Beyond Low Plasma T3: Local Thyroid Hormone Metabolism during Inflammation and Infection

Abstract

Decreased serum thyroid hormone concentrations in severely ill patients were first reported in the 1970s, but the functional meaning of the observed changes in thyroid hormone levels, together known as nonthyroidal illness syndrome (NTIS), remains enigmatic. Although the common view was that NTIS results in overall down-regulation of metabolism in order to save energy, recent work has shown a more complex picture. NTIS comprises marked variation in transcriptional and translational activity of genes involved in thyroid hormone metabolism, ranging from inhibition to activation, dependent on the organ or tissue studied. Illness-induced changes in each of these organs appear to be very different during acute or chronic inflammation, adding an additional level of complexity. Organ- and timing-specific changes in the activity of thyroid hormone deiodinating enzymes (deiodinase types 1, 2, and 3) highlight deiodinases as proactive players in the response to illness, whereas the granulocyte is a novel and potentially important cell type involved in NTIS during bacterial infection. Although acute NTIS can be seen as an adaptive response to support the immune response, NTIS may turn disadvantageous when critical illness enters a chronic phase necessitating prolonged life support. For instance, changes in thyroid hormone metabolism in muscle during critical illness may be relevant for the pathogenesis of myopathy associated with prolonged ventilator dependence. This review focuses on NTIS as a timing-related and organ-specific response to illness, occurring independently from the decrease in serum thyroid hormone levels and potentially relevant for disease progression.

Thyroid Function and Dysfunction in Term and Premature Equine Neonates

“…A variety of mechanisms have been described to explain the hormonal changes in NTIS. As recently reviewed,34, 35 NTIS likely results from a combination of central hypothyroidism, altered local TH metabolism, and an acute phase response that leads to decreased TH‐binding proteins. TRH neurons in the hypothalamus appear to play a key role in altering the set point of the hypothalamic‐pituitary‐thyroid axis.…”

Thyroid hormone metabolism in innate immune cells

“…Increased D3 activity therefore results in decreased intracellular levels of T 3 together with the production of free iodide (I − ). One hypothesis explaining the role of D3 in microbial killing is that the iodide produced by D3 is utilized by MPO together with hydrogen peroxidase (H 2 O 2 ) to generate hypoiodite (IOH), a toxic compound that is capable of killing bacteria (Klebanoff 1967, Boelen et al 2011. The reduction of intracellular T 3 levels could theoretically also result in altered gene transcription, but no TH-responsive genes have been found in neutrophils yet.…”

“…We have previously suggested as a possible explanation that the iodide produced by D3 could be used by the MPO system together with H 2 O 2 to generate hypoiodite, a toxic compound that is capable of killing bacteria (Fig. 1) (Klebanoff 1967, Boelen et al 2011.…”

Physiological responses of growing pigs to high ambient temperature and/or inflammatory challenges

“…Accordingly, Castro et al (2013) reported that the continuous intravenous infusion of 3.5 to 5.0 µg of LPS kg −1 BW per hour for 48 h induced a reduction in T 3 and T 4 levels in serum and in specific tissues, including heart, liver, kidney cortex, and skeletal muscle. Theoretically, as thyroid hormones play an important role in stimulating metabolic rate, their down-regulation would contribute to reduce the energy expenditure by non-immune tissues and then spare energy to support the immune response (Fliers et al, 1997;Boelen et al, 2011).…”