Euthyroid Sick Syndrome: Is It a Misnomer?

Abstract

THE TERM euthyroid sick syndrome (ESS) identifies abnormalities in thyroid function tests observed in patients with systemic nonthyroidal illnesses (NTIs) and those undergoing surgery or fasting (1, 2). The term nonthyroidal illness syndrome (NTIS) has also been employed to describe these abnormalities (3). These abnormalities result from variable, usually reversible, disturbances in the hypothalamo-pituitary-thyroid axis, thyroid hormone binding to serum proteins, tissue uptake of thyroid hormones, and/or thyroid hormone metabolism. Several recent reviews have addressed these issues (3–6). I shall focus mainly on the clinical diagnosis, significance, and treatment of ESS. Abnormalities of thyroid function in NTIS have been classified as 1) low T3 syndrome, 2) low T3-low T4 syndrome, 3) high T4 syndrome, and 4) other abnormalities (7). Although serum concentrations of total T3 and T4 are now measured routinely by similar RIAs, several methods have been employed for measurement of the small, biologically active, free fraction of T3 and T4 (8–14). Most workers in the field view the measurement of free thyroid hormones by equilibrium dialysis as the gold standard, and the ultrafiltration method is comparable or a close second. Until recently, tracer equilibrium dialysis was believed to be the most accurate procedure for measurement of free T3 or T4. This is expected to be increasingly replaced by the newer, more accurate, equilibrium dialysis/RIA (12, 14); reasonably priced kits are available commercially for free T4 measurement by this procedure (Nichols Diagnostics, San Juan Capistrano, CA) and should be available soon for free T3 measurement. A detailed discussion of methods of measurement of free thyroid hormones is beyond the scope of this minireview, and the reader is referred to several studies comparing available procedures (9, 10, 13). The analog methods for free thyroid hormone measurements are popular in several countries outside of the United States. These methods yield free thyroid hormone readings in NTI that are similar to those from the index method and different from those by the tracer equilibrium dialysis or equilibrium dialysis/RIA procedures (9, 10, 13). For this review, I have relied mainly on free thyroid hormone levels measured by the newer equilibrium dialysis/RIA procedure when data are available, or those measured by tracer dialysis and/or ultrafiltration procedures. Low serum total T3 is the most common abnormality in NTI. It is observed in about 70% of hospitalized patients. Serum total T3 may vary from undetectable to normal in patients with systemic illness, and the mean value is approximately 40% of the normal level. The serum free T3 concentration as measured by direct equilibrium dialysis/RIA [free T3(D)] is also decreased, but less severely, and the mean value is approximately 60% that of normal (14). The serum free T3 concentration measured by ultrafiltration is either normal or reduced (11). Low values were observed in patients given dopamine. It is curious that free T3 was often low in NTI when measured by equilibrium dialysis (14) and typically normal when measured by ultrafiltration (11). The discrepancy is possibly explained by the lower total T3 and more severe NTI in patients determined by equilibrium dialysis than by ultrafiltration. Free T3 in systemic illness has also been measured by a variety of other techniques and has been found to be low, but the accuracy of these procedures is questionable in NTI patients (8, 10, 15). When measured, the daily production rate (PR) of T3 is decreased in NTI (16, 17), which supports the finding in NTI of low free T3(D). Serum total T4 and free T4(D) and, when measured, daily PR-T4 are normal in the low T3 syndrome (12, 16, 18, 19). A decreased serum free T3(D) concentration and PR-T3 at a time when the serum free T4(D) concentration and PR-T4 are normal reflect decreased conversion of T4 to T3 in NTI (12, 16, 18, 19). The serum concentration of rT3 is increased in NTI, except in renal failure (20). However, daily PR-rT3 is normal, and the increase in the serum rT3 level is related mainly to the delayed MCR of rT3, which is predominantly due to decreased activity of the type I iodothyronine 5′-monodeiodinase (5′-MDI) in tissues (16); 5′-MDI deiodinates T4 to T3 and rT3 to 3,3′-diiodothyronine (T2) (21). The low T3 and low T4 syndrome is observed in severely ill, frequently moribund, patients, usually admitted to medical intensive care units. Low serum total T4 correlates with a bad prognosis (22). The serum concentration of free T4, as measured by equilibrium dialysis/RIA [free T4(D)], is normal in most NTI patients with low total T4 (12). Interestingly, total T4 is often low in NTI patients even when their serum concentration of immunoassayable T4-binding globulin (TBG) is clearly normal (8). However, the free T4 index is frequently low in these patients (7, 9, 10). This combination of findings in NTI has been explained by the p