Pathogenesis
  Altered serum thyroid hormone concentrations in nonthyroidal disorders reflect the net effect of multiple disturbances of thyroid hormone metabolism. These include transient changes in 1) the hypothalamic-pituitary-thyroid gland axis, 2) hormone binding in serum, 3) hormone uptake into tissues, 4) hormone clearance, production and degradation rates, as well as 5) receptor and post- receptor events (1-3).

Reduced total T4 concentrations are primarily due to impaired T4 binding to serum carrier proteins, presumably by circulating inhibitors (Table 1) (2,3). These inhibitors may also interfere with in vitro free T4 assays, inhibit T4 uptake by rat and human hepatocytes (3), and impair T4 transfer from serum to tissues in vivo in humans (3).


Table 1: Potential serum binding inhibitors in nonthyroidal illnesses

Uremic serum Non-uremic serum Pharmacological agents 
CMPF NEFA/albumin Salsalate/salicylate* 
Indoxyl sulfate* Bilirubin/albumin Furosemide 
Hippuric acid* Oleic acid Heparin/NEFA 
Interleukin-1 beta Interleukin-6 Some NSAIDs 
Tumor necrosis factor Tumor necrosis factor Dilantin 
* Dialyzable in vitro 
NEFA = non-esterified fatty acids  NSAIDs = nonsteroidal anti-inflammatory drugs such as fenclofenac and mefenamic acid 


T4 production and degradation rates are within the normal range of values in patients with nonthyroidal illnesses (1-3), consistent with normal TSH values in most patients and normal thyroid gland function1–3. Free T4 values determined by direct equilibrium dialysis are frequently increased in nonthyroidal illnesses without TSH being suppressed (Figure 2). These elevated free T4 values may be secondary to reduced serum clearance rates of T4 (1,2). Compared to healthy euthyroid subjects with reduced serum T4 binding, patients with nonthyroidal disorders and decreased serum T4 binding have impaired fractional transfer rates of T4 from blood to tissues (1-3). Sick sera impairs T4 uptake into perfused rat liver and into rat and human hepatocytes (3). Reduced T4 uptake into tissues may lower T4 clearance rates and, thereby increase free T4 values by direct equilibrium dialysis in nonthyroidal illnesses and with caloric deprivation (1-3). Decreased total and free T3 levels in patients with nonthyroidal illnesses and caloric deprivation may primarily reflect reduced T3 production from T4 in extrathyroidal tissues (1-3). Reduced T3 binding to serum carrier proteins may play a lesser role. Decreased T3 production from T4 may be secondary to impaired T4 uptake into tissues like liver, rather than to decreased 5'-de-iodinase activity (3). Circulating inhibitors in sera from sick patients decrease T4 uptake by rat and human hepatocytes and by perfused rat liver resulting in reduced T4 availability for T3 production (3). In fasted subjects and with fructose administration, reduced T4 uptake into liver may relate to reduced ATP levels which, in turn, may impair the active transport of T4 into tissues (3). Thus, a number of factors may impair T4 uptake into tissues like liver and decrease T4 availability for T3 production in patients with nonthyroidal illnesses (3).

In patients with nonthyroidal disorders, fractional T4 transfer rates from serum to rapidly equilibrating tissues like liver are lowest in the most severely ill patients, who also have the highest free fractions of T4 by equilibrium dialysis (2). In contrast, in healthy euthyroid patients, fractional T4 transfer rates from serum to rapidly equilibrating tissues are highest in those with the highest free fractions of T42. Both T4 binding to serum carrier proteins and T4 fractional transfer rates from serum to rapidly equilibrating tissues may be reduced by circulating inhibitors in nonthyroidal disorders (3).

The effects of reduced serum T4 binding to serum carrier proteins on fractional transfer rates of T4 from serum to rapidly equilibrating tissues may be accounted for by determining the ratio of these two parameters. The ratio of fractional T4 transfer rates from serum to rapidly equilibrating tissues and free fractions of T4 in sera is directly correlated with T3 production rates in nonthyroidal disorders and altered binding states (Figure 5).


Figure 5:



Relationship between the ratio of fractional transfer rate of T4 between serum and rapidly equilibrating tissues like liver, to altered T4 binding to serum carrier proteins as indicated by the free fraction of T4 by equilibrium dialysis, and T3 production rates. Mean data are from patients with critical nonthyroidal illnesses, fasting, ethanol withdrawal, and healthy euthyroid subjects with altered T4 binding states, expressed as percent of the normal mean.

Data from EM Kaptein (2) and EM Kaptein (1).


In other words, critically ill patients have the highest free fractions of T4, the lowest T4 fractional transfer rates, and the lowest T3 production rates, which may reflect the highest concentration of circulating inhibitors (3). These findings are consistent with in vitro findings that sick sera may impair T4 uptake into liver, which may be rate limiting and reduce T3 production from T4 in nonthyroidal disorders (3).

Caution must be used in interpreting T3 production and degradation rates determined from serum kinetic studies in vivo (12). Since T3 is primarily produced and degraded in extrathyroidal tissues, T3 can be produced from T4 and degraded without entering the circulation. Thus, total body production and degradation rates of T3 may be underestimated when determined from serum tracer studies in normal subjects as well as in patients with nonthyroidal illnesses or with caloric deprivation.

Elevated total and free reverse T3 concentrations in patients with nonthyroidal illnesses and with caloric deprivation are primarily due to impaired reverse T3 clearance rates, since reverse T3 production rates from T4 appear to be normal (1-3). Decreased reverse T3 serum clearance rates in nonthyroidal illnesses appear to reflect the net effect of impaired reverse T3 fractional transfer rates from serum to tissue sites of degradation such as liver, and decreased reverse T3 binding by serum carrier proteins (1-3). Normal reverse T3 production rates from T4 in nonthyroidal disorders, suggests that free T4 availability to tissues producing reverse T3 is normal (1-3). However, as with T3 , reverse T3 production and degradation primarily occurs in tissues and, thus, total body reverse T3 production and degradation rates may be underestimated by serum tracer kinetic studies in vivo.

If T4 entry into tissues is rate limiting for reverse T3 production, as it may be for T3 production, normal reverse T3 production rates in nonthyroidal disorders suggest normal T4 entry into reverse T3 producing tissues, which therefore, may differ from T3 producing tissues, and may be extrahepatic1–3. Normal reverse T3 concentrations in patients with acute or chronic renal failure may relate to normal clearance and production rates, while reduced reverse T3 levels in patients with nephrotic syndrome appear to be secondary to impaired reverse T3 production rates (2).

In patients dying of severe nonthyroidal illnesses, tissue levels of total T3 were normal in heart and skeletal muscle but reduced in cerebral cortex, hypothalamus, pituitary, liver, kidney, and lung, while total T4 levels were normal in cerebral cortex but reduced in liver, compared to tissues of trauma victims (13). However, total tissue T3 and T4 content may not reflect thyroid hormone availability to nuclear sites of action any more than total serum thyroid hormone levels reflect free hormone available for uptake into tissues. Tissue effects of T3 are mediated by T3 nuclear receptor proteins, which appear to be normal in liver tissues from patients with chronic liver diseases, as are the expression of thyroid hormone-regulated mRNAs encoding T4-binding globulin, sex hormone-binding globulin, cortisol-binding globulin, and transthyretin (14). These findings indicate that free T4 and T3 availability to tissues may be normal and that patients with nonthyroidal illnesses may indeed be euthyroid.

Serum TSH levels may transiently decrease during the first few days of critical illness (8). Serum TSH bioactivity was increased in 64% of critically ill euthyroid patients (7), and may relate to transiently decreased TSH sialylation (8). TSH bioactivity correlated inversely with total T4, total T3, and Gammacoat free T4 (Travenol, USA) but not with serum TSH levels, suggesting that more severely ill patients with lower total T4 and total T3 values, may have more bioactive TSH7. Interestingly, free T4 estimates by direct equilibrium dialysis are typically normal or elevated in critically ill patients, and have a direct, rather than an inverse relationship, with serum TSH concentrations (15). These latter findings could also be interpreted to indicate a state of T4 resistance in severe nonthyroidal illnesses (1,2).

In patients with chronic renal failure, 10% of serum TSH values may be above the normal range in the absence of hypothyroidism (16). TSH carbohydrate branching and sialylation may be altered in these patients, while bioactivity may be normal (16). As patients begin to recover from acute nonthyroidal illnesses, serum TSH levels may rise, in some instances, to hypothyroid levels, as total T4, free T4, and total T3 levels return to normal (2,3). These findings may reflect normalization of T4 binding to serum carrier proteins resulting in transient decreases in ambient free T4 levels, increased T4 transport into tissues for T3 deiodination, perhaps transiently increased sialylation and reduced bioactivity of TSH, as well as decreased hypothalamic-pituitary suppression with caloric replacement and decreased glucocorticoid responses to stress (1-3). Additional alterations of TSH in nonthyroidal illnesses include blunted TSH responses to TRH, and altered diurnal rhythms (1-3,16). The clinical significance of these findings remains to be elucidated.