|
Elaine M. Kaptein
University of Southern California, Los Angeles, CA 90033, USA In patients with nonthyroidal illnesses and/or altered nutritional states, changes in thyroid hormone metabolism appear to reflect a continuum which relates primarily to the severity of the underlying disorder (1-4). For example, in critically ill patients, mortality rates are highest in those with lowest total T4 values, and total T4 values are lowest in patients with end-stage renal failure who have the highest serum creatinine values. Among patients with less severe nonthyroidal illnesses who have normal total T4 values, the sickest patients have the lowest total T3 levels (1-4). Changes in thyroid hormone metabolism in patients with nonthyroidal illnesses include transient alterations of 1) the hypothalamic-pituitary-thyroid axis, 2) thyroid hormone binding to serum carrier proteins, 3) thyroid hormone uptake by extrathyroidal tissues, 4) thyroid hormone production and degradation rates, and 5) changes at the thyroid hormone receptor level (1-4). By definition, these changes are reversible with recovery from the nonthyroidal illness and are not secondary to hypothalamic, pituitary, or thyroid diseases. Alterations of peripheral T4 and T3 metabolism in nonthyroidal illnesses appear to be hormone specific, but not disease specific (1). Reduced total T4 values are primarily due to impaired T4 binding to serum carrier proteins, while T4 production rates are usually normal, and T4 transfer rates from serum to extravascular sites are reduced, resulting in normal or elevated serum free T4 values. Decreased serum total and free T3 concentrations reflect reduced T3 production from T4 in extrathyroidal tissues, which in turn may be primarily due to inhibition of T4 uptake by tissues such as liver resulting in reduced T4 availability for 5'-deiodination (1,3). In contrast, alterations of reverse T3 metabolism appear to be disease specific (1). Most patients with non-renal and non-HIV related illnesses have elevated total and free reverse T3 levels secondary to reduced reverse T3 clearance rates, while reverse T3 production rates are unaltered. In contrast, patients with renal diseases have disease specific alterations of reverse T3 distribution and metabolism (1). The relationship between serum TSH and serum free T4 by direct equilibrium dialysis is altered in patients with nonthyroidal illnesses compared to normal euthyroid subjects and patients with primary hypothyroidism or non-pituitary hyperthyroidism (5). As a result, during nonthyroidal illnesses serum TSH concentrations may no longer provide an endogenous bioassay of the overall free thyroid hormone status. Serum TSH alterations in euthyroid patients with nonthyroidal illnesses include 1) transiently reduced or elevated basal TSH values, 2) blunted TSH response to TRH, 3) diminished or absent diurnal rhythms of TSH, and 4) altered TSH glycosylation and bioactivity (4,5). Free T4 values in patients with nonthyroidal illnesses are highly method dependent (5-7). Methods that measure free T4 on undiluted serum samples will best reflect in vivo conditions. However, currently these methods are not available for clinical use (5-7). Methods using diluted serum samples underestimate free T4 concentrations in proportion to the dilution factor when T4 binding inhibitors are present, as in the low T4 state of nonthyroidal illness and with salicylate addition to normal sera (6), for example. In non- equilibrium dialysis methods, all weakly bound inhibitors of T4 binding to serum carrier proteins are diluted. In contrast, equilibrium dialysis methods dilute dialyzable inhibitors to a greater extent than nondialyzable inhibitors (7). Dilution of small inhibitors such as 3-carboxy- 4-methyl-5-propyl-2-furan propanoic acid (CMPF), indoxyl sulfate, and hippuric acid, which accumulate in patients with end-stage renal failure (2), may result in falsely low free T4 levels by direct equilibrium dialysis, i.e. with direct measurement of free T4 in the dialyzate by RIA, as well as by non-dialysis methods (8). Indeed, in patients with end-stage renal failure, free T4 values were below the reference range in 27% of patients when measured by direct equilibrium dialysis (Nichols Institute/Nihon Medi + Physics, Japan) and in 50% when measured by Amerlex-MAB FT4 kit (Johnson & Johnson Clinical Diagnostics, Bucks, UK)(8). This contrasts to the normal free T4 values by these two methods in the majority of non-renal patients with the low T4 state of nonthyroidal illnesses (6,9). This in vitro reduction in free T4 levels by direct equilibrium dialysis may be greatest in patients with the highest concentrations of inhibitors, such as critically ill patients with the lowest serum total T4 concentrations (6), and in patients with end-stage renal failure who have high concentrations of dialyzable inhibitors (2,3,8). These in vitro artifacts of free T4 measurements by direct equilibrium dialysis may also account in part for the low TSH and low free T4 values observed in some critically ill patients (10). |
