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Cited by 82Thyroid Disorders and TreatmentsAdrenal Hormones and DisordersGrowth Hormone and Insulin-like Growth Factors

Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness

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Mebis, Liese, Debaveye, Yves, Ellger, Björn, Derde, Sarah, Ververs, Eric-Jan, Langouche, Lies, Darras, Veerle M, Fliers, Eric +2 more·2009·Critical Care
DOI 10.1186/cc8043PMC PMC2784366
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Abstract

Introduction: Prolonged critically ill patients reveal low circulating thyroid hormone levels without a rise in thyroid stimulating hormone (TSH). This condition is labeled "low 3,5,3'-tri-iodothyronine (T 3) syndrome" or "nonthyroidal illness syndrome (NTI)" or "euthyroid sick syndrome". Despite the low circulating and peripheral tissue thyroid hormone levels, thyrotropin releasing hormone (TRH) expression in the hypothalamus is reduced and it remains unclear which mechanism is responsible. We set out to study whether increased hypothalamic T 3 availability could reflect local thyrotoxicosis and explain feedback inhibition-induced suppression of the TRH gene in the context of the low T 3 syndrome in prolonged critical illness. Methods: Healthy rabbits were compared with prolonged critically ill, parenterally fed animals. We visualized TRH mRNA in the hypothalamus by in situ-hybridization and measured mRNA levels for the type II iodothyronine diodinase (D2), the thyroid hormone transporters monocarboxylate transporter (MCT) 8, MCT10 and organic anion co-transporting polypeptide 1C1 (OATP1C1) and the thyroid hormone receptors α (TRα) and β (TRβ) in the hypothalamus. We also measured the activity of the D2 and type III iodothyronine deiodinase (D3) enzymes. Results: In the hypothalamus of prolonged critically ill rabbits with low circulating T3 and TSH, we observed decreased TRH mRNA, increased D2 mRNA and increased MCT10 and OATP1C1 mRNA while MCT8 gene expression was unaltered as compared with healthy controls. This coincided with low hypothalamic thyroxine (T 4) and low-normal T 3 concentrations, without a change at the thyroid hormone receptor level. Conclusions: Although expression of D2 and of the thyroid hormone transporters MCT10 and OATP1C1 were increased in the hypothalamus of prolonged critical ill animals, hypothalamic T 4 and T 3 content or thyroid hormone receptor expression were not elevated. Hence, decreased TRH gene expression, and hereby low TSH and T3 during prolonged critical illness, is not exclusively brought about by hypothalamic thyrotoxicosis, and infer other TRH suppressing factors to play a role.

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  • Illness results in increased hypothalamic DIO2 mRNA expression and activity while hypothalamic DIO3 decreases.

    “Illness results in increased DIO2 mRNA expression and activity [12, 15–17] while hypothalamic DIO3 decreases [18, 19].”

    From An update on non-thyroidal illness syndrome (2021) · cites this paper as [12]

    The Results report increased hypothalamic D2 mRNA in prolonged critically ill rabbits. D2 activity only tended to increase and the difference was not significant; D3 activity did not decrease, instead tending to be higher. Thus the paper supports the mRNA portion but not the activity or D3 portions. (LLM, conf=0.90)

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  • The alterations in hypothalamic MCT10 and OATP1C1 expression during critical illness are unrelated to local tissue T3 concentrations and their functional consequences are unknown at present.

    “Of note, these alterations are unrelated to local tissue T3 concentrations and their functional consequences are unknown at present [12].”

    From An update on non-thyroidal illness syndrome (2021) · cites this paper as [12]

    The Results report increased hypothalamic MCT10 and OATP1C1 expression in critically ill rabbits, while local T3 did not differ significantly from controls. That does not establish that transporter expression is unrelated to T3 concentrations. The Introduction says the transporters’ role in hypothalamic feedback during critical illness is unknown, supporting the statement about uncertain functional consequences. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Hypothalamic TR mRNA expression does not change dramatically during NTIS, but the increase in hypothalamic DIO2 and decrease in hypothalamic DIO3 observed during acute inflammation is exaggerated in mice lacking TRβ.

    “Hypothalamic TR mRNA expression does not change dramatically during NTIS [12], but the increase in hypothalamic DIO2 and decrease in hypothalamic DIO3 observed during acute inflammation is exaggerated in mice lacking TRβ [18].”

    From An update on non-thyroidal illness syndrome (2021) · cites this paper as [12]

    The Results report no significant difference in hypothalamic TRα1, TRα2, TRβ1 or TRβ2 expression between prolonged critically ill rabbits and healthy controls. This supports the [12] clause for that rabbit model, but the unqualified wording extends the finding to NTIS generally. The separate claim about TRβ-deficient mice is attributed to [18], not this source. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Reduced hypothalamic TRH expression, portal serum TRH and pituitary TSH content have been observed both in NTIS patients and NTIS animal models.

    “Indeed, reduced hypothalamic TRH expression, portal serum TRH and pituitary TSH content have been observed both in NTIS patients [65] and NTIS animal models [12, 19, 66, 67].”

    From An update on non-thyroidal illness syndrome (2021) · cites this paper as [12]

    The Results (page unavailable) report markedly reduced hypothalamic TRH expression in critically ill rabbits and decreased circulating TSH. The paper does not report portal-serum TRH or pituitary TSH content; those measures cannot be inferred from circulating TSH. The separate citation [65] is attached to the patient finding, so this verdict concerns the animal-model claim. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Prolonged critical illness results in low circulating T4, T3, and TSH and decreased TRH mRNA in the PVN.

    “prolonged critical illness results in low T 4 , T 3 , and TSH concentration in the circulation and decreased TRH mRNA level in the PVN (209, 210).”

    From Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions (2014) · cites this paper as [210]

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Authors
Mebis, L., Debaveye, Y., Ellger, B., Derde, S., Ververs, E.-J., Langouche, L., Darras, V. M., Fliers, E., Visser, T. J., & Van den Berghe, G.
Affiliations
  • KU Leuven (BE)
  • Erasmus MC (NL)
ORCID
Venue
Critical Care
Publisher
Springer Science and Business Media LLC
Published
2009-09-11
Volume
13
Issue
5
Pages
R147-R147
ISSN
1364-8535 (ISSN-L)
DOI
10.1186/cc8043
PMC
PMC2784366
OpenAlex
W2128933624
Cited by
82
References
35
Citations by year
2025: 1 · 2024: 1 · 2023: 3 · 2022: 10 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 4 · 2016: 7 · 2015: 4 · 2014: 7 · 2013: 7 · 2012: 5
FWCI
5.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Critical Care (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UvA-DARE (University of Amsterdam) (publishedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • Lirias (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • Pure Amsterdam UMC (submittedVersion)
  • RePub (Erasmus University Rotterdam) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • B. Braun-Stiftung
  • Fonds Wetenschappelijk Onderzoek
  • Vlaamse regering
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Keywords
hypothalamic-pituitary-thyroid axis, prolonged critical illness, low T3 syndrome, thyrotropin-releasing hormone, thyroid hormone transporters, MCT10, OATP1C1, MCT8, thyroid hormone receptor, thyrotoxicosis, thyroid-stimulating hormone, rabbit model
MeSH terms
Iodothyronine Deiodinase Type II, Animals, Euthyroid Sick Syndromes, Fluorescence, Hypothalamus, Iodide Peroxidase, Male, Pituitary Gland, Rabbits, RNA, Suppression, Genetic, Thyroid Gland, Thyrotoxicosis, Thyrotropin-Releasing Hormone, Polymerase Chain Reaction, Critical Illness, Sequence Analysis, DNA, Models, Animal, Organic Anion Transporters

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