What is the role of triiodothyronine and reverse triiodothyronine in the pathophysiology of euthyroid sick syndrome?

Updated: Aug 28, 2020
  • Author: Serhat Aytug, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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In healthy people, 20% of T3 production comes from thyroidal secretion and 80% from peripheral deiodination from T4. In NTI, thyroidal production of T3 is normal, but the peripheral production of T3 is decreased. The fractional rate of transport of T3 to tissues is unaltered. Production of T3 is decreased, but its clearance is unchanged. Production of rT3 is unchanged, while its clearance is diminished.

In rat hepatocytes, rT3 and T4 have been demonstrated to be transported in the same mechanism, which implies that a diminished transport of rT3 to the liver would accompany inhibition of transport of T4 to the liver (eg, as in during calorie deprivation). Because the liver is the main site of disposal of T3, this leads to a diminished metabolic clearance rate of rT3 and T4.

Another explanation could be reduced 5'-deiodinase tissue activity, resulting in decreased T3 production from T4 and reduced breakdown of rT3. The decreased production of T3 during early and late starvation has been explained as either a diminished activity of the enzyme (deiodinase) itself or a deficiency of cytosolic cofactors, such as NADPH or glutathione. Specific deiodinative enzymes, 3 of which have been identified, affect deiodination of iodothyronines. Type 1 deiodinase is present in the liver, kidney, and thyroid and affects both 5 and 5' deiodination of T3. Type 2 deiodinase is present in the brain, pituitary, and brown adipose tissue and is active only in 5' deiodination. Type 3 deiodinase is found particularly in the brain, skin, and placenta, and it deiodinates iodothyronines at the 5 locations.

Both type II and type III enzymes are insensitive to 6-propylthiouracil (PTU). Alterations of serum thyroid hormone parameters in cases of calorie deprivation exhibit similarities to the changes observed in NTI. Fasted animals had decreased 5'-deiodinase activity. The activity of type 1 deiodinase is inhibited by 6-PTU. Because it is a selenoprotein and selenium deficiency is common in critically ill patients, selenium deficiency also may contribute to its malfunction.

Cytokines, such as IL-1 beta, TNF-alpha, and interferon-gamma, decrease type 1 deiodinase mRNA in vitro. Infusion of TNF-alpha decreases serum T3 and increases rT3. Soluble TNF-alpha, soluble TNF-alpha receptor, soluble IL-2 receptor antagonist, and IL-6 are inversely correlated with serum T3 levels. The elevations of soluble TNF-alpha receptor and IL-6 were independent determinants of serum T3 and accounted for 35% and 14%, respectively, of the change in T3. These cytokine changes can be concluded to occur concomitantly with changes in T3 and may play a pathogenic role through mechanisms that are not clearly defined. The increase of endogenous cortisol during illness apparently is not involved in inhibition of type I deiodinase.

Using an adenovirus model in mice hepatocyte primary cultures, it was demonstrated that forced expression of steroid receptor co-activator 1 (SRC-1) prevented the cytokine induced inhibition of type 1 deiodinase activity, suggesting the involvement of receptor co-activators in the nonthyroidal illness. [10]

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