Ultrasonographic And Computational Insight Into The Thyroid Disorders

Abstract

Objective of this research is to evaluate thyroid dysfunction states (euthyroidism, hypothyroidism, hyperthyroidism and resistance to thyroid hormones) by using thyroid function tests (TFTs) of the hospital based subjects in central Nepal followed by thyroid ultrasonographic (USG) examinations and to explore the related impacts on the molecular levels by means of nanoscale molecular dynamics (NAMD) simulations of thyroid hormone receptors (THRs). To develop the complex correlations among thyroid variables and to find the conformational changes, energy distributions and thermal properties such as heat capacity, diffusion and conduction of THRs in the cases of overt thyroid disorders are the major physics questions which have been solved in this research. Euthyroidism, hypothyroidism and resistance to thyroid hormones (RTH) are associated with the structural and physical properties of liganded, unliganded and mutated THRs, respectively. In a total of 3425 thyroid patients, there were 70.45% euthyroid, 18.95% subclinical hypothyroid, 3.30% overt hypothyroid, 5.11% subclinical hyperthyroid and 2.19% overt hyperthyroid subjects. An isolated group of 48 patients fell in the category of RTH who have elevated serum free triiodothyronine (FT3) and thyroxin (FT4) but not suppressed thyroid stimulating hormone (TSH) affected by point mutation on THR- gene. Thyroid USG and TFTs of euthyroid subjects recommend age- and gender-specific reference levels of thyroid lobe volume, FT3, FT4 and TSH. Normal thyroid size first increases and then decreases whereas FT4 first decreases and then slightly increases with aging. Right thyroid lobe of males has greater size than that of females in all age-groups except in menarche and menopause. There is a linear relation between FT3 and FT4 and their correlation increases from euthyroidism (r = 0.1) to overt thyroid dysfunctions (r = 0.91, p <0.001). The four parameter logistic (4PL) model has been better fitted(R 2 = 0.97, p <0.001) supporting non-linear relation between ln(TSH) and FT4 in both hypothyroidism and hyperthyroidism on the basis of euthyroidism. The fitted non-linear curves are response trajectories of pituitary TSH by the deviation in serum FT4. The negative correlations and slopes of the linear fits in ln(TSH) vs FT4 or FT3 are indicatorsn of negative feedback mechanism in the thyroid cycle. Hypothyroid patients suffer from goitre, thyroiditis, benign type of nodular and/or cystic lesions, diffused echogenicity and vascularity. Some patients with normal TFTs also have cystic and/or hypoechoic and even malignant lesions in the thyroid gland. The patients with THR- mutations suffer from RTH and goitre. Thyroid dysfunction is a consequence of THR-malfunctions due to its unliganded and/or mutated forms. In both constrained and unconstrained dynamics, temperature auto-correlations and echo-curves show distinct characteristics of T3 liganded and unliganded THRs. Under the effect of anharmonicity on the phase coherent state of normal modes, the dephasing time lies in a range of 0.6-0.8 ps when the THR-systems are perturbed suddenly. T3 makes some increase in heat capacity upon binding to THR- ligand binding domain (LBD) in both anhydrous and hydrous states that signifies the effect of receptor-ligand interactions, and hydrophobic, vibrational and conformational changes. The specific heat of the THR isoforms in solution ranges from2000 to 2200 Jkg 1K 1 at 310 K which is about 20% higher than that in anhydrous state in agreement with the experimental results. Providing temperature relaxation from 310 K to 200 K across protein-water interface in nanodroplets, the thermal diffusivity of THRs ranges from 1.28 10 7 to 1.57 107m 2/s which is around 1.46 10/s for water. The thermal conductivity of THRs lies in the range of 0.26–0.30 Wm which is about half the value, 0.64 Wm 1 K 1 for water at 310 K. In euthyroidism, the THRT3 isoforms with lower thermal conductivity are responsible for the regulation of body scale temperature through thermogenesis and metabolism. The hypothyroid patients with lower hormone-receptor interactions suffer from cold intolerance. The point mutations like L330S on THR- LBD make changes on Ramachandran plots, solvent accessible surface area, radial distribution functions, root mean square deviations and fluctuations, and interaction and internal energies in comparison with its wild type. These physical parameters reflect that L330S-mutant causes steric hindrance while binding T3 into THR- LBD resulting RTH in the thyroid patients. Thus, prevalence of thyroid disorders, correlations among thyroid variables and physical properties of THRs responsible for thyroid dysfunction states are explored clinically and computationally.