Thyroid hormone receptors are down-regulated in skeletal muscle of patients with non-thyroidal illness syndrome secondary to non-septic shock

Lado-Abeal, Joaquín; Romero, Amparo; Castro‐Piedras, Isabel; Rodriguez-Perez, Alfonso; Álvarez-Escudero, Julián

doi:10.1530/eje-10-0376

Cited by 25 publications

(20 citation statements)

References 48 publications

(61 reference statements)

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“…Characteristic patterns of NTIS have been described in a multitude of acute and chronic somatic illnesses including states of shock (284), circulatory arrest (285, 286), respiratory failure (65), community-acquired pneumonia (287), sepsis (288), chronic respiratory (289, 290) and cardiovascular (61, 64, 66, 291, 292) disease, renal failure (293–298), COPD (289), gastrointestinal diseases (299–301), autoimmune diseases (71, 302, 303), and cancer (130, 290, 304). Phenotypes of NTIS with high and high-normal FT4 concentrations have been described in dementia and frailty in elderly persons (305).…”

Section: Thyroid Allostasis In Various Physiological and Pathologicalmentioning

confidence: 99%

Thyroid Allostasis–Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming

Hoermann²,

et al. 2017

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The hypothalamus–pituitary–thyroid feedback control is a dynamic, adaptive system. In situations of illness and deprivation of energy representing type 1 allostasis, the stress response operates to alter both its set point and peripheral transfer parameters. In contrast, type 2 allostatic load, typically effective in psychosocial stress, pregnancy, metabolic syndrome, and adaptation to cold, produces a nearly opposite phenotype of predictive plasticity. The non-thyroidal illness syndrome (NTIS) or thyroid allostasis in critical illness, tumors, uremia, and starvation (TACITUS), commonly observed in hospitalized patients, displays a historically well-studied pattern of allostatic thyroid response. This is characterized by decreased total and free thyroid hormone concentrations and varying levels of thyroid-stimulating hormone (TSH) ranging from decreased (in severe cases) to normal or even elevated (mainly in the recovery phase) TSH concentrations. An acute versus chronic stage (wasting syndrome) of TACITUS can be discerned. The two types differ in molecular mechanisms and prognosis. The acute adaptation of thyroid hormone metabolism to critical illness may prove beneficial to the organism, whereas the far more complex molecular alterations associated with chronic illness frequently lead to allostatic overload. The latter is associated with poor outcome, independently of the underlying disease. Adaptive responses of thyroid homeostasis extend to alterations in thyroid hormone concentrations during fetal life, periods of weight gain or loss, thermoregulation, physical exercise, and psychiatric diseases. The various forms of thyroid allostasis pose serious problems in differential diagnosis of thyroid disease. This review article provides an overview of physiological mechanisms as well as major diagnostic and therapeutic implications of thyroid allostasis under a variety of developmental and straining conditions.

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Section: Thyroid Allostasis In Various Physiological and Pathologicalmentioning

confidence: 99%

Thyroid Allostasis–Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming

Hoermann²,

et al. 2017

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“…patients, we showed that decreased THRB mRNA expression levels were associated with decreased protein level (Lado-Abeal et al 2010). MCT8 is so far the best-characterized TH transporter.…”

Section: Discussionmentioning

confidence: 78%

Septic shock non-thyroidal illness syndrome causes hypothyroidism and conditions for reduced sensitivity to thyroid hormone

Castro¹,

Quisenberry²,

Calvo³

et al. 2013

Journal of Molecular Endocrinology

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Non-thyroidal illness syndrome (NTIS) is part of the neuroendocrine response to stress, but the significance of this syndrome remains uncertain. The aim of this study was to investigate the effect of lipopolysaccharide (LPS)-induced NTIS on thyroid hormone (TH) levels and TH molecular targets, as well as the relationship between septic shock nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation and TH receptor b (THRB) gene expression at a multi-tissue level in a pig model. Prepubertal domestic pigs were given i.v. saline or LPS for 48 h. Serum and tissue TH was measured by chemiluminescence and RIA. Expression of THRs and cofactors was measured by real-time PCR, and deiodinase (DIO) activity was measured by enzyme assays. Tissue NF-kB nuclear binding activity was evaluated by EMSA. LPS-treated pigs had decreased TH levels in serum and most tissues. DIO1 expression in liver and kidney and DIO1 activity in kidney decreased after LPS. No changes in DIO2 activity were observed between groups. LPS induced an increase in hypothalamus, thyroid, and liver DIO3 activity. Among the other studied genes, monocarboxylate transporter 8 and THRB were the most commonly repressed in endotoxemic pigs. LPS-induced NF-kB activation was associated with a decrease in THRB gene expression only in frontal lobe, adrenal gland, and kidney cortex. We conclude that LPS-induced NTIS in pigs is characterized by hypothyroidism and tissue-specific reduced TH sensitivity. The role of NF-kB in regulating THRB expression during endotoxemia, if any, is restricted to a limited number of tissues.

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“…On the other hand, desensitization has been suggested as a possible adaptation against exposure to excessive TH concentrations. For example, decreased TRa expression was reported in the heart of mice with myocardial infarction (29), as well as in skeletal muscle from patients with non-thyroidal illness syndrome (28). To the best of the authors' knowledge, this is the first study to evaluate TRb protein expression after acute versus chronic T3 treatment in vivo.…”

Section: Adaptations During Hyperthyroidism and Withdrawal 857mentioning

confidence: 89%

Changes in Hepatic TRβ Protein Expression, Lipogenic Gene Expression, and Long-Chain Acylcarnitine Levels During Chronic Hyperthyroidism and Triiodothyronine Withdrawal in a Mouse Model

Ohba

Sinha

Singh

et al. 2017

Thyroid

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Background: Thyroid hormone (TH) has important roles in regulating hepatic metabolism. It was previously reported that most hepatic genes activated by a single triiodothyronine (T3) injection became desensitized after multiple injections, and that approximately 10% of target genes did not return to basal expression levels after T3 withdrawal, despite normalization of serum TH and thyrotropin (TSH) levels. To determine the possible mechanism(s) for desensitization and incomplete recovery of hepatic target gene transcription and their effects on metabolism, mRNA and/or protein expression levels of key regulators of TH action were measured, as well as metabolomic changes after chronic T3 treatment and withdrawal. Methods: Adult male mice were treated with daily injections of T3 (20 lg/100 g body weight) for 14 days followed by the cessation of T3 for 10 days. Livers were harvested at 6 hours, 24 hours, and 14 days after the first T3 injection, and at 10 days after withdrawal, and then analyzed by quantitative reverse transcription polymerase chain reaction, Western blotting, and metabolomics. Results: Although TH receptor (TRa and TRb) mRNAs decreased slightly after chronic T3 treatment, only TRb protein decreased before returning to basal expression level after withdrawal. The expression of other regulators of TH action was unchanged. TRb protein expression was also decreased in adult male monocarboxylate transporter-8 (Mct8)-knockout mice, an in vivo model of chronic intrahepatic hyperthyroidism. Previously, increased hepatic long-chain acylcarnitine levels were found after acute TH treatment. However, in this study, long-chain acylcarnitine levels were unchanged after chronic T3, and paradoxically increased after T3 withdrawal. Pathway analyses of the previous microarray results showed upregulation of lipogenic genes after acute T3 treatment and withdrawal. Phosphorylation of acetyl-CoA carboxylase also decreased after T3 withdrawal. Conclusions: Decreased hepatic TRb protein expression occurred after chronic T3 exposure in adult male wild-type and Mct8-knockout mice. Gene array pathway and metabolomics analyses showed abnormalities in hepatic lipogenic gene expression and acylcarnitine levels, respectively, after withdrawal, despite normalization of serum TSH and TH levels. These findings may help explain the variable clinical presentations of some patients during hyperthyroidism and recovery, since TRb protein, target gene expression, and metabolic adaptive changes can occur in individual tissues without necessarily being reflected by circulating TH and TSH concentrations.

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Thyroid hormone receptors are down-regulated in skeletal muscle of patients with non-thyroidal illness syndrome secondary to non-septic shock

Cited by 25 publications

References 48 publications

Thyroid Allostasis–Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming

Thyroid Allostasis–Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming

Septic shock non-thyroidal illness syndrome causes hypothyroidism and conditions for reduced sensitivity to thyroid hormone

Changes in Hepatic TRβ Protein Expression, Lipogenic Gene Expression, and Long-Chain Acylcarnitine Levels During Chronic Hyperthyroidism and Triiodothyronine Withdrawal in a Mouse Model

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