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 apparently reduce the availability of T₄ to sites of disposal as reflected by the increased fractional disposal rate of T₄ (0.101±0.018 d⁻¹, nl 0.021±0.003, P < 0.001). The decreased serum T₃ binding was associated with the expected increases in MCR (18.80±2.22 liter/d per m², nl 13.74±1.30, P < 0.05) and total volume of distribution (26.55±4.80 liter/m², nl 13.10±2.54, P < 0.01). However, the unaltered Kii suggested an extravascular binding impairment comparable to that found in serum. The decreased T₃ production rate (6.34±0.53 μg/d per m², nl 23.47±2.12, P < 0.005) appeared to result from reduced peripheral T₄ to T₃ conversion because of decreased 5′-deiodination rather than from a decreased T₄ availability. This view was supported by the normality of the rT₃ production rate. The normal Kii values for rT₃ indicated a comparable defect in serum and extravascular rT₃ binding. The reduced MCR (25.05±6.03 liter/d per m², nl 59.96±8.56, P < 0.005) and FCR (191.0±41.19%, nl 628.0±199.0, P < 0.02) for rT₃ are compatible with an impairment of the rT₃ deiodination rate.

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.