The most prevalent and pronounced anomaly in the parameters of thyroid function during NTI is a depression in the serum total and free T₃ levels. This manifestation, which is present in 70% or more of hospitalized patients, may be considered, with a few notable exceptions (discussed later), the sine qua non of the euthyroid sick syndrome.4,5 The likelihood of finding a depression of serum T₃ varies with the severity of the NTI; in one study, it occurred in 23% of patients on regular hospital wards, 56% of those in intensive care units, 76% of those undergoing coronary artery bypass, and 86% of those receiving heart transplants.5 The depression in serum T₃ may be pronounced, achieving levels below those seen in hypothyroid persons.6,7 Concomitant reductions in thyroid hormone–binding proteins account for less than one-third of the observed decrease in serum T₃ level4; much of the remainder is attributable to a decreased peripheral monodeiodination of serum T₄ (discussed later). Serum free T₃, as measured by equilibrium dialysis, also is decreased in as many as 50% of patients with NTI. Given the frequency and magnitude of the T₃ depression during severe
NTI, the finding of a normal or elevated T₃ concentration in this setting occasionally is the first indication of a coexistent thyro-toxicosis.8 Serum reverse T₃ (rT₃), a metabolically inert metabolite of T₄ obtained through 5-deiodination, has long been valued as a diagnostic tool in the distinction of sick euthyroid patients (elevated rT₃) from patients with hypothyroidism (depressed rT₃), although this is not always reliable.9,10 As with T₄ and T₃, serum rT₃ is predominantly protein bound in the circulation. Beyond its role as the “alternate” metabolite of T₄, rT₃ has the ability to act as both substrate and inhibitor of type I and type II 5′-monodeiodinases, thereby potentially contributing to the decreased production of T₃ seen in NTI.11

Thyroxine levels enjoy a greater degree of stability than do T₃ levels during NTI of mild or moderate severity. However, with increasing gravity of the underlying illness, the serum total T₄ levels may be subnormal in as many as 20% to 50% of hospitalized patients.5,6 and 7,12,13 Extremely low serum T₄ levels portend a fatal outcome to an extent that rivals traditional prognostic indices (see later). Conversely, a rise in T₄ levels accompanies the recovery phase of illness in patients who survive critical illness (see Fig. 36-1). Hyperthyroxinemia may be seen occasionally in NTI, although this generally occurs in a predictable fashion in association with certain hepatic disorders or acute psychiatric illnesses, or in conjunction with specific medications (see later).