Elevated 3,5-Diiodothyronine Concentrations in the Sera of Patients with Nonthyroidal Illnesses and Brain Tumors

Abstract

This study reports the development of a highly sensitive and reproducible RIA for the measurement of 3,5-diiodothyronine (3,5-T2) in human serum and tissue. The RIA employs 3-bromo-5-[125I]iodo-L-thyronine (3-Br-5-[125I]T1) as tracer, which was synthesized carrier free by an interhalogen exchange from 3,5-dibromo-L-thyronine (3,5-Br2T0). The detection limits were 1.0 fmol/g and 0.8 pmol/L in human brain tissue and serum, respectively. T3, diiodothyroacetic acid, and 3-monoiodothyronine cross-reacted with a 3,5-T2 antibody to the extent of 0.06%, 0.13%, and 0.65%, respectively. Serum concentrations of 3,5-T2 were measured in 62 healthy controls and 4 groups of patients with nonthyroidal illness, i.e. patients with sepsis (n = 24), liver diseases (n = 23), head and/or brain injury n = 15), and brain tumors (n = 21). The mean serum level of 3,5-T2 in the healthy subjects was 16.2 +/- 6.4 pmol/L. Concentrations of 3,5-T2 were significantly elevated in patients with sepsis (46.7 +/- 48.8 pmol/L; P< 0.01), liver diseases (24.8 +/- 14.9 pmol/L; P < 0.01), head and/or brain injury (24.1 +/- 11.3 pmol/L; P < 0.05), and brain tumors (21.6 +/- 4.8 pmol/L; P < 0.01). In all 4 patient groups, serum levels of T3 were significantly reduced, confirming the existence of a low T3 syndrome in these diseases. Serum concentrations of 3,5-T2 were significantly elevated in patients with hyperthyroidism (n = 9) and were reduced in patients with hypothyroidism (n = 8). The levels of T4, T3, and 3,5-T2 were measured in normal human tissue samples from the pituitary gland and various brain regions and in brain tumors. In normal brain tissue, the concentrations of 3,5-T2 ranged between 70-150 fmol/g, and the ratio of T3 to 3,5-T2 was approximately 20:1. In brain tumors, however, T3 levels were markedly lower, resulting in a ratio of T3 to 3,5-T2 of approximately 1:1. Recent findings suggest a physiological, thyromimetic role of 3,5-T2, possibly stimulating mitochondrial respiratory chain activity. Should this prove to be correct, then the increased availability of 3,5-T2 in nonthyroidal illness may be one factor involved in maintaining clinical euthyroidism in patients with reduced serum levels of T3 during nonthyroidal illness.

Thyroid: biological actions of ‘nonclassical’ thyroid hormones

“…Although conversion of T 3 to T 2 has not been demonstrated in vitro, indirect evidence indicates that T 2 is indeed formed from T 3 in vivo through deiodination (Moreno et al 2002). Serum concentrations of T 2 in humans are within the picomolar range (16 pM in healthy individuals to 50 pM maximum in individuals with nonthyroidal illness; Pinna et al 1997). Rat intra-hepatic T 2 concentrations are 1.5 fmol/100 mg (Moreno et al 2002).…”

Pituitary Hyperplasia, Hormonal Changes and Prolactinoma Development in Males Exposed to Estrogens—An Insight From Translational Studies

“…This metabolite exerts thyromimetic activity, suppresses TSH and stimulates GH [145][146][147], though not as strongly as T 3 [139]. Moreover, the local concentration of 3,5-T 2 in human brain tumors and pituitary adenomas is significantly increased in comparison with nontumoral regions of the human brain [140]. Further experimental research and analyses are needed to shed more light on this still largely unexplored area.…”

“…Both T 4 and T 3 may bind to its membrane integrin αvβ3 receptor and activate mitogen-activated protein kinase (MAPK) cascade and phosphorylation processes, including ERα phosphorylation (dashed arrow). Increased concentration of T 2 , demonstrated in pituitary adenomas, may contribute to progression of prolactinoma through stimulation of energy metabolism in mitochondria[132][133][134][135][136][137][138][139][140].…”

Physiological Role and Use of Thyroid Hormone Metabolites - Potential Utility in COVID-19 Patients

“…3,5-T2 increases mitochondrial oxygen consumption in rats rapidly (103). Increased 3,5-T2 levels in disease have been interpreted as compensation for low cellular T3 levels (104). Survival in chronically cold-exposed animals is improved due to activation of thermogenesis, stimulation of boxidation, and up-regulation of F(0)-F(1)-ATP synthase.…”