4 receptor mutations in a cohort of Italian obese patients: description and functional characterization of a novel mutation.

Mutations in the human melanocortin-4 receptor (MC4-R) gene may account for up to 5.8% of morbid nonsyndromic obesity. We have screened 120 unrelated obese patients for variants of the MC4-R gene. Four heterozygous missense variants were detected, including two polymorphisms (Val(103)Ile and Ile(251)Leu) previously described in the literature. A novel heterozygous mutation (Glu(308)Lys) was detected in a 36-yr-old female patient. Compared with the wild-type receptor, cells expressing the mutated receptor showed a reduced stimulation of cAMP production and a reduction of radioactive alpha MSH binding. No segregation of the mutation with the obese phenotype could be demonstrated. A second, potentially pathogenic mutation (Ser(30)Phe) was detected in a 31-yr-old female patient. Functional analysis of the mutated receptor showed no change in the affinity to the natural ligand alpha MSH nor limited ability to stimulate cAMP production. Sixty lean subjects were also screened, and no additional variants of the MC4-R gene were observed, except for two individuals with the Val(103)Ile polymorphism. In conclusion, we have screened a population of Italian obese subjects for MC4-R variants, demonstrating a 1.7% prevalence of potentially pathogenic mutations. A novel heterozygous missense mutation (Glu(308)Lys) that impairs MC4-R functional activity in vitro was characterized.

Role for inner ring deiodination preventing transcutaneous passage of thyroxine.

Creams containing thyroid hormone are commonly employed for cosmetic purposes. To verify whether T(4) applied to the skin surface can enter the bloodstream either directly or as a metabolite, a cream containing L-T(4) [3,5,3',5'-tetraiodothyronine (T(4))] was self-applied by volunteers for 2 wk. No significant variations in urinary iodide, TSH, and serum (total and free) T(4) and T(3) concentrations were observed at any time relative to pretreatment values, whereas rT(3) concentrations increased significantly 6 and 12 h after cream application. The increased rT(3) concentration led us to investigate the presence of inner ring type III deiodinase (D3) activity in human skin. Using human surgical discard skin, we found that T(4) can be carried across human epidermis in a liposome cream. Substantial inner ring deiodination was suggested by the fact that only 10% of transferred thyroid hormone remained as T(4), and T(3) was not detected. We then measured D3 activity in a surgical skin specimen. The K(m) for T(3) was 1.74 nmol/liter, and the maximum velocity was 23.5 fmol/microg microsomal protein/h. In conclusion, our study indicates that normal human skin serves as a substantial, but incomplete, barrier to T(4) passage. D3 plays an important role in augmenting T(4) blockade by inactivating T(4) to rT(3).