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Cited by 214Thyroid Disorders and TreatmentsClinical Nutrition and GastroenterologyAdrenal Hormones and Disorders

An update on non-thyroidal illness syndrome

Open access
Fliers, E., Boelen, A.·2021·Journal of Endocrinological Investigation
DOI 10.1007/s40618-020-01482-4PMC PMC8285315
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Abstract

The non-thyroidal illness syndrome (NTIS) was first reported in the 1970s as a remarkable ensemble of changes in serum TH (TH) concentrations occurring in probably any severe illness. Ever since, NTIS has remained an intriguing phenomenon not only because of the robustness of the decrease in serum triiodothyronine (T3), but also by its clear correlation with morbidity and mortality. In recent years, it has become clear that (parenteral) feeding in patients with critical illness should be taken into account as a major determinant not only of NTIS but also of clinical outcome. Moreover, both experimental animal and clinical studies have shown that tissue TH concentrations during NTIS do not necessarily reflect serum low TH concentrations and may decrease, remain unaltered, or even increase according to the organ and type of illness studied. These differential changes now have a solid basis in molecular studies on organ-specific TH transporters, receptors and deiodinases. Finally, the role of inflammatory pathways in these non-systemic changes has begun to be clarified. A fascinating role for TH metabolism in innate immune cells, including neutrophils and monocytes/macrophages, was reported in recent years, but there is no evidence at this early stage that this may be a determinant of susceptibility to infections. Although endocrinologists have been tempted to correct NTIS by TH supplementation, there is at present insufficient evidence that this is beneficial. Thus, there is a clear need for adequately powered randomized clinical trials (RCT) with clinically relevant endpoints to fill this knowledge gap.

AI snapshot

Written from the paper’s full text.

TL;DR

NTIS is a complex, organ- and tissue-specific set of changes in thyroid hormone physiology during illness, not simply low serum thyroid hormone concentrations. Current evidence is insufficient to recommend thyroid hormone treatment, and adequately powered randomized clinical trials with clinically relevant endpoints are needed.

Key findings

  • In an LPS-induced acute illness mouse model, serum T3 and T4 fell only after 24 h, while molecular changes occurred almost simultaneously across the hypothalamus, pituitary, thyroid, and liver.
  • IL-6 knockout mice show a smaller decrease in serum T3 during acute illness; in human volunteers, short-term IL-6 infusion decreased serum TSH, but daily injections over 42 days caused only a modest T3 decrease and transient increases in rT3 and free T4.
  • Tissue thyroid hormone concentrations during NTIS do not necessarily mirror serum levels and may decrease, remain unchanged, or increase depending on organ and illness type, with differential changes in TH transporters, deiodinases, and receptors.
  • There is no clinical evidence to support TH treatment of NTIS in critically ill patients; reported studies were not adequately powered, and normalizing serum TH concentrations does not equal normalizing tissue TH concentrations or local TH action.

Methods

  • Narrative review of experimental animal and clinical studies on NTIS, including human observational data, postmortem tissue studies, and randomized trial subanalyses.
  • Main analysis is a qualitative synthesis of organ-specific thyroid hormone transporters, deiodinases, receptors, inflammatory pathways, nutritional status, and clinical implications.
  • No primary data collection or systematic review methodology is reported.

Limitations

  • Stated: there is insufficient evidence that TH supplementation is beneficial in NTIS, no definitive conclusion about efficacy can be made, and most treatment studies were not adequately powered to detect clinically meaningful differences.
  • Stated: no direct evidence supports the hypothesis that reduced circulating active T3 is a beneficial adaptation, and no solid data answer whether neuroendocrine changes in prolonged critical illness are harmful or should be treated.
  • Evident: as a narrative review, it lacks a systematic search strategy or formal quality appraisal, and it synthesizes heterogeneous animal models, patient populations, and illness stages.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s40618-020-01482-4

Cites

97 of 97 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

58 of 130 cited sources checked · 33 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    TH needs to be taken up in cells by specific transporters including monocarboxylate transporter 8 (MCT8), monocarboxylate transporter 10 (MCT10) and organic anion transporting polypeptide family 1C1 (OATP1C1) to exert its action at the cellular level.

    “In the past two decades it has become clear that TH needs to be taken up in cells by specific transporters including monocarboxylate transporter 8 (MCT8), monocarboxylate transporter 10 (MCT10) and organic anion transporting polypeptide family 1C1 (OATP1C1) to exert its action at the cellular level [1].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [1] Visser WE, Friesema EC, Visser TJ (2011) Minireview: thyroid hormone transporters: the knowns and the unknowns. Mol Endocrinol 25(1):1–14. https://doi.org/10.1210/me.2010-0095 source
  • Premisecitation

    Illness results in marked downregulation of liver DIO1 both in humans and experimental animals.

    “Illness results in marked downregulation of DIO1 both in humans and experimental animals [15, 20, 21].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [15] Boelen A, Kwakkel J, Thijssen-Timmer DC, Alkemade A, Fliers E, Wiersinga WM (2004) Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice. J Endocrinol 182(2):315–323 source

      The Liver and circulation section reports decreased liver D1 mRNA expression and activity after LPS administration in mice, supporting the experimental-animal part of the claim. The paper’s discussion of human illness concerns the hypothalamus, not liver D1, so this source does not support the human part. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [20] Peeters RP, Kester MH, Wouters PJ, Kaptein E, Visser TJ, Van den BG (2005) Increased thyroxine sulfate levels in critically ill patients as a result of a decreased hepatic type I deiodinase activity. J Clin Endocrinol Metab 90(12):6460–6465 source
    • cites [21] Debaveye Y, Ellger B, Mebis L, Darras VM, Van den BG (2008) Regulation of tissue iodothyronine deiodinase activity in a model of prolonged critical illness. Thyroid 18(5):551–560 source
  • Premisecitation

    Lethal bacterial sepsis affects hepatic TH transport only marginally.

    “Unexpectedly, lethal bacterial sepsis affects hepatic TH transport only marginally [7].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] Boelen A, van der Spek AH, Bloise F, de Vries EM, Surovtseva OV, van Beeren M, Ackermans MT, Kwakkel J, Fliers E (2017) Tissue thyroid hormone metabolism is differentially regulated during illness in mice. J Endocrinol 233(1):25–36. https://doi.org/10.1530/JOE-16-0483 source
  • Premisecitation

    The same observation of unaltered UCP3 and myogenin mRNA expression was made in mice with chronic inflammation and bacterial sepsis.

    “The same observation was made in mice with chronic inflammation and bacterial sepsis [7].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [7] Boelen A, van der Spek AH, Bloise F, de Vries EM, Surovtseva OV, van Beeren M, Ackermans MT, Kwakkel J, Fliers E (2017) Tissue thyroid hormone metabolism is differentially regulated during illness in mice. J Endocrinol 233(1):25–36. https://doi.org/10.1530/JOE-16-0483 source

      The “Illness-induced alteration in muscle thyroid hormone metabolism” section reports unchanged muscle Myog (myogenin) mRNA in bacterial sepsis, but higher Myog expression in mice with chronic inflammation—not unchanged expression. The paper does not report UCP3 expression in the passages found (searched for UCP3 with myogenin and both illness models). No page number is available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    In muscle, local conversion of T4 to T3 by DIO2 is important for muscle function both in rodents and in humans.

    “In muscle, local conversion of T4 toT3 by DIO2 is important for muscle function both in rodents and in humans [4, 26, 27].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [4] Hennemann G, Docter R, Friesema EC, de Jong M, Krenning EP, Visser TJ (2001) Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocr Rev 22(4):451–476 source
    • cites [26] Maia AL, Kim BW, Huang SA, Harney JW, Larsen PR (2005) Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans. J Clin Invest 115(9):2524–2533 source

      The section “D2-generated T3 in human skeletal muscle” (page not provided) shows that human skeletal muscle cells convert T4 to T3 through D2. It does not establish that this conversion is important for muscle function, and the cited passages provide no rodent muscle-function finding. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [27] Gereben B, Zeold A, Dentice M, Salvatore D, Bianco AC (2008) Activation and inactivation of thyroid hormone by deiodinases: local action with general consequences. Cell MolLife Sci 65(4):570–590 source
  • May combine two claims. 54
  • Classified as probably not a substantial claim. 32

  • May combine two claims.

    Premisecitation

    High glucocorticoid levels suppress the pituitary response to TRH in man, and glucocorticoid treatment is associated with downregulation of TR neurons in the human PVN.

    “Hypothalamic TRH is also modulated by glucocorticoids, as high glucocorticoid levels suppress the pituitary response to TRH in man [69], while a postmortem study in human hypothalamus showed that glucocorticoid treatment is associated with downregulation of TR neurons in the human PVN [14].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [69] Nicoloff JT, Fisher DA, Appleman MD Jr (1970) The role of glucocorticoids in the regulation of thyroid function in man. J Clin Invest 49(10):1922–1929. https://doi.org/10.1172/JCI106411 source

      The citation to this paper [69] supports the first clause, not the separate postmortem finding cited to [14]. In the Discussion (page unavailable), the paper attributes glucocorticoid suppression to reduced hypothalamic TRF secretion, rather than a suppressed pituitary response to TRF; it also notes that glucocorticoids did not inhibit TRF’s direct action on the rat pituitary. (LLM, conf=0.84)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [14] Alkemade A, Friesema EC, Unmehopa UA, Fabriek BO, Kuiper GG, Leonard JL, Wiersinga WM, Swaab DF, Visser TJ, Fliers E (2005) Neuroanatomical pathways for thyroid hormone feedback in the human hypothalamus. J Clin Endocrinol Metab 90(7):4322–4334 source

      Citation [14] is attached to the claim about glucocorticoid treatment and neurons in the human PVN, not the preceding claim about pituitary response. The Discussion reports low TRH mRNA expression in the PVN of a patient with hyperthyroidism, but our copy does not link that finding to glucocorticoid treatment. Searches for glucocorticoids, cortisol, corticosteroids, and treatment-related downregulation found no passage addressing the attributed association; page numbers were unavailable. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In the hypothalamus, DIO2 is expressed in glial cells and tanycytes and DIO3 is expressed in neurons of the paraventricular nucleus (PVN), supraoptic nucleus (SON) and IFN.

    “In the hypothalamus, DIO2 is expressed in glial cells and tanycytes and DIO3 is expressed in neurons of the paraventricular nucleus (PVN), supraoptic nucleus (SON) and IFN [14].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Alkemade A, Friesema EC, Unmehopa UA, Fabriek BO, Kuiper GG, Leonard JL, Wiersinga WM, Swaab DF, Visser TJ, Fliers E (2005) Neuroanatomical pathways for thyroid hormone feedback in the human hypothalamus. J Clin Endocrinol Metab 90(7):4322–4334 source

  • May combine two claims.

    Premisecitation

    Liver DIO3 is differentially regulated during illness: acute inflammation in mice results in decreased DIO3 levels but prolonged critical illness, both in patients and in rabbits, increases DIO3.

    “Liver DIO3 is differentially regulated during illness: acute inflammation in mice results in decreased DIO3 levels [15] but prolonged critical illness, both in patients and in rabbits, increases DIO3 [21, 22].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [15] Boelen A, Kwakkel J, Thijssen-Timmer DC, Alkemade A, Fliers E, Wiersinga WM (2004) Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice. J Endocrinol 182(2):315–323 source

      The citation to this paper is attached to the claim that acute inflammation decreases liver DIO3 in mice. The Liver and circulation section reports decreased liver D1 expression and activity after LPS, not D3; the RNA isolation and real-time PCR section mentions D3 primers but gives no liver D3 result. Searches for liver D3 and type 3 deiodinase found no passage establishing the claimed decrease. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [21] Debaveye Y, Ellger B, Mebis L, Darras VM, Van den BG (2008) Regulation of tissue iodothyronine deiodinase activity in a model of prolonged critical illness. Thyroid 18(5):551–560 source
    • cites [22] Peeters RP, Wouters PJ, Kaptein E, van Toor H, Visser TJ, Van den Berghe G (2003) Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. J Clin Endocrinol Metab 88(7):3202–3211 source

      The Abstract and Discussion (pages unavailable) report induced liver D3 in critically ill patients, supporting the patient portion of the claim. The paper does not establish that the increase is specific to prolonged illness; the Discussion says the observed differences could not be explained by illness duration. It provides no rabbit evidence for the portion attributed jointly to [21, 22]. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The response of DIO3 to illness might depend on energy status; fasting results in increased liver DIO3 activity in rodents and prolonged illness is associated with diminished food intake.

    “The response of DIO3 to illness might depend on energy status; fasting results in increased liver DIO3 activity in rodents [23, 24] and prolonged illness is associated with diminished food intake [25].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [23] Boelen A, Vos X, Surovtseva O, Belegri E, Saaltink DJ, Vreugdenhil E, Kalsbeek A, Kwakkel J, Fliers E (2012) Leptin administration restores the fasting-induced increase of hepatic type 3 deiodinase expression in mice. Thyroid 22(2):192–199. https://doi.org/10.1089/thy.2011.0289 source
    • cites [24] de Vries EM, van Beeren HC, Ackermans MT, Kalsbeek A, Fliers E, Boelen A (2015) Differential effects of fasting vs. food restriction on liver thyroid hormone metabolism in male rats. J Endocrinol 224(1):25–35. https://doi.org/10.1530/JOE-14-0533 source
    • cites [25] Langouche L, Vander Perre S, Marques M, Boelen A, Wouters PJ, Casaer MP, Van den Berghe G (2013) Impact of early nutrient restriction during critical illness on the nonthyroidal illness syndrome and its relation with outcome: a randomized, controlled clinical study. J Clin Endocrinol Metab 98(3):1006–1013. https://doi.org/10.1210/jc.2012-2809 source

  • May combine two claims.

    Premisecitation

    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].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] Mebis L, Debaveye Y, Ellger B, Derde S, Ververs EJ, Langouche L, Darras VM, Fliers E, Visser TJ, Van den BG (2009) Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness. Crit Care 13(5):R147 source

      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

  • May combine two claims.

    Premisecitation

    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].”
    Quote in the paperSubstantial claim4 of 6 sources checked
    • cites [12] Mebis L, Debaveye Y, Ellger B, Derde S, Ververs EJ, Langouche L, Darras VM, Fliers E, Visser TJ, Van den BG (2009) Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness. Crit Care 13(5):R147 source

      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)

      Experimental — accuracy not yet measured
    • cites [15] Boelen A, Kwakkel J, Thijssen-Timmer DC, Alkemade A, Fliers E, Wiersinga WM (2004) Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice. J Endocrinol 182(2):315–323 source
    • cites [16] Fekete C, Gereben B, Doleschall M, Harney JW, Dora JM, Bianco AC, Sarkar S, Liposits Z, Rand W, Emerson C, Kacskovics I, Larsen PR, Lechan RM (2004) Lipopolysaccharide induces type 2 iodothyronine deiodinase in the mediobasal hypothalamus: implications for the nonthyroidal illness syndrome. Endocrinology 145(4):1649–1655 source
    • cites [17] Boelen A, Kwakkel J, Wieland CW, St Germain DL, Fliers E, Hernandez A (2009) Impaired bacterial clearance in type 3 deiodinase-deficient mice infected with Streptococcus pneumoniae. Endocrinology 150(4):1984–1990. https://doi.org/10.1210/en.2008-1133 source

      In “Illness-induced alterations in thyroid hormone metabolism” (page unavailable), the paper reports that D3 mRNA expression and activity decreased during infection in the liver of wild-type mice. It does not report a decrease in hypothalamic D3, the part of the citing sentence to which this source is attached. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [18] Boelen A, Kwakkel J, Chassande O, Fliers E (2009) Thyroid Hormone Receptor beta mediates acute illness-induced alterations in central thyroid hormone metabolism. J Neuroendocrinol 21:465–472 source
    • cites [19] Boelen A, Kwakkel J, Wiersinga WM, Fliers E (2006) Chronic local inflammation in mice results in decreased TRH and type 3 deiodinase mRNA expression in the hypothalamic paraventricular nucleus independently of diminished food intake. J Endocrinol 191(3):707–714 source

  • May combine two claims.

    Premisecitation

    Muscle DIO2 is differentially affected during illness: acute inflammation in mice increases muscle Dio2 mRNA expression, while bacterial sepsis decreases Dio2 mRNA expression both in mice and humans.

    “Muscle DIO2 is differentially affected during illness. Acute inflammation in mice increases muscle Dio2 mRNA expression, while bacterial sepsis decreases Dio2 mRNA expression both in mice [28] and humans [29].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [28] Kwakkel J, van Beeren HC, Ackermans MT, Platvoet-ter Schiphorst MC, Fliers E, Wiersinga WM, Boelen A (2009) Skeletal muscle deiodinase type 2 regulation during illness in mice. JEndocrinol 203(2):263–270 source
    • cites [29] Rodriguez-Perez A, Palos-Paz F, Kaptein E, Visser TJ, Dominguez-Gerpe L, Varez-Escudero J, Lado-Abeal J (2008) Identification of molecular mechanisms related to nonthyroidal illness syndrome in skeletal muscle and adipose tissue from patients with septic shock. ClinEndocrinol (Oxf) 68(5):821–827 source

  • May combine two claims.

    Premisecitation

    DIO2 knockdown impairs macrophage phagocytosis while blunting the cytokine response upon stimulation with bacterial endotoxin.

    “In addition, DIO2 knockdown impairs macrophage phagocytosis while blunting the cytokine response upon stimulation with bacterial endotoxin [36, 37].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [36] Kwakkel J, Surovtseva OV, de Vries EM, Stap J, Fliers E, Boelen A (2014) A novel role for the thyroid hormone-activating enzyme type 2 deiodinase in the inflammatory response of macrophages. Endocrinology 155(7):2725–2734. https://doi.org/10.1210/en.2013-2066 source
    • cites [37] van der Spek AH, Surovtseva OV, Jim KK, van Oudenaren A, Brouwer MC, Vandenbroucke-Grauls C, Leenen PJM, van de Beek D, Hernandez A, Fliers E, Boelen A (2018) Regulation of intracellular triiodothyronine is essential for optimal macrophage function. Endocrinology 159(5):2241–2252. https://doi.org/10.1210/en.2018-00053 source

      The section on D2KO macrophages reports impaired phagocytosis and reduced GM-CSF transcription after LPS stimulation. But these experiments used D2 knockout cells rather than DIO2 knockdown, and the other measured cytokine responses were unchanged. The Discussion says the findings accord with earlier knockdown data, but this paper does not establish a generally blunted cytokine response from knockdown. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    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].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [12] Mebis L, Debaveye Y, Ellger B, Derde S, Ververs EJ, Langouche L, Darras VM, Fliers E, Visser TJ, Van den BG (2009) Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness. Crit Care 13(5):R147 source

      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
    • cites [18] Boelen A, Kwakkel J, Chassande O, Fliers E (2009) Thyroid Hormone Receptor beta mediates acute illness-induced alterations in central thyroid hormone metabolism. J Neuroendocrinol 21:465–472 source

  • May combine two claims.

    Premisecitation

    Activation of macrophages results in increased DIO2 expression together with increased TRα1 and MCT10, pointing to increased TH action in these cells during inflammation.

    “Activation of macrophages results in increased DIO2 expression together with increased TRα1 and MCT10, together pointing to increased TH action in these cells during inflammation [36].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] Kwakkel J, Surovtseva OV, de Vries EM, Stap J, Fliers E, Boelen A (2014) A novel role for the thyroid hormone-activating enzyme type 2 deiodinase in the inflammatory response of macrophages. Endocrinology 155(7):2725–2734. https://doi.org/10.1210/en.2013-2066 source

  • May combine two claims.

    Premisecitation

    DIO2 is the main deiodinase present in macrophages and TRα1 is their dominant TR.

    “DIO2 is the main deiodinase present in macrophages and TRα1 is their dominant TR [36].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] Kwakkel J, Surovtseva OV, de Vries EM, Stap J, Fliers E, Boelen A (2014) A novel role for the thyroid hormone-activating enzyme type 2 deiodinase in the inflammatory response of macrophages. Endocrinology 155(7):2725–2734. https://doi.org/10.1210/en.2013-2066 source

      In the section on D2 expression in macrophages (page unavailable), D2 mRNA was detected in the RAW264.7 macrophage cell line, while D1 and D3 mRNA were near the detection limit. The same section reports TRα1 and TRα2 expression, no detectable TRβ, and an increase in TRα1—but not TRα2—after LPS stimulation. It does not establish that TRα1 is the dominant receptor isoform. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In the same animal model, bacterial sepsis reduces TH signaling coinciding with increased DIO3 and decreased DIO2 expression, while chronic inflammation decreases DIO3 expression.

    “In the same animal model, bacterial sepsis reduces TH signaling coinciding with increased DIO3 and decreased DIO2 expression, while chronic inflammation decreases DIO3 expression [48].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [48] Bloise FF, van der Spek AH, Surovtseva OV, Ortiga-Carvalho TM, Fliers E, Boelen A (2016) Differential effects of sepsis and chronic inflammation on diaphragm muscle fiber type, thyroid hormone metabolism, and mitochondrial function. Thyroid 26(4):600–609. https://doi.org/10.1089/thy.2015.0536 source

  • May combine two claims.

    Premisecitation

    Liver TRα and TRβ expression in rodents decrease during acute illness but not during chronic inflammation and bacterial sepsis.

    “Liver TRα and TRβ expression in rodents decrease during acute illness [15, 39] but not during chronic inflammation and bacterial sepsis.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [15] Boelen A, Kwakkel J, Thijssen-Timmer DC, Alkemade A, Fliers E, Wiersinga WM (2004) Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice. J Endocrinol 182(2):315–323 source

      The Liver and circulation section reports decreased liver TR1 mRNA within eight hours of LPS administration in mice, supporting a decrease in one liver receptor transcript during acute illness. It does not report decreases in both liver TRα and TRβ. The citation precedes the chronic-inflammation and bacterial-sepsis clause, so that clause is not attributed to this source. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [39] Beigneux AP, Moser AH, Shigenaga JK, Grunfeld C, Feingold KR (2003) Sick euthyroid syndrome is associated with decreased TR expression and DNA binding in mouse liver. Am J Physiol Endocrinol Metab 284(1):E228–E236 source

  • May combine two claims.

    Premisecitation

    DIO2 knockdown increases mortality in zebrafish embryos during pneumococcal meningitis, which can be restored by T3 administration during infection.

    “Finally, DIO2 knockdown increases mortality in zebrafish embryos during pneumococcal meningitis, which can be restored by T3 administration during infection [37].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [37] van der Spek AH, Surovtseva OV, Jim KK, van Oudenaren A, Brouwer MC, Vandenbroucke-Grauls C, Leenen PJM, van de Beek D, Hernandez A, Fliers E, Boelen A (2018) Regulation of intracellular triiodothyronine is essential for optimal macrophage function. Endocrinology 159(5):2241–2252. https://doi.org/10.1210/en.2018-00053 source

  • May combine two claims.

    Premisecitation

    Acute inflammation in mice decreases muscle DIO3 while chronic inflammation in the same species increases muscle DIO3.

    “Acute inflammation in mice decreases muscle DIO3 [31] while chronic inflammation in the same species increases muscle DIO3.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [31] Kwakkel J, Chassande O, van Beeren HC, Fliers E, Wiersinga WM, Boelen A (2010) Thyroid hormone receptor alpha modulates lipopolysaccharide-induced changes in peripheral thyroid hormone metabolism. Endocrinology 151(4):1959–1969. https://doi.org/10.1210/en.2009-1049 source

  • May combine two claims.

    Premisecitation

    In patients with a variety of chronic liver diseases, hepatic TRα1, TRα2 and TRβ1 and T3-target gene expression are unchanged, indicating a euthyroid condition in the liver of these patients despite reduced serum TH levels.

    “However, in patients with a variety of chronic liver diseases, hepatic TRα1, TRα2 and TRβ1 and T3-target gene expression are unchanged, indicating a euthyroid condition in the liver of these patients despite reduced serum TH levels [41].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [41] Chamba A, Neuberger J, Strain A, Hopkins J, Sheppard MC, Franklyn JA (1996) Expression and function of thyroid hormone receptor variants in normal and chronically diseased human liver. J Clin Endocrinol Metab 81(1):360–367 source

  • May combine two claims.

    Premisecitation

    A lack of DIO3 impairs the bacterial killing capacity of mice upon infection with Streptococcus pneumonia and increases the mortality of zebrafish embryos with pneumococcal meningitis.

    “A lack of DIO3 impairs the bacterial killing capacity of mice upon infection with Streptococcus pneumonia [17] and clearly increases the mortality of zebrafish embryos with pneumococcal meningitis.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [17] Boelen A, Kwakkel J, Wieland CW, St Germain DL, Fliers E, Hernandez A (2009) Impaired bacterial clearance in type 3 deiodinase-deficient mice infected with Streptococcus pneumoniae. Endocrinology 150(4):1984–1990. https://doi.org/10.1210/en.2008-1133 source

      The Bacterial outgrowth section (page unavailable) reports significantly higher bacterial loads in the lungs and spleens of D3-deficient mice after S. pneumoniae infection, supporting impaired clearance. The Abstract and discussion describe reduced microbial killing as a probable explanation, not a directly established result. The zebrafish clause follows the [17] citation and is not attributed to this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    NTIS affects D1 via NF-κB, as the IL-1-β induced decrease in DIO1 and TRβ mRNA expression in HepG2 cells depends on NF-kB signaling.

    “In addition to DIO2, NTIS affects D1 via NF-κB. This is clear, e.g., from the observation that the IL-1-β induced decrease in DIO1 and TRβ mRNA expression in HepG2 cells, which is a hepatocyte derived cell line, depends on NF-kB signaling [59, 60].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [59] Kwakkel J, Wiersinga WM, Boelen A (2006) Differential involvement of nuclear factor-kappaB and activator protein-1 pathways in the interleukin-1beta-mediated decrease of deiodinase type 1 and thyroid hormone receptor beta1 mRNA. J Endocrinol 189(1):37–44 source

      The Discussion (journal pp. 37–44) says NF-κB inhibition prevented the IL-1β-induced decrease in TRβ1 mRNA in HepG2 cells. It also says NF-κB inhibition alone did not prevent the D1/DIO1 mRNA decrease; only simultaneous inhibition of NF-κB and AP-1 did. Thus the claim overstates NF-κB dependence for DIO1. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [60] Kwakkel J, Wiersinga WM, Boelen A (2007) Interleukin-1beta modulates endogenous thyroid hormone receptor alpha gene transcription in liver cells. JEndocrinol 194(2):257–265 source

  • May combine two claims.

    Premisecitation

    Diminished food intake plays an additional role as NTIS is associated with diminished appetite and nutritional intake.

    “Diminished food intake plays an additional role as NTIS is associated with diminished appetite and nutritional intake [71–74].”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [71] Schutz P, Bally M, Stanga Z, Keller U (2014) Loss of appetite in acutely ill medical inpatients: physiological response or therapeutic target? Swiss Med Wkly 144:w13957. https://doi.org/10.4414/smw.2014.13957 source

      The Pathophysiology of PEM due to acute and chronic illness section describes reduced food intake associated with inflammatory responses, supporting the general point about diminished intake during illness. It does not identify NTIS or establish an association between NTIS and diminished appetite or nutritional intake; searches for NTIS and thyroid-related terms found no such passage. Page numbers were not available in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [72] Richmand DA, Molitch ME, O’Donnell TF (1980) Altered thyroid hormone levels in bacterial sepsis: the role of nutritional adequacy. Metabolism 29(10):936–942 source
    • cites [73] Chourdakis M, Kraus MM, Tzellos T, Sardeli C, Peftoulidou M, Vassilakos D, Kouvelas D (2012) Effect of early compared with delayed enteral nutrition on endocrine function in patients with traumatic brain injury an open-labeled randomized trial. J Parent Enteral Nutr 36(1):108–116 source
    • cites [74] Ouchi K, Matsubara S, Matsuno S (1991) Effects of supplementary parenteral nutrition on thyroid hormone patterns in surgical patients with liver cirrhosis. Nutrition 7(3):189–192

  • May combine two claims.

    Premisecitation

    Liver TRβ1 expression decreases during acute inflammation in mice and limited availability of SRC-1 might be partly responsible for the illness induced decrease of liver DIO1.

    “Indeed, liver TRβ1 expression decreases during acute inflammation in mice [15, 39, 77] and limited availability of SRC-1, a shared coactivator for TR and inflammatory signaling pathways, might be partly responsible for the illness induced decrease of liver DIO1 [78, 79].”
    Quote in the paperNot a substantial claim1 of 5 sources checked
    • cites [15] Boelen A, Kwakkel J, Thijssen-Timmer DC, Alkemade A, Fliers E, Wiersinga WM (2004) Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice. J Endocrinol 182(2):315–323 source
    • cites [39] Beigneux AP, Moser AH, Shigenaga JK, Grunfeld C, Feingold KR (2003) Sick euthyroid syndrome is associated with decreased TR expression and DNA binding in mouse liver. Am J Physiol Endocrinol Metab 284(1):E228–E236 source
    • cites [77] Beigneux AP, Moser AH, Shigenaga JK, Grunfeld C, Feingold KR (2000) The acute phase response is associated with retinoid X receptor repression in rodent liver. J Biol Chem 275(21):16390–16399 source
    • cites [78] Yu J, Koenig RJ (2000) Regulation of hepatocyte thyroxine 5’-deiodinase by T3 and nuclear receptor coactivators as a model of the sick euthyroid syndrome. J Biol Chem 275(49):38296–38301 source
    • cites [79] Yu J, Koenig RJ (2006) Induction of type 1 iodothyronine deiodinase to prevent the nonthyroidal illness syndrome in mice. Endocrinology 147(7):3580–3585 source

  • May combine two claims.

    Premisecitation

    Inhibition of RelA prevents the LPS-induced DIO2 increase in a cell culture of primary tanycytes, while tanycyte-specific knock down of RelA in mice showed that NF-κB is essential for the LPS-induced hypothalamic DIO2 increase and TRH decrease in vivo.

    “Inhibition of RelA prevents the LPS-induced DIO2 increase in a cell culture of primary tanycytes [63], while tanycyte-specific knock down of RelA in mice showed that NF-κB is essential for the LPS-induced hypothalamic DIO2 increase and TRH decrease in vivo [64].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [63] de Vries EM, Kwakkel J, Eggels L, Kalsbeek A, Barrett P, Fliers E, Boelen A (2014) NFkappaB signaling is essential for the lipopolysaccharide-induced increase of type 2 deiodinase in tanycytes. Endocrinology 155(5):2000–2008. https://doi.org/10.1210/en.2013-2018 source
    • cites [64] de Vries EM, Nagel S, Haenold R, Sundaram SM, Pfrieger FW, Fliers E, Heuer H, Boelen A (2016) The role of hypothalamic NF-kappaB Signaling in the response of the HPT-Axis to acute inflammation in female mice. Endocrinology 157(7):2947–2956. https://doi.org/10.1210/en.2016-1027 source

  • May combine two claims.

    Premisecitation

    Toleration of a nutritional deficit during the first week of critical illness results in fewer complications and accelerated recovery.

    “the toleration of a nutritional deficit during the first week of critical illness resulted in fewer complications and accelerated recovery [91].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [91] Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, Van Cromphaut S, Ingels C, Meersseman P, Muller J, Vlasselaers D, Debaveye Y, Desmet L, Dubois J, Van Assche A, Vanderheyden S, Wilmer A, Van den Berghe G (2011) Early versus late parenteral nutrition in critically ill adults. N Engl J Med 365(6):506–517. https://doi.org/10.1056/NEJMoa1102662 source

  • May combine two claims.

    Premisecitation

    In mice with acute illness induced by LPS, D2 mRNA is strongly increased in the hypothalamus whereas preproTRH mRNA expression does not change.

    “In the hypothalamus, D2 mRNA was strongly increased whereas preproTRH mRNA expression did not change after LPS.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [15] Boelen A, Kwakkel J, Thijssen-Timmer DC, Alkemade A, Fliers E, Wiersinga WM (2004) Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice. J Endocrinol 182(2):315–323 source

  • May combine two claims.

    Premisecitation

    Targeting fasting blood glucose concentrations with intensive insulin treatment in children with critical illness to values mimicking a fasting response results in improved outcomes but aggravates peripheral NTIS.

    “targeting of fasting blood glucose concentrations with intensive insulin treatment in children with critical illness to values mimicking a fasting response, resulted in improved outcomes, but at the same time aggravated peripheral NTIS.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [92] Vlasselaers D, Milants I, Desmet L, Wouters PJ, Vanhorebeek I, van den Heuvel I, Mesotten D, Casaer MP, Meyfroidt G, Ingels C, Muller J, Van Cromphaut S, Schetz M, Van den Berghe G (2009) Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study. Lancet 373(9663):547–556. https://doi.org/10.1016/S0140-6736(09)60044-1 source
    • cites [93] Gielen M, Mesotten D, Wouters PJ, Desmet L, Vlasselaers D, Vanhorebeek I, Langouche L, Van den Berghe G (2012) Effect of tight glucose control with insulin on the thyroid axis of critically ill children and its relation with outcome. J Clin Endocrinol Metab 97(10):3569–3576. https://doi.org/10.1210/jc.2012-2240 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The central lowering of T4 could be harmful.

    “By contrast, the central lowering of T4 could be harmful (for review see Fliers et al., [83].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [83] Fliers E, Bianco AC, Langouche L, Boelen A (2015) Thyroid function in critically ill patients. Lancet Diabetes Endocrinol 3(10):816–825. https://doi.org/10.1016/S2213-8587(15)00225-9 source

  • May combine two claims.

    Premisecitation

    These responses include increased tissue expression of monocarboxylate transporters, upregulation of type-2 deiodinase activity, and increased sensitivity at the receptor level.

    “These responses include increased tissue expression of monocarboxylate transporters, upregulation of type-2 deiodinase activity, and increased sensitivity at the receptor level [87].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [87] Van den Berghe G (2014) Non-thyroidal illness in the ICU: a syndrome with different faces. Thyroid. https://doi.org/10.1089/thy.2014.0201 source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    In mild illness, only a decrease in serum T3 levels is seen, but with increasing severity and duration of the illness there appears to be a drop in serum T4 as well.

    “In mild illness, only a decrease in serum T3 levels was seen but with increasing severity and duration of the illness there appeared to be a drop in serum T4 as well.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    A healthy liver predominantly expresses DIO1, with very low DIO3 expression.

    “A healthy liver predominantly expresses DIO1, with very low DIO3 expression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Tissue thyroid hormone (TH) concentrations during NTIS do not necessarily reflect serum low TH concentrations and may decrease, remain unaltered, or even increase according to the organ and type of illness studied.

    “both experimental animal and clinical studies have shown that tissue TH concentrations during NTIS do not necessarily reflect serum low TH concentrations and may decrease, remain unaltered, or even increase according to the organ and type of illness studied.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    TH transport in the human liver is differentially affected during illness: MCT8 expression increases in prolonged critical illness compared to acute illness, while MCT10 expression does not differ between these groups.

    “TH transport in the human liver is differentially affected during illness: MCT8 expression increases in prolonged critical illness compared to acute illness, while MCT10 expression does not differ between these groups [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Mebis L, Paletta D, Debaveye Y, Ellger B, Langouche L, D’Hoore A, Darras VM, Visser TJ, Van den Berghe G (2009) Expression of thyroid hormone transporters during critical illness. Eur J Endocrinol 161(2):243–250. https://doi.org/10.1530/EJE-09-0290 source

  • May combine two claims.

    Premisenone given

    In mice, muscle TH transporter expression is low during acute inflammation and bacterial sepsis but remains unchanged during chronic inflammation.

    “In mice, muscle TH transporter expression is low during acute inflammation and bacterial sepsis but remains unchanged during chronic inflammation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    NTIS has a clear correlation with morbidity and mortality.

    “NTIS has remained an intriguing phenomenon not only because of the robustness of the decrease in serum triiodothyronine (T3), but also by its clear correlation with morbidity and mortality.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Reduced cellular TH uptake by itself would cause tissue hypothyroidism, but this is generally not observed.

    “In theory, reduced cellular TH uptake by itself would cause tissue hypothyroidism, but this is generally not observed.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The decrease in serum triiodothyronine (T3) in non-thyroidal illness syndrome (NTIS) is robust.

    “NTIS has remained an intriguing phenomenon not only because of the robustness of the decrease in serum triiodothyronine (T3), but also by its clear correlation with morbidity and mortality.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Once elevated, rT3 does not increase much more in patients with more severe illness.

    “Once elevated, rT3 does not increase much more in patients with more severe illness.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Serum from patients with NTIS inhibits T4 uptake in rat hepatocytes, mediated in part by increased non-esterified fatty acids (NEFA) and bilirubin and by decreased albumin.

    “Using deiodination of T4 as a measure of cellular transport of T4 into rat hepatocytes, various older studies [4, 5, 6] reported that serum from patients with NTIS inhibits T4 uptake, mediated in part by increased non-esterified fatty acids (NEFA) and bilirubin and by decreased albumin.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] Hennemann G, Docter R, Friesema EC, de Jong M, Krenning EP, Visser TJ (2001) Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocr Rev 22(4):451–476 source
    • cites [5] Vos RA, De Jong M, Bernard BF, Docter R, Krenning EP, Hennemann G (1995) Impaired thyroxine and 3,5,3’-triiodothyronine handling by rat hepatocytes in the presence of serum of patients with nonthyroidal illness. J Clin Endocrinol Metab 80(8):2364–2370. https://doi.org/10.1210/jcem.80.8.7629231 source
    • cites [6] Sarne DH, Refetoff S (1985) Measurement of thyroxine uptake from serum by cultured human hepatocytes as an index of thyroid status: reduced thyroxine uptake from serum of patients with nonthyroidal illness. J Clin Endocrinol Metab 61(6):1046–1052. https://doi.org/10.1210/jcem-61-6-1046 source

  • May combine two claims.

    Premisecitation

    A variety of changes in TH transporters, deiodinase and TR action have been observed in different organs and tissues both during acute and chronic illness, while serum TH levels are uniformly downregulated.

    “A variety of changes in TH transporters, deiodinase and TR action have been observed in different organs and tissues both during acute and chronic illness, while serum TH levels are uniformly downregulated [3, 11].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Boelen A, Kwakkel J, Fliers E (2011) Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection. Endocr Rev 32(5):670–693. https://doi.org/10.1210/er.2011-0007 source
    • cites [11] Mebis L, Van den Berghe G (2011) Thyroid axis function and dysfunction in critical illness. Best Pract Res Clin Endocrinol Metab 25(5):745–757. https://doi.org/10.1016/j.beem.2011.03.002 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MCT8 and OATP1C1 are of crucial importance for the regulation of TH activity in the brain and thus for brain development.

    “MCT8 and OATP1C1 are of crucial importance for the regulation of TH activity in the brain and thus for brain development [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Groeneweg S, Visser WE, Visser TJ (2017) Disorder of thyroid hormone transport into the tissues. Best Pract Res Clin Endocrinol Metab 31(2):241–253. https://doi.org/10.1016/j.beem.2017.05.001 source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    It is now generally accepted that serum rT3 may be normal or even reduced in some NTIS cases.

    “However, it is now generally accepted that serum rT3 may be normal or even reduced in some NTIS cases.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    There is no evidence at this early stage that TH metabolism in innate immune cells may be a determinant of susceptibility to infections.

    “A fascinating role for TH metabolism in innate immune cells, including neutrophils and monocytes/macrophages, was reported in recent years, but there is no evidence at this early stage that this may be a determinant of susceptibility to infections.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Hypothalamic MCT10 and OATP1C1 expression increases during critical illness in experimental animals while hypothalamic MCT8 mRNA expression does not change.

    “Hypothalamic MCT10 and OATP1C1 expression increases during critical illness in experimental animals while hypothalamic MCT8 mRNA expression does not change.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Early studies pointed to increased serum reverse T3 (rT3) resulting from decreased degradation of rT3 during NTIS.

    “Early studies pointed to increased serum reverse T3 (rT3) resulting from decreased degradation of rT3 during NTIS, when several labs with access to immunoassays for both T3 and rT3 observed this discrepancy between these two metabolites of T4.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Acute illness lowers hepatic Slc16A2 (MCT8) and Slc16A10 (MCT10) mRNA expression, whereas chronic inflammation results in decreased Slc16A2 and increased Slc16A10 mRNA expression.

    “For example, acute illness lowers Slc16A2 (MCT8) and Slc16A10 (MCT10) mRNA expression, whereas chronic inflammation results in a combination of decreased Slc16A2 and increased Slc16A10 mRNA expression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Prolonged illness in rabbits results in markedly increased MCT10 expression while MCT8 mRNA expression does not change.

    “Prolonged illness in rabbits results in markedly increased MCT10 expression while MCT8 mRNA expression does not change.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    TH action is determined by intracellular T3 concentration and TR status.

    “TH action is determined by intracellular T3 concentration and TR status.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    This may result in a coordinated breakdown of both T4 and T3, finally leading to increased intracellular T2 levels.

    “This may result in a coordinated breakdown of both T4 and T3, finally leading to increased intracellular T2 levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    UCP3 increases in skeletal muscle of mice during acute sepsis and inflammation as well as in skeletal muscle of NTIS patients, coinciding with increased DIO2 expression.

    “UCP3, which is a T3 target gene, increases in skeletal muscle of mice during acute sepsis [42] and inflammation [43] as well as in skeletal muscle of NTIS patients, coinciding with increased DIO2 expression [44].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [42] Sun X, Wray C, Tian X, Hasselgren PO, Lu J (2003) Expression of uncoupling protein 3 is upregulated in skeletal muscle during sepsis. Am J Physiol EndocrinolMetab 285(3):E512–E520 source
    • cites [43] Yu F, Gothe S, Wikstrom L, Forrest D, Vennstrom B, Larsson L (2000) Effects of thyroid hormone receptor gene disruption on myosin isoform expression in mouse skeletal muscles. Am J Physiol Regul Integr Comp Physiol 278(6):R1545–R1554 source
    • cites [44] Lado-Abeal J, Romero A, Castro-Piedras I, Rodriguez-Perez A, Varez-Escudero J (2010) Thyroid hormone receptors are down-regulated in skeletal muscle of patients with non-thyroidal illness syndrome secondary to non-septic shock. Eur J Endocrinol 163(5):765–773 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Both T3 and T2 are known to regulate mitochondrial activity in skeletal muscle.

    “Of note, both T3 and T2 are known to regulate mitochondrial activity in skeletal muscle [45, 46].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Harper ME, Seifert EL (2008) Thyroid hormone effects on mitochondrial energetics. Thyroid 18(2):145–156 source
    • cites [46] Moreno M, Lombardi A, Silvestri E, Lanni A, Goglia F (2008) Metabolic effects of thyroid hormone derivatives. Thyroid 18(2):239–253 source

  • May combine two claims.

    Premisecitation

    TRα and TRβ mRNA expression are increased in liver biopsies of patients with chronic liver disease prior to liver transplantation, in association with low serum T3 and T4 levels.

    “In contrast, TRα and TRβ mRNA expression are increased in liver biopsies of patients with chronic liver disease prior to liver transplantation, in association with low serum T3 and T4 levels [40].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Williams GR, Franklyn JA, Neuberger JM, Sheppard MC (1989) Thyroid hormone receptor expression in the “sick euthyroid” syndrome. Lancet 2(8678–8679):1477–1481 source

  • May combine two claims.

    Premisecitation

    DIO3 is expressed in human neutrophils and present in intracellular granules involved in bacterial killing and in neutrophil extracellular traps (NETs).

    “DIO3 is also expressed in human neutrophils [34] and present in intracellular granules involved in bacterial killing and in neutrophil extracellular traps (NETs) [34].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] van der Spek AH, Bloise FF, Tigchelaar W, Dentice M, Salvatore D, van der Wel NN, Fliers E, Boelen A (2016) The thyroid hormone inactivating enzyme Type 3 deiodinase is present in bactericidal granules and the cytoplasm of human neutrophils. Endocrinology 157(8):3293–3305. https://doi.org/10.1210/en.2016-1103 source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisereasoning

    These findings are in line with chronic inflammation mouse and rat models.

    “These findings are in line with chronic inflammation mouse and rat models.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Many studies indicate a dominant role for cytokines in the pathogenesis of NTIS but fail to pinpoint one particular cytokine as the crucial mediator.

    “In sum, many studies indicate a dominant role for cytokines in the pathogenesis of NTIS but fail to pinpoint one particular cytokine as the crucial mediator.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    One of the key features of NTIS is the absence of increased serum TSH in the face of markedly decreased serum T3 and T4, pointing to altered set-point regulation of the hypothalamus-pituitary-thyroid (HPT) axis.

    “One of the key features of NTIS is the absence of increased serum TSH in the face of markedly decreased serum T3 and T4, pointing to altered set-point regulation of the hypothalamus-pituitary-thyroid (HPT) axis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    The determination of rT3 is not routinely available in many hospitals and does not reliably distinguish between hypothyroidism and NTIS.

    “The determination of rT3 is, however, not routinely available in many hospitals and does not reliably distinguish between hypothyroidism and NTIS.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Finding positive anti thyroid peroxidase (TPO) antibody titers supports the diagnosis of primary hypothyroidism but does not prove it.

    “Finding positive anti thyroid peroxidase (TPO) antibody titers supports the diagnosis of primary hypothyroidism but does not prove it.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A causal role for IL-6 is likely since IL-6 knockout mice show a smaller decrease in serum T3 during acute illness, although acute injection of IL-6 failed to induce NTIS in mice.

    “A causal role for IL-6 is likely since IL-6 knockout mice show a smaller decrease in serum T3 during acute illness [52], although acute injection of IL-6 failed to induce NTIS in mice [51].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [52] Boelen A, Maas MA, Lowik CW, Platvoet MC, Wiersinga WM (1996) Induced illness in interleukin-6 (IL-6) knock-out mice: a causal role of IL-6 in the development of the low 3,5,3’-triiodothyronine syndrome. Endocrinology 137(12):5250–5254 source
    • cites [51] Boelen A, Platvoet-ter Schiphorst MC, Bakker O, Wiersinga WM (1995) The role of cytokines in the lipopolysaccharide-induced sick euthyroid syndrome in mice. J Endocrinol 146(3):475–483 source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    If both T3 and T4 are very low a potentially fatal outcome may be assumed.

    “If both T3 and T4 are very low a potentially fatal outcome may be assumed.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    A clearly elevated TSH suggests the presence of prior hypothyroidism.

    “Potential caveats include a clearly elevated TSH suggesting the presence of prior hypothyroidism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Infusion of TNFα in humans alters serum T3, TSH and rT3, while blocking TNFα by a recombinant TNF receptor-IgG fusion protein does not prevent these changes.

    “The same holds true for TNFα, as infusion of this cytokine in humans alters serum T3, TSH and rT3, while blocking TNFα by a recombinant TNF receptor-IgG fusion protein does not prevent these changes [57].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] van der Poll T, Endert E, Coyle SM, Agosti JM, Lowry SF (1999) Neutralization of TNF does not influence endotoxininduced changes in thyroid hormone metabolism in humans. Am J Physiol 276(2):R357-362. https://doi.org/10.1152/ajpregu.1999.276.2.R357 source

  • May combine two claims.

    Premisecitation

    In human volunteers, short-term infusion of IL-6 induces decreased serum TSH concentrations, but daily injections over 42 days only cause a modest decrease in T3 and a transient increase in rT3 and free T4.

    “In human volunteers, short-term infusion of IL-6 induces decreased serum TSH concentrations, but daily injections over 42 days only cause a modest decrease in T3 and a transient increase in rT3 and free T4 [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Stouthard JM, Endert E, Bakker PJ, Veenhof CH, Sauerwein HP, Romijn JA (1994) Effects of acute and chronic interleukin-6 administration on thyroid hormone metabolism in humans. J Clin Endocrinol Metab 79(5):1342–1346 source

  • May combine two claims.

    Premisenone given

    A relatively high ratio of serum T3-T4, a low thyroid hormone-binding ratio and a low serum concentration of rT3 favor the presence of hypothyroidism over NTIS and vice versa.

    “In addition to a high serum TSH concentration, a relatively high ratio of serum T3–T4, a low thyroid hormone-binding ratio and a low serum concentration of rT3 favor the presence of hypothyroidism over NTIS and vice versa.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Whether the observed changes are beneficial or deleterious may depend on disease type and severity, the need of prolonged vital support, and environmental factors including parenteral nutrition.

    “This may depend on disease type and severity, the need of prolonged vital support, and environmental factors including parenteral nutrition.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The clinical implications of NTIS in the prolonged phase of critical illness when patients receive nutrition but continue to depend on intensive medical care are uncertain.

    “The clinical implications of NTIS in the prolonged phase of critical illness when patients receive nutrition but continue to depend on intensive medical care, is uncertain.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    The reduced amount of circulating active T3 could be interpreted as an attempt by the body to decrease the metabolic rate, reduce energy expenditure, and prevent protein breakdown, thereby promoting survival.

    “Teleologically, the reduced amount of circulating active T3 could be interpreted as an attempt by the body to decrease the metabolic rate, reduce energy expenditure, and prevent protein breakdown, thereby promoting survival.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    At this stage we do not know whether infusing hypothalamic releasing factors can improve clinical outcomes.

    “Unfortunately at this stage we do not know whether this approach can improve clinical outcomes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    In the clinical setting, less information is available on the timing and the relative role of central versus peripheral mechanisms in the pathogenesis of NTIS.

    “In the clinical setting, less information is available on the timing and the relative role of central versus peripheral mechanisms in the pathogenesis of NTIS.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    There is no direct evidence to support the hypothesis that the reduced amount of circulating active T3 is an attempt to promote survival.

    “It should be noted, however, that at this time, there is no direct evidence support this hypothesis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Use of anticonvulsants and glucocorticoids can lower (F)T4.

    “Moreover, use of anticonvulsants and glucocorticoids should be noted, since these agents can lower (F)T4.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    No solid data are available to answer the question if the neuroendocrine changes in prolonged critical illness are harmful and should be treated.

    “No solid data are available to answer the question if the neuroendocrine changes in prolonged critical illness are harmful and should be treated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Infusing hypothalamic releasing factors, including TRH, in prolonged critically ill patients can reactivate the thyroid axis and induce an anabolic response.

    “Infusing hypothalamic releasing factors, including TRH, in these prolonged critically ill patients has been shown to be able to reactivate the thyroid axis and induce an anabolic response.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Hyperthyroidism is the typical cause of suppression of TSH below 0.01 mU/L, but it is rarely difficult to exclude this diagnosis in the setting of severely depressed T4 and T3.

    “Hyperthyroidism is the typical cause of suppression of TSH below 0.01 mU/L, but it is rarely difficult to exclude this diagnosis in the setting of severely depressed T4 and T3.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Inactivation of T4-rT3 and T3-T2, as part of the fasting response, might be a beneficial adaptation during acute illness.

    “and that the inactivation of T4–rT3 and T3–T2, as part of the fasting response, might be a beneficial adaptation during acute illness.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Peripheral mechanisms related to macronutrient restriction occur already in the acute phase in critical illness and appear beneficial.

    “Peripheral mechanisms related to macronutrient restriction occur already in the acute phase in critical illness and appear beneficial.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    NTIS is not limited to decreased serum TH concentrations during illness, but comprises complex organ and tissue-specific changes in TH metabolism as a reflection of marked changes in local inflammatory pathways, and nutritional status.

    “This may be partly explained by the fact that NTIS is not limited to decreased serum TH concentrations during illness, but comprises complex organ and tissue-specific changes in TH metabolism as a reflection of marked changes in local inflammatory pathways, and nutritional status.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation

    The net result of altered tissue TH metabolism may be beneficial or maladaptive, dependent on disease duration and severity.

    “The net result of altered tissue TH metabolism may be beneficial or maladaptive, dependent on disease duration and severity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Most studies used rather high doses of either T4 or T3, probably inducing further suppression of pituitary TSH release.

    “Furthermore, most studies used rather high doses of either T4 or T3, probably inducing further suppression of pituitary TSH release.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Inactivation of T3 to rT3, as part of the fasting response, might be a beneficial adaptation during acute illness.

    “The subanalysis suggested that the inactivation of T3 to rT3, as part of the fasting response, might be a beneficial adaptation during acute illness [25].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Langouche L, Vander Perre S, Marques M, Boelen A, Wouters PJ, Casaer MP, Van den Berghe G (2013) Impact of early nutrient restriction during critical illness on the nonthyroidal illness syndrome and its relation with outcome: a randomized, controlled clinical study. J Clin Endocrinol Metab 98(3):1006–1013. https://doi.org/10.1210/jc.2012-2809 source

  • May combine two claims.

    Premisenone given

    Critical illness is associated with loss of appetite and poor nutritional intake.

    “Critical illness is associated with loss of appetite and poor nutritional intake.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Whether the observed changes in critically ill patients defined as NTIS are beneficial or deleterious is currently unknown.

    “Whether the observed changes in critically ill patients defined as NTIS are beneficial or deleterious is currently unknown.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Deceased patients with NTIS had decreased TRH mRNA expression in the hypothalamic paraventricular nucleus, correlating with decreased ante mortem plasma TSH and T3 concentrations.

    “This concept was supported by a study reporting that deceased patients with NTIS had decreased TRH mRNA expression in the hypothalamic paraventricular nucleus, correlating with decreased ante mortem plasma TSH and T3 concentrations [65].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Fliers E, Guldenaar SE, Wiersinga WM, Swaab DF (1997) Decreased hypothalamic thyrotropin-releasing hormone gene expression in patients with nonthyroidal illness. J Clin Endocrinol Metab 82(12):4032–4036 source
80 of 80

  • The paper relies on this without support.

    Animal models of NTIS are relevant to human NTIS.

    “In mice, muscle TH transporter expression is low during acute inflammation and bacterial sepsis but remains unchanged during chronic inflammation.”

  • The paper relies on this without support.

    The cited studies' findings are reliable and can be used to draw conclusions about NTIS.

    “Multiple mechanisms are known to be simultaneously involved in the pathogenesis of NTIS.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • T3 is described as converting to rT3 and to T2

    Minor

    The nutritional subanalysis describes T3 inactivation as conversion to rT3. Elsewhere, the paper states that DIO3 converts T3 to T2 and T4 to rT3.

1 of 1

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Authors
Fliers, E., & Boelen, A.
Affiliations
  • Amsterdam UMC Location University of Amsterdam (NL)
  • Amsterdam University Medical Centers (NL)
Corresponding author
Fliers, E.
ORCID
Venue
Journal of Endocrinological Investigation
Publisher
Springer Science and Business Media LLC
Published
2020-12-15
Volume
44
Issue
8
Pages
1597-1607
ISSN
  • 0391-4097 (ISSN-L)
  • 1720-8386
DOI
10.1007/s40618-020-01482-4
PMC
PMC8285315
OpenAlex
W3112055569
Semantic Scholar
d7f0ff8bc65037551ff01b95625ed1c4dafc3647
Cited by
199
References
95
Citations by year
2026: 38 · 2025: 34 · 2024: 47 · 2023: 40 · 2022: 27 · 2021: 12
FWCI
12.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Endocrinological Investigation (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
Amsterdam UMC
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Nursing › Nutrition and Dietetics › Clinical Nutrition and Gastroenterology
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
low T3 syndrome, critical illness, triiodothyronine, thyroid hormone transporters, thyroid hormone receptor, thyroid hormone deiodinases, inflammatory signaling, innate immunity, neutrophils, monocytes/macrophages, parenteral nutrition, thyroid hormone replacement, morbidity and mortality
MeSH terms
Diagnosis, Differential, Euthyroid Sick Syndromes, Humans, Thyroid Hormones, Disease Management

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

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