What is the role of deiodination in the pathophysiology of euthyroid sick syndrome?

Updated: Apr 27, 2017
  • Author: Serhat Aytug, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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Answer

Peripheral deiodination of T4 to T3 is impaired, largely secondary to decreased activity of type 1 deiodinase enzyme, which deiodinates T4 to T3. Diminished enzyme activity accounts for decreased deiodination of T4 to T3.

Type 1 deiodinase enzyme deiodinates T4 to T3. Diminished enzyme activity results in decreased deiodination of T4 to T3. The role of type 1 deiodinase in the pathogenesis of NTIs has been extensively studied, as type 1 deiodinase is involved in the production of serum T3 (which is decreased during illness) via outer-ring deiodination and in the clearance of rT3 (leading to increased rT3 concentrations during illness in humans) via inner-ring deiodination. Type 1 deiodinase is localized in the plasma membrane and largely expressed in liver, kidney, thyroid, and pituitary. It is positively regulated by T3. Nonthyroidal illness induces a marked decrease in liver type 1 deiodinase mRNA expression and its activity in critically ill patients and in various NTI animal models. [3]

Type 2 deiodinase enzyme is localized in the endoplasmic reticulum of the cells and deiodinates T4 into biologically active T3. Type 2 deiodinase is the main enzyme involved in the production of tissue T3 and is largely involved in local thyroid hormone metabolism. Type 2 deiodinase is negatively regulated by thyroid hormone, both pretranscription and posttranscription, as T3 down-regulates type 2 deiodinase mRNA expression, while T4 and rT3 (which are both substrates for type 2 deiodinase) affect type 2 deiodinase activity via increasing type 2 deiodinase ubiquitination and subsequent proteasomal degradation. [4]

Multiple studies have demonstrated the major role of type 2 deiodinase in the central part of hypothalamic-pituitary-thyroid axis that is altered during illness. The unresponsiveness of the hypothalamic-pituitary-thyroid axis to low serum thyroid hormone levels has been suggested to be mediated by increased production of T3 via elevated type 2 deiodinase activity in tanycytes (specialized cells that the wall of the third ventricle), as mice lacking the TR-beta do not show an illness-induced hypothalamic TRH decrease . In addition, global type 2 deiodinase knockout mice do not show a suppression of TRH upon lipopolysaccharide stimulation. [3]

Inflammation-induced type 2 deiodinase up-regulation in the hypothalamus was found to be independent of the fall in serum thyroid hormone concentrations, in contrast to type 2 deiodinase expression in other brain areas, such as the cortex and pituitary. [5]

A role for inflammatory cytokines was suggested, as lipopolysaccharide administration results in a rapid increase of pro-inflammatory cytokines, including TNF-alpha, IL-1, and IL-6. The type 2 deiodinase promoter contains nuclear factor (NF)–kappa-B–responsive elements and is thus sensitive to inflammatory signal transduction pathways. [6, 7] NF-kappa-B is therefore seen as a possible mediator of the inflammation-induced increase in type 2 deiodinase expression in the hypothalamus.

Type 3 deiodinase is localized in the plasma membrane of cells and can be considered as the major thyroid hormone–inactivating enzyme, as it catalyzes inner-ring deiodination of both T4 and T3, resulting in the production of biologically inactive rT3 and rT2 . Type 3 deiodinase is highly expressed in the placenta during fetal development and protects the fetus from overexposure of T3. In the adult, type 3 deiodinase is expressed in brain neurons, liver, and some parts of the immune system, although physiological levels are considerably low. [8]

Illness influences type 3 deiodinase expression and activity in the liver, but the results from animal studies vary. Although liver type 3 deiodinase mRNA expression and activity levels are decreased during acute and chronic inflammation and sepsis, hepatic type 3 deiodinase expression and activity are increased in rabbits with prolonged critical illness. Slightly increased type 3 deiodinase activity is also observed in the livers of severely ill patients.

During prolonged critical illness, decreased food intake might be an important factor in regulating liver deiodinases. Fasting for 36  hours or reducing food intake by 50% for 3 weeks results in pronounced increase of type 3 deiodinase expression and activity in the liver. As prolonged illness is associated with persistently diminished food intake, the differences in type 3 deiodinase activity between the several illness models might be explained by the dominant role of reduced food intake. One of the major hormones that are sensitive to food intake is leptin. In the setting of acute and chronic inflammation, serum leptin levels are higher via IL-1 beta, whereas serum leptin levels are diminished in prolonged critical illness. The reduction in leptin levels is known to be important for the increase in type 3 deiodinase activity during fasting in mice and thus might also be important for the regulation of type 3 deiodinase during illness. [3]

An alternative explanation is that reduced tissue uptake of T4 secondary to deficiency of cytosolic cofactors (eg, nicotinamide adenine dinucleotide phosphate [NADPH], glutathione) results in decreased substrate for type 1 deiodinase enzyme. Type 1 deiodinase is a selenoprotein; because selenium deficiency is common in critically ill patients, some propose that selenium deficiency may contribute to type 1 deiodinase malfunction. Cytokines (eg, IL-1 beta, TNF-alpha, interferon-gamma) decrease type 1 deiodinase messenger RNA (mRNA) in vitro. Type 1 deiodinase does not exist in the pituitary, where T3 levels are within the reference range, because of enhanced local deiodination. This indicates that an enhancement of intrapituitary T4 to T3 conversion exists due to pituitary-specific and brain-specific type 2 deiodinase.


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