Peripheral Serum Thyroxine, Triiodothyronine and Reverse Triiodothyronine Kinetics in the Low Thyroxine State of Acute Nonthyroidal Illnesses

Abstract

A B S T R A C T The low thyroxine (T4) state of acute critical nonthyroidal illnesses is characterized by marked decreases in serum total T4 and triiodothyronine (T3) with elevated reverse T3 (rT3) values. To better define the mechanisms responsible for these alterations, serum kinetic disappearance studies of labeled T4, T3, or rT3 were determined in 16 patients with the low T4 state and compared with 27 euthyroid controls and a single subject with near absence of thyroxine-binding globulin. Marked increases in the serum free fractions of T4 (0.070±0.007%, normal [nl] 0.0315±0.0014, P <0.001), T3 (0.696±0.065%, nl 0.310±0.034, P <0.001), and rT3 (0.404±0.051%, nl 0.133±0.007, P < 0.001) by equilibrium dialysis were observed indicating impaired serum binding. Noncompartmental analysis of the kinetic data revealed an increased metabolic clearance rate (MCR) of T4 (1.69±0.22 liter/d per m2, nl 0.73±0.05, P < 0.001) and fractional catabolic rate (FCR) (32.8±2.6%, nl 12.0±0.8, P < 0.001), analogous to the euthyroid subject with low thyroxine-binding globulin. However, the reduced rate of T4 exit from the serum (Kii) (15.2±4.6 d-1, nl 28.4±3.9, P < 0.001) indicated an impairment of extravascular T4 binding that exceeded the serum binding defect. This defect did not apparThis work was presented in part at the 6th International Congress of Endocrinology, Melbourne, Australia, February, 1980 (Abstract No. 364), and at the 61st Annual Endocrine Society Meeting, Wash., D. C., June, 1980 These alterations in thyroid hormones indices and kinetic parameters for T4, T3, and rT3 in the low T4 state of acute nonthyroidal illnesses can be accounted for by: (a) decreased binding of T4, T3, and rT3 to vascular and extravascular sites with a proportionately greater impairment of extravascular T4 binding, and (b) impaired 5'-deiodination activity affecting both T4 and rT3 metabolism.

Changes in metabolism of TRH in euthyroid sick syndrome

“…low T 3 syndrome), usually elevated reverse T 3 (rT 3 ) levels, normal basal thyrotropin (TSH) serum concentrations, blunted TSH response to thyrotropin-releasing hormone (TRH) testing and decreased nocturnal TSH surge (1)(2)(3). Free T 4 values, as determined by equilibrium dialysis, are frequently increased and may be secondary to reduced serum clearance rates of T 4 (4).…”

Nonthyroidal illness syndrome in patients with subarachnoid hemorrhage due to intracranial aneurysm

“…The decrease of the T4 levels in NTIS are probably due to a decreased T4 production (decreased hypothalamic TRH secretion) and to an increase of its metabolic clearance 5,10,11 . Total T4 serum levels are reduced in proportion to the severity and, probably, to the duration of the disease 5 . In acute traumas, as well as, in heart bypass surgeries or in short duration fasting, the serum levels of T4 do not decrease.…”

“…However, with the increase in the severity of the diseases the fall in the T4 levels might be prominent. T4 serum levels below 4 ng/mL are associated with a 50% probability of death and with levels below 2 ng/mL the probability reaches the 80% 5,24 .…”

“…The main laboratory characteristics of NTIS is a decrease of the serum T3, accompanied by an increase of T3 reverse levels, associated or not with normal levels of TSH and total T4 [2][3][4] . The fall of T3 serum concentrations is due to the decrease of the conversion of T4 to T3 in the peripheral tissue, including liver and kidneys, that are responsible for the genesis of T3 which maintains the physiologic circulating levels of this hormone 2,3,5 . Another step which might affect the transformation of T4 into T3 is the difficulty of T4 entrance into the cell where it is metabolized [6][7][8] .…”

Toll-like receptor-MyD88 and Fc receptor pathways of mast cells mediate the thyroid dysfunctions observed during nonthyroidal illness

“…These illnesses include bacterial infections, burns, myocardial infarction, respiratory distress syndrome, cirrhosis, end-stage renal disease, psychosis, and starvation. The key serum biochemical changes in NTI, although varying with the type and severity of the initiating illness, consist of: (i) increased reverse tri-iodothyronine (T3), principally due to decreased activity of type I deiodinase (3), an enzyme in peripheral tissues (mainly liver) that converts reverse T3 to di-iodo-thyronine and, in decreasing order of affinity, thyroxine (T4) to T3 and T3 to di-iodothyronine; (ii) decreased T3, also secondary to decreased type I deiodinase activity (4); (iii) decreased T4 more likely due to a reduced binding capacity and/or affinity of serum carrier proteins for T4, given that the T4 production rate appears similar to that of healthy euthyroid individuals with low or absent T4-binding globulin (5,6); and (iv) inappropriately normal or low levels of thyroid stimulating hormone (TSH) with respect to the decreased thyroid hormone levels. This defective TSH production is likely of hypothalamic origin in light of demonstrated reduction in TSH-releasing hormone (TRH) secretion from paraventricular nucleus neurons (7)(8)(9) and blunting of the physiological nocturnal TSH surge (10).…”