The DOI matches its Crossref record; 97 of the 97 references it cites were found in a registry or an index; 58 of the 130 sources its claims cite were checked for support.
An update on non-thyroidal illness syndrome
Open accessAbstract
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.
Overview
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.
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Figures
![Fig. 1 Schematic representation of the variety of changes occurring during critical illness. Solid lines represent a causal relation, while a dashed line represents a probable effect. The scheme is based on both experimental and human studies. The net result of altered tissue TH metabolism may be beneficial or maladaptive, dependent on disease duration and severity. Reproduced from Fliers E et al. Lancet Diabetes Endocrinol 3: 816–825, 2015 [83] with permission from Elsevier](/paper-figures/78bd82a4f083468f85edc8d95175ed63/an-update-on-non-thyroidal-illness-syndrome-figure-1.jpg)
Verification
Claims the paper makes
45 No basis given · 35 No full text of the sources · 30 Own interpretation · 21 Supported · 20 Partly supported · 13 Not checked yet · 7 Supported so far · 1 Not supported · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > TH transport and metabolism
What the sources say
- Supportedcites [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
The Abstract states that thyroid hormone acts intracellularly, so it must cross the plasma membrane, and that transporter proteins mediate this process. It identifies MCT8, MCT10, and OATP1C1 as specific thyroid hormone transporters. No page number is supplied in our copy. (LLM, conf=0.95)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Illness results in marked downregulation of DIO1 both in humans and experimental animals [15, 20, 21].”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Unexpectedly, lethal bacterial sepsis affects hepatic TH transport only marginally [7].”
§ An update on non-thyroidal illness syndrome > Introduction > TH transport and metabolism
What the sources say
- Supportedcites [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 Discussion explicitly states that lethal bacterial sepsis affects hepatic TH transport only marginally. The liver-results section repeats this conclusion and reports decreased Slc16A2 mRNA after 48 hours, while Slc16A10 did not change. (LLM, conf=0.95)
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The same observation was made in mice with chronic inflammation and bacterial sepsis [7].”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In muscle, local conversion of T4 toT3 by DIO2 is important for muscle function both in rodents and in humans [4, 26, 27].”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Not checked — no full text of the sourcecites [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
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“DIO3 protein is highly expressed in infiltrating murine neutrophils during both bacterial infection and sterile inflammation [32, 33].”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Partly supportedcites [32] Boelen A, Kwakkel J, Alkemade A, Renckens R, Kaptein E, Kuiper G, Wiersinga WM, Visser TJ (2005) Induction of type 3 deiodinase activity in inflammatory cells of mice with chronic local inflammation. Endocrinology 146(12):5128–5134 sourceExperimental — accuracy not yet measured
The Turpentine-induced sterile abscess section reports D3 staining in inflammatory cells around a murine abscess, including polymorphonuclear granulocytes. It does not establish the same finding during bacterial infection: the LPS administration section reports low hindlimb muscle/subcutis D3 activity after bacterial-endotoxin treatment and does not report D3 staining in infiltrating neutrophils. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [33] Boelen A, Boorsma J, Kwakkel J, Wieland CW, Renckens R, Visser TJ, Fliers E, Wiersinga WM (2008) Type 3 deiodinase is highly expressed in infiltrating neutrophilic granulocytes in response to acute bacterial infection. Thyroid 18(10):1095–1103. https://doi.org/10.1089/thy.2008.0090 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In contrast, chronic inflammation in mice results in simultaneously increased DIO2 and DIO3 activity [28].”
§ An update on non-thyroidal illness syndrome > Introduction > TH action
What the sources say
- Supportedcites [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
The Animal experiments section identifies turpentine injection as a model of local chronic inflammation in mice. The Discussion reports that muscle D2 and D3 activity increased together after turpentine injection compared with pair-fed controls. The D2 increase was most prominent during the early phase, at days 1 and 2; the claim does not establish an increase throughout the illness. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Supported
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In the paper
“Furthermore, NADPH-oxidase activity is impaired in stimulated neutrophils of DIO3 knock-out mice compared to wild type neutrophils [35].”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Partly supportedcites [35] van der Spek AH, Jim KK, Karaczyn A, van Beeren HC, Ackermans MT, Darras VM, Vandenbroucke-Grauls C, Hernandez A, Brouwer MC, Fliers E, van de Beek D, Boelen A (2018) The thyroid hormone inactivating type 3 deiodinase is essential for optimal neutrophil function: observations from three species. Endocrinology 159(2):826–835. https://doi.org/10.1210/en.2017-00666 sourceExperimental — accuracy not yet measured
The section “D3KO neutrophils exhibit impaired NADPH oxidase activity” reports reduced activity after stimulation compared with WT neutrophils. However, Figure 3D and the Discussion specify that the effect occurred only in neutrophils from female mice, not male mice; the claim omits that limitation. Page numbers are not available in the supplied copy. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
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In the paper
“In addition, decreased availability of glutathione (GSH), a co-factor required for DIO1 catalytic activity, may also play a role [80].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Partly supportedcites [80] Wajner SM, Goemann IM, Bueno AL, Larsen PR, Maia AL (2011) IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells. JClinInvest 121(5):1834–1845. https://doi.org/10.1172/JCI44678 sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) proposes that depletion of intracellular GSH impairs D1 function, and Figure 4 reports that an antioxidant prevented IL-6-induced suppression of D1 activity in HepG2 cells. This supports the hedged suggestion that reduced GSH may play a role. It does not establish GSH as a required D1 cofactor or show downregulation of hepatic DIO1 expression during NTIS; Figure 4 instead reports increased DIO1 mRNA in the treated cells. (LLM, conf=0.85)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
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In the paper
“The Dio1 gene is positively regulated via a TR/RXR heterodimer which suggests that decreased TR or/and reduced RXR expression may play a role in the downregulation of hepatic DIO1 during NTIS [76].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Partly supportedcites [76] Amma LL, Campos-Barros A, Wang Z, Vennstrom B, Forrest D (2001) Distinct tissue-specific roles for thyroid hormone receptors beta and alpha1 in regulation of type 1 deiodinase expression. Mol Endocrinol 15(3):467–475 sourceExperimental — accuracy not yet measured
The TR Gene Expression section identifies TR–RXR complexes bound to DNA, and the D1 Abnormalities section reports markedly reduced hepatic D1 expression in TR-deficient mice (page numbers unavailable). These findings support the proposed role of TR in hepatic D1 regulation, but the paper does not test reduced RXR expression or downregulation during NTIS. (LLM, conf=0.87)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Not checked — no full text of the sourcecites [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
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
The Results section (page not provided) reports reduced preproTRH mRNA in the hypothalamic PVN of mice with chronic inflammation. The Discussion reports reduced pituitary TSHβ mRNA, not pituitary TSH content; the paper does not report portal-serum TRH measurements. This supports only part of the claim as applied to NTIS animal models, not the separate patient claim cited to another source. (LLM, conf=0.89)
- Not checked — no full text of the sourcecites [66] Blake NG, Eckland DJ, Foster OJ, Lightman SL (1991) Inhibition of hypothalamic thyrotropin-releasing hormone messenger ribonucleic acid during food deprivation. Endocrinology 129(5):2714–2718. https://doi.org/10.1210/endo-129-5-2714 source
- Not checked — no full text of the sourcecites [67] Kakucska I, Romero LI, Clark BD, Rondeel JM, Qi Y, Alex S, Emerson CH, Lechan RM (1994) Suppression of thyrotropin-releasing hormone gene expression by interleukin-1-beta in the rat: implications for nonthyroidal illness. Neuroendocrinology 59(2):129–137 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Cellular studies clearly showed that proinflammatory cytokines can downregulate various components of TH synthesis and metabolism in thyrocytes [58] and hepatocytes [59–61].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Supportedcites [58] de Vries EM, Fliers E, Boelen A (2015) The molecular basis of the non-thyroidal illness syndrome. J Endocrinol 225(3):R67-81. https://doi.org/10.1530/JOE-15-0133 source
The citation to this paper, [58], is attached to the thyrocyte portion of the sentence, not the hepatocyte portion. In “The effect of cytokines on TH synthesis,” the paper states that cytokines downregulate multiple components of the thyroid hormone synthesis pathway in thyrocytes, including thyroglobulin, thyroid peroxidase, iodide uptake, and D1. (LLM, conf=0.94)
- Supportedcites [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 Abstract reports that IL-1β reduced deiodinase type 1 and thyroid hormone receptor β1 mRNA in HepG2 liver-derived cells, supporting the hepatocyte-related portion of the sentence. The thyrocyte portion is attached to a different citation. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [61] Jakobs TC, Schmutzler C, Meissner J, Kohrle J (1997) The promoter of the human type I 5’-deiodinase gene–mapping of the transcription start site and identification of a DR+4 thyroid-hormone-responsive element. Eur J Biochem 247(1):288–297 source
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“The NF-κB protein family consists of several subunits of which the 65kD subunit of NF-κB (RelA) activates the Dio2 promoter [16, 62].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Not checked — no full text of the sourcecites [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
- Supportedcites [62] Zeold A, Doleschall M, Haffner MC, Capelo LP, Menyhert J, Liposits Z, da Silva WS, Bianco AC, Kacskovics I, Fekete C, Gereben B (2006) Characterization of the nuclear factor-kappa B responsiveness of the human dio2 gene. Endocrinology 147(9):4419–4429 source
In the section on hdio2 promoter responsiveness to p65 (page not provided), coexpression of the NF-κB p65 subunit increased human dio2 promoter activity in both HC11 and U87 cells. The Discussion identifies p65 as RelA. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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Every source the paper cites for this claim was checked and supports it.
In the paper
“Experimental studies in healthy volunteers during food deprivation showed that administration of leptin may partially reverse this process [75].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Supportedcites [75] Chan JL, Heist K, Depaoli AM, Veldhuis JD, Mantzoros CS (2003) The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest 111(9):1409–1421 source
The discussion following Figure 4 reports that replacement-dose leptin during fasting prevented key changes in the hypothalamic-pituitary-gonadal and thyroid axes and partly prevented changes in total IGF-1 in healthy men. It also notes that other fasting-induced changes were unaffected, consistent with the claim's qualified wording, “may partially reverse.” (LLM, conf=0.92)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“During prolonged critical illness, several tissue responses reported from both animal and human studies could be interpreted as compensatory to low thyroid hormone availability.”
§ An update on non-thyroidal illness syndrome > Remaining questions > Is thyroid hormone signaling disrupted during prolonged NTIS?
What the sources say
- Supportedcites [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
The “Prolonged critical illness” section describes changes in patient tissue biopsies and an animal model that could increase local thyroid hormone availability. It concludes that peripheral tissues appear to adapt to reduced thyroid hormone production. No page number is provided in our copy. (LLM, conf=0.94)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“This was followed by almost simultaneous molecular changes in the pituitary, the thyroid gland and the liver.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of the hypothalamus vs. peripheral mechanisms in the fall of serum T3 and T3?
What the sources say
- Supportedcites [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 Abstract states that LPS rapidly induced interleukin-1 mRNA expression and that this was followed by almost simultaneous changes in the pituitary, thyroid and liver. The Pituitary, Thyroid, and Liver and circulation sections report the corresponding changes in gene expression. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Studies in mice on the time course of the changes in thyroid hormone metabolism in the HPT axis during acute illness induced by bacterial endotoxin (lipopolysaccharide; LPS) showed a rapid induction of interleukin-1beta mRNA expression in the hypothalamus, pituitary, thyroid and liver.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of the hypothalamus vs. peripheral mechanisms in the fall of serum T3 and T3?
What the sources say
- Supportedcites [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 Discussion reports strong induction of IL-1 mRNA in the hypothalamus, pituitary, thyroid and liver after LPS administration. It says expression peaked within 1 hour in the pituitary, thyroid and liver and at 3–4 hours in the hypothalamus. Our copy renders the cytokine as “IL-1” rather than spelling out “interleukin-1beta.” (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The results of TH treatment in critical illness have been largely negative in terms of clinical benefit (for review, see Fliers et al.) [83].”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
What the sources say
- Supportedcites [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
The Treatment and management of NTIS section states that randomized trials of T3 or T4 in critical illness have been largely negative in terms of clinical benefit. The review also cautions that the trials were few and small, so no definitive conclusion about effectiveness can yet be made. (LLM, conf=0.95)
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In the paper
“Many experimental and clinical studies pointed to a biphasic neuroendocrine pattern in critical illness as conceptualized by dr Van den Berghe and colleagues (see reviews [87, 94]).”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of the hypothalamus vs. peripheral mechanisms in the fall of serum T3 and T3?
What the sources say
- Supportedcites [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
The section “NTI in Acute and Prolonged Critical Illness: Different Neuroendocrine Paradigms” distinguishes the acute response from the prolonged-illness response. Its discussion and Figure 1 describe different thyroid-axis patterns in those two phases, supporting the cited review as evidence for a biphasic neuroendocrine pattern in critical illness (page not provided). (LLM, conf=0.88)
- Supportedcites [94] Teblick A, Langouche L, Van den Berghe G (2019) Anterior pituitary function in critical illness. Endocr Connect 8(8):R131–R143. https://doi.org/10.1530/EC-19-0318 source
The Introduction states that the hormonal response to critical illness follows a biphasic pattern, and the Conclusion explicitly describes biphasic changes in the neuroendocrine axes. The Introduction cites reviews by Van den Berghe and colleagues for this pattern (References 3–4). (LLM, conf=0.92)
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In the paper
“Serum T3 and T4 fell only after 24 h.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of the hypothalamus vs. peripheral mechanisms in the fall of serum T3 and T3?
What the sources say
- Supportedcites [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 states that decreased liver D1 expression was followed by decreased serum T3 and T4 levels after 24 hours. This directly supports the claimed timing in LPS-treated mice. (LLM, conf=0.95)
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In the paper
“Further statistical analysis showed that the further reduction of T3 was associated with improving patient mortality rates [92, 93].”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of reduced caloric intake?
What the sources say
- Not checked — no full text of the sourcecites [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
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
The Results (page not available) report that tight glucose control further reduced T3 and the T3/rT3 ratio, and that a lower ratio statistically explained part of the benefit in earlier live ICU discharge. The analysis did not show that a reduction in T3 alone was associated with a lower mortality rate; its measured outcome was time to live ICU discharge. (LLM, conf=0.88)
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In the paper
“This was clearly shown in a study involving patients who were critically ill and received TH treatment [84].”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
What the sources say
- Partly supportedcites [84] Peeters RP, Van der GS, Wouters PJ, Darras VM, Kaptein E, Visser TJ, Van den BG (2005) Tissue thyroid hormone levels in critical illness. J Clin Endocrinol Metab 90(12):6498–6507 sourceExperimental — accuracy not yet measured
The Discussion reports that treated critically ill patients had higher serum T3, accompanied by higher tissue T3, but the increase in liver T3 was twice the increase in serum T3. This supports a tissue-specific response to treatment. It does not clearly demonstrate the stated comparison between normalized serum and normalized tissue hormone levels: serum T3 in treated patients remained in the low-normal range, and the paper does not establish whether tissue levels normalized. (LLM, conf=0.84)
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In the paper
“Together, this suggested almost simultaneous involvement of the whole HPT axis in the downregulation of thyroid hormone metabolism during acute illness [15].”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of the hypothalamus vs. peripheral mechanisms in the fall of serum T3 and T3?
What the sources say
- Supportedcites [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 Abstract states that the authors’ results suggested almost simultaneous involvement of the whole HPT axis in downregulating thyroid hormone metabolism during acute illness. The Discussion likewise describes near-simultaneous changes in its central and peripheral components. These findings come from mice with LPS-induced acute illness. (LLM, conf=0.95)
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In the paper
“In this case, serum TH may play a role as TH treatment of these rabbits restores muscle transporter expression to normal [13].”
§ An update on non-thyroidal illness syndrome > Introduction > TH transporters
What the sources say
- Not checked — no full text of the sourcecites [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
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In the paper
“Interestingly, changes in liver TH transporter expression differs between various animal models of NTIS.”
§ An update on non-thyroidal illness syndrome > Introduction > TH transport and metabolism
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“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.”
§ An update on non-thyroidal illness syndrome > Abstract
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“Likewise, acute and chronic NTIS animal models show differential changes in hepatic MCT8 and MCT10 expression.”
§ An update on non-thyroidal illness syndrome > Introduction > TH transporters
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“Similar changes were observed in patients, as MCT8 expression was remarkably low in muscle tissue of patients during acute surgical stress compared to patients with prolonged illness [13].”
§ An update on non-thyroidal illness syndrome > Introduction > TH transporters
What the sources say
- Not checked — no full text of the sourcecites [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
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In the paper
“By inference, hypothalamic TH availability probably increases during NTIS.”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
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In the paper
“Therefore, it is likely that reduced cellular uptake, if present, is just one of many factors involved in NTIS.”
§ An update on non-thyroidal illness syndrome > Introduction > TH transport and metabolism
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“Like the TH transporters and the deiodinases, TR expression levels are also affected in a differential way during NTIS [3].”
§ An update on non-thyroidal illness syndrome > Introduction > TH transport and metabolism
What the sources say
- Not checked — no full text of the sourcecites [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
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In the paper
“Changes in DIO1, DIO2 and DIO3 expression and activity during NTIS have been reported in a variety or organs and tissues [3].”
§ An update on non-thyroidal illness syndrome > Introduction > TH transport and metabolism
What the sources say
- Not checked — no full text of the sourcecites [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
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In the paper
“NTIS generally decreases TH transport in hepatocytes at the level of the plasma membrane.”
§ An update on non-thyroidal illness syndrome > Introduction > TH transport and metabolism
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“Although endocrinologists have been tempted to correct NTIS by TH supplementation, there is at present insufficient evidence that this is beneficial.”
§ An update on non-thyroidal illness syndrome > Abstract
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“These differential changes now have a solid basis in molecular studies on organ-specific TH transporters, receptors and deiodinases.”
§ An update on non-thyroidal illness syndrome > Abstract
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“In contrast to the situation during primary hypothyroidism, however, decreased serum TH concentrations did not coincide with increased serum TSH.”
§ An update on non-thyroidal illness syndrome > Introduction
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In the paper
“Thus, increased intracellular T3 availability appears to play a crucial role in macrophage function.”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
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In the paper
“These findings strongly support a critical role for the TH inactivating enzyme DIO3 in neutrophil function during infection.”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
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“The effects of illness on T3 signaling in muscle also depends on the type of illness.”
§ An update on non-thyroidal illness syndrome > Introduction > TH action
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In the paper
“An early clinical observation was that interleukin 6 (IL-6), a systemic, proinflammatory cytokine, is negatively correlated with serum T3 concentrations in hospitalized patients [49].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Not checked — no full text of the sourcecites [49] Boelen A, Platvoet-ter Schiphorst MC, Wiersinga WM (1993) Association between serum interleukin-6 and serum 3,5,3’- triiodothyronine in nonthyroidal illness. J Clin Endocrinol Metab 77(6):1695–1699 source
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In the paper
“T3 concentrations in post mortem human hypothalamic samples of NTIS patients are lower compared to patients with acute death from trauma [38].”
§ An update on non-thyroidal illness syndrome > Introduction > TH action
What the sources say
- Not checked — no full text of the sourcecites [38] Arem R, Wiener GJ, Kaplan SG, Kim HS, Reichlin S, Kaplan MM (1993) Reduced tissue thyroid hormone levels in fatal illness. Metabolism 42(9):1102–1108 source
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“Liver TRα and TRβ mRNA expression are differentially affected during illness, depending of its severity and duration.”
§ An update on non-thyroidal illness syndrome > Introduction > TH action
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In the paper
“This suggests that TRβ modulates the illness induced changes in hypothalamic deiodinase expression.”
§ An update on non-thyroidal illness syndrome > Introduction > TH action
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In the paper
“By contrast, DIO2 mRNA expression and activity remain unchanged in skeletal muscle tissue of patients with acute surgical stress compared to healthy controls [30].”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Not checked — no full text of the sourcecites [30] Mebis L, Langouche L, Visser TJ, Van den Berghe G (2007) The type II iodothyronine deiodinase is up-regulated in skeletal muscle during prolonged critical illness. J Clin Endocrinol Metab 92(8):3330–3333 source
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In the paper
“The differential regulation of TH transporter, deiodinase and TR expression in acute inflammation, chronic inflammation and sepsis supports the concept that the net result of altered cellular TH metabolism during NTIS determines organ function during specific stages of illness.”
§ An update on non-thyroidal illness syndrome > Introduction > TH action
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“Acute inflammation profoundly decreases TRα1 and TRβ1 mRNA expression in the mouse diaphragm in association with decreased expression of co-activators involved in nuclear receptor activation [47].”
§ An update on non-thyroidal illness syndrome > Introduction > TH action
What the sources say
- Not checked — no full text of the sourcecites [47] Feingold KR, Moser A, Patzek SM, Shigenaga JK, Grunfeld C (2009) Infection decreases fatty acid oxidation and nuclear hormone receptors in the diaphragm. J Lipid Res 50(10):2055–2063 source
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In the paper
“The combination of differentially regulated DIO2 and DIO3 activities is likely to result in altered T3 bioavailability and, therefore, T3 signaling in muscle during illness.”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
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In the paper
“Recently, it became clear that the cellular function of neutrophils and macrophages, both important players of the innate immune system, highly depends on the availability of intracellular TH, regulated via DIO3 and DIO2 respectively.”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
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“One key element is the role of inflammation.”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
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“However, muscle UCP3 and myogenin mRNA expression, which are both T3 target genes, are unaltered in septic patients compared to controls [29].”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Not checked — no full text of the sourcecites [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
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In the paper
“This implies that decreased TR expression may be an adaptation to restore T3 signaling in muscle during sepsis.”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
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In the paper
“TR expression in the diaphragm, the main respiratory muscle with high energy demands, is also affected during inflammation.”
§ An update on non-thyroidal illness syndrome > Introduction > TH action
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In the paper
“Multiple mechanisms are known to be simultaneously involved in the pathogenesis of NTIS.”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
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In the paper
“Likewise, muscle DIO3 is increased in septic patients.”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
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In the paper
“However, blockade of IL-1 signaling in healthy volunteers by recombinant human IL-1 receptor antagonist does not prevent the endotoxin induced alterations in THs [56].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Not checked — no full text of the sourcecites [56] van der Poll T, Van Zee KJ, Endert E, Coyle SM, Stiles DM, Pribble JP, Catalano MA, Moldawer LL, Lowry SF (1995) Interleukin-1 receptor blockade does not affect endotoxin-induced changes in plasma thyroid hormone and thyrotropin concentrations in man. J Clin Endocrinol Metab 80(4):1341–1346 source
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In the paper
“One of the mechanisms involved is central downregulation of the HPT axis, resulting in persistently low serum TH concentrations.”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
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In the paper
“Liver DIO1 expression and activity are downregulated during NTIS.”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
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In the paper
“Recent studies indicate a role for the inflammatory signal transduction pathway nuclear factor κB (NF-κB) in the pathogenesis of NTIS.”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
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In the paper
“It is clear that the typical clinical features of severe hypothyroidism with or without the presence of a goiter are absent in patients with NTIS, even in the presence of a very low serum T3.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
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In the paper
“Other proinflammatory cytokines including interleukin 1β (IL-1β), soluble interleukin-2 receptor (sIL-2R) and tumor necrosis factor (TNF)α are elevated in septic NTIS patients [50].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Not checked — no full text of the sourcecites [50] Monig H, Arendt T, Meyer M, Kloehn S, Bewig B (1999) Activation of the hypothalamo-pituitary-adrenal axis in response to septic or non-septic diseases–implications for the euthyroid sick syndrome. Intensive Care Med 25(12):1402–1406 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Like chronic IL-6 administration, chronic IL-1β administration in rats induces NTIS [55].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Not checked — no full text of the sourcecites [55] Hermus AR, Sweep CG, Demacker PN, van der Meer MJ, Kloppenborg PW, van der Meer JW (1992) Continuous infusion of interleukin-1 beta in rats induces a profound fall in plasma levels of cholesterol and triglycerides. Arterioscler Thromb 12(9):1036–1043. https://doi.org/10.1161/01.atv.12.9.1036 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The illness-induced suppression of TRH in the hypothalamic paraventricular nucleus (PVN) is probably mediated by increased local T3 production, resulting from increased DIO2 expression in tanycytes in combination with decreased DIO3 expression in neurons [68].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Not checked — no full text of the sourcecites [68] de Vries EM, Surovtseva O, Vos WG, Kunst RF, van Beeren M, Kwakkel J, Chassande O, Ackermans MT, Fliers E, Boelen A (2019) Downregulation of Type 3 deiodinase in the hypothalamus during inflammation. Thyroid 29(9):1336–1343. https://doi.org/10.1089/thy.2019.0201 source
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Inflammatory mediators contribute to the illness induced alteration in both DIO2 and DIO3.”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“As a potential complicating factor, serum TSH may be relatively low in critically ill patients with concomitant hypothyroidism as a result of a variety of drugs, for example dopamine which inhibits TSH release (for review see Fliers et al. [81]).”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
What the sources say
- Not checked — no full text of the sourcecites [81] Fliers E, Alkemade A, Wiersinga WM (2001) The hypothalamic-pituitary-thyroid axis in critical illness. Best Pract Res Clin Endocrinol Metab 15(4):453–464 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“The drop in serum leptin during food deprivation is known to induce a decrease in TRH expression in the hypothalamic PVN via leptin receptor mediated changes in neuropeptidergic pathways, ultimately resulting in diminished TSH secretion from the anterior pituitary and decreased TH levels.”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In an acute NTIS mouse model, an increase in serum IL-6 and TNFα concentrations precedes the decrease in serum T3 and T4 [51].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Not checked — no full text of the sourcecites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Furthermore, a stress-induced elevation of glucocorticoids in animals contributes to suppressed serum TSH, T4 and T3 levels [70].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Not checked — no full text of the sourcecites [70] Bianco AC, Nunes MT, Hell NS, Maciel RM (1987) The role of glucocorticoids in the stress-induced reduction of extrathyroidal 3,5,3’-triiodothyronine generation in rats. Endocrinology 120(3):1033–1038. https://doi.org/10.1210/endo-120-3-1033 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In support of an important role for IL-6, chronic IL-6 infusions result in decreased serum T4, T3 and hypothalamic TRH expression in rats [53].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Not checked — no full text of the sourcecites [53] van Haasteren GA, van der Meer MJ, Hermus AR, Linkels E, Klootwijk W, Kaptein E, van Toor H, Sweep CG, Visser TJ, de Greef WJ (1994) Different effects of continuous infusion of interleukin-1 and interleukin-6 on the hypothalamic-hypophysial-thyroid axis. Endocrinology 135(4):1336–1345. https://doi.org/10.1210/endo.135.4.7925094 source
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The reported studies thus far were not adequately powered to detect clinically meaningful differences.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At present, there is no clinical evidence to support TH treatment of NTIS in critically ill patients.”
§ An update on non-thyroidal illness syndrome > Conclusion
plain- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“This prolonged phase of critical illness is characterized by an overall suppression of several neuroendocrine axes including the HPT axis.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of the hypothalamus vs. peripheral mechanisms in the fall of serum T3 and T3?
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“a subanalysis of this trial showed that late feeding enhanced the changes in circulating concentrations of serum TH.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of reduced caloric intake?
What the sources say
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A number of small studies showed that iv TRH in combination with GHRP2can restore circulating concentrations of TH and TSH pulsatility to a remarkable extent [88].”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
What the sources say
- Not checked — no full text of the sourcecites [88] Van den Berghe G, Baxter RC, Weekers F, Wouters P, Bowers CY, Iranmanesh A, Veldhuis JD, Bouillon R (2002) The combined administration of GH-releasing peptide-2 (GHRP-2), TRH and GnRH to men with prolonged critical illness evokes superior endocrine and metabolic effects compared to treatment with GHRP-2 alone. Clin Endocrinol 56(5):655–669 source
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The question whether interventions aimed at normalizing TH concentrations in patients with NTIS in the framework of protracted critical illness are beneficial has not been answered to date.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings seem to point to insufficient hypothalamic drive of pituitary TSH release in protracted critical illness.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“In the prolonged phase of critical illness, hypothalamic thyrotropin releasing hormone (TRH) expression is suppressed as shown both in animal and human studies, contributing to reduced TSH secretion and reduced thyroidal hormone release.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of the hypothalamus vs. peripheral mechanisms in the fall of serum T3 and T3?
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Ability to tolerate a fasting response thus seemed to be beneficial.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of reduced caloric intake?
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“NTIS rather represents a complex set of marked and differential changes in TH physiology, both at the level of the HPT axis and at the organ and tissue level (Fig. 1).”
§ An update on non-thyroidal illness syndrome > Conclusion
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these findings suggest that thyroid economy is affected by decreased nutritional intake during acute critical illness”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of reduced caloric intake?
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, peripheral TH metabolism is clearly affected by decreased nutritional intake during acute critical illness.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of reduced caloric intake?
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A small RCT [85] in patients with dilated cardiomyopathy showed beneficial effects of medium-term (3 months) levothyroxine treatment on cardiac performance, whereas another RCT [86] showed that the TH analogue 3,5 di-iodothyropropionic acid improved some hemodynamic variables in heart failure.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
What the sources say
- Not checked — no full text of the sourcecites [86] Goldman S, McCarren M, Morkin E, Ladenson PW, Edson R, Warren S, Ohm J, Thai H, Churby L, Barnhill J, O’Brien T, Anand I, Warner A, Hattler B, Dunlap M, Erikson J, Shih MC, Lavori P (2009) DITPA (3,5-diiodothyropropionic acid), a thyroid hormone analog to treat heart failure: phase II trial veterans affairs cooperative study. Circulation 119(24):3093–3100. https://doi.org/10.1161/CIRCULATIONAHA.108.834424 source
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, at present there are no studies on the use of hypothalamic neuropeptides in patients with protracted critical illness reporting clinically relevant endpoints related to morbidity and mortality.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“A small RCT [85] in patients with dilated cardiomyopathy showed beneficial effects of medium-term (3 months) levothyroxine treatment on cardiac performance, whereas another RCT [86] showed that the TH analogue 3,5 di-iodothyropropionic acid improved some hemodynamic variables in heart failure.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
What the sources say
- Not checked — no full text of the sourcecites [85] Moruzzi P, Doria E, Agostoni PG (1996) Medium-term effectiveness of L-thyroxine treatment in idiopathic dilated cardiomyopathy. Am J Med 101(5):461–467 source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Moreover, this strategy improved bone markers and anabolic variables.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Although the use of TH treatment in patients with heart failure has not been adequately studied, some trials have reported encouraging findings.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“As fasting in healthy individuals induces complex changes in the HPT axis including low serum T3 without increased TSH, decreased caloric intake during severe illness is likely to contribute to the development of NTIS [90].”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of reduced caloric intake?
What the sources say
- Not checked — no full text of the sourcecites [90] Boelen A, Wiersinga WM, Fliers E (2008) Fasting-induced changes in the hypothalamus-pituitary-thyroid axis. Thyroid 18(2):123–129 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Only a small number of RTCs involving heterogeneous NTIS patient groups, ranging from protracted critical illness to elective heart surgery in otherwise healthy participants, have assessed the effects of treatment with THs.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
plain- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In sum, no definitive conclusion about the efficacy of TH treatment in patients in the ICU with NTIS can be made at present.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“both the central (hypothalamus and pituitary) and peripheral (thyroid gland and target organs) components of the HPT axis show robust changes during NTIS.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of the hypothalamus vs. peripheral mechanisms in the fall of serum T3 and T3?
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, in many patients admitted to the ICU a subsequent prolonged phase of critical illness sets in.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of the hypothalamus vs. peripheral mechanisms in the fall of serum T3 and T3?
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, normalizing TH concentrations in serum does not equal normalizing TH tissue concentrations and local TH action.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
plain- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Indeed, many studies support the concept that the acute phase of critical illness induces rapid neuroendocrine changes directing the organism toward a catabolic state to ensure provision of energy sources, postponing anabolic processes.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of the hypothalamus vs. peripheral mechanisms in the fall of serum T3 and T3?
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 54
- Probably not a substantial claim. 32
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Disputedcites [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 sourceExperimental — accuracy not yet measured
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.
- Could not verifycites [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 sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Disputed
Every source the paper cites for this claim was checked and supports it.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Supportedcites [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
The Results report D2 staining in hypothalamic glial cells and cells lining the third ventricle, and D3 staining in neurons of the IFN, PVN, and SON. The Discussion identifies tanycytes among the D2-immunoreactive cells described in earlier rat studies, while noting that this study could not distinguish tanycyte processes from blood-vessel walls in some human staining. (LLM, conf=0.90)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Could not verifycites [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 sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Could not verify
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Not checked — no full text of the sourcecites [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
- Supportedcites [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
The Hepatic deiodinase activity and expression section reports significantly increased liver D3 activity in 36-hour-fasted rats. The Discussion also suggests that caloric restriction may affect liver D3 activity during prolonged illness. The diminished-food-intake clause is separately cited to [25]. (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Of note, these alterations are unrelated to local tissue T3 concentrations and their functional consequences are unknown at present [12].”
§ An update on non-thyroidal illness syndrome > Introduction > TH transporters
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Illness results in increased DIO2 mRNA expression and activity [12, 15–17] while hypothalamic DIO3 decreases [18, 19].”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Supportedcites [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
This source is cited for the DIO2 clause; the DIO3 clause has separate citations. The Hypothalamus results report increased D2 mRNA in LPS-treated mice, and the Discussion reports increased hypothalamic D2 activity during acute LPS-induced illness in rats. The paper reports the activity finding from another study rather than measuring it in these mice. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [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
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
- Supportedcites [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
The citation is attached to the decrease in hypothalamic DIO3, not the preceding DIO2 activity claim. The Discussion reports significantly decreased D3 mRNA expression in tissue samples containing the hypothalamic PVN after turpentine-induced inflammation; no page number is provided in our copy. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Supportedcites [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
The Muscle D2 expression section reports increased muscle D2 mRNA after turpentine injection, most prominently on days 1–2, and decreased mRNA 48 hours after S. pneumoniae infection in mice. The Introduction identifies the infection model as causing sepsis. The claim’s human finding is attached to a different citation, not this source. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In addition, DIO2 knockdown impairs macrophage phagocytosis while blunting the cytokine response upon stimulation with bacterial endotoxin [36, 37].”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Supportedcites [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
The Phagocytosis section reports lower particle uptake after D2 knockdown in macrophages. The Cytokine expression section reports attenuated LPS-induced IL-1β and GM-CSF mRNA expression, though IL-10 and IFNβ were unaffected; thus the cytokine finding concerns specific proinflammatory markers, not all cytokines. (LLM, conf=0.93)
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
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In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > TH action
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Supportedcites [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
The results section on inflammation-induced D2 reports that LPS stimulation increased D2 mRNA in RAW264.7 macrophages and that TRα1 and MCT10 also increased. The Discussion describes D2 as contributing to local T3 production and proposes that this may enhance the macrophage immune response, consistent with the citing sentence’s inference about thyroid hormone action. (LLM, conf=0.90)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“DIO2 is the main deiodinase present in macrophages and TRα1 is their dominant TR [36].”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > TH action
What the sources say
- Supportedcites [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
The ‘Inflammation modulates diaphragm fiber type’ section reports increased Dio3 at 24 hours and decreased Dio2 at 40 hours after sepsis, and describes the sepsis findings as consistent with decreased TH signaling. The same section reports decreased Dio3 during chronic inflammation at 48 and 120 hours; the sepsis-related expression changes occurred at different times. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Liver TRα and TRβ expression in rodents decrease during acute illness [15, 39] but not during chronic inflammation and bacterial sepsis.”
§ An update on non-thyroidal illness syndrome > Introduction > TH action
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Finally, DIO2 knockdown increases mortality in zebrafish embryos during pneumococcal meningitis, which can be restored by T3 administration during infection [37].”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Supportedcites [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 ‘A lack of D2 impairs survival of zebrafish embryos during pneumococcal meningitis’ reports significantly increased mortality after D2 knockdown compared with controls, and says T3 addition rescued the effect. The Figure 1 caption also describes T3 addition to the D2-knockdown group during bacterial meningitis. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Acute inflammation in mice decreases muscle DIO3 [31] while chronic inflammation in the same species increases muscle DIO3.”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Supportedcites [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
The Forelimb muscle results report that LPS-induced acute inflammation decreased muscle D3 mRNA in wild-type mice. Citation [31] is attached to the acute-inflammation clause, not the separate claim about chronic inflammation. The measured outcome was mRNA expression, not D3 activity. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > TH action
What the sources say
- Supportedcites [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
The Discussion (page not specified in our copy) reports similar TRα1, TRα2, and TRβ1 protein levels and no significant difference in thyroid hormone-regulated mRNAs between normal and chronically diseased liver. It describes the maintained mRNA expression despite reduced circulating thyroid hormones as consistent with tissue euthyroidism. The claim's “indicating” is an inference, as it is in the source. (LLM, conf=0.90)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Diminished food intake plays an additional role as NTIS is associated with diminished appetite and nutritional intake [71–74].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Supportedcites [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 that LPS decreased liver TRβ1 and D1 mRNA expression in mice. The Discussion describes limited SRC-1 availability as a possible explanation for decreased liver D1 expression, matching the claim’s cautious wording. Our copy does not provide passage-level page numbers. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Not checked — no full text of the sourcecites [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
- Supportedcites [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
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
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Every source the paper cites for this claim was checked and supports it.
In the paper
“the toleration of a nutritional deficit during the first week of critical illness resulted in fewer complications and accelerated recovery [91].”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of reduced caloric intake?
What the sources say
- Supportedcites [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
The introduction (p. 507) describes the late-initiation strategy as tolerating hypocaloric nutrition during the first week while providing early enteral nutrition. The Discussion reports that withholding parenteral nutrition until day 8 was associated with fewer ICU infections and shorter ventilation, ICU, and hospital stays. The finding applies to ICU adults at nutritional risk who were not chronically malnourished, compared with early supplemental parenteral nutrition. (LLM, conf=0.91)
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In the paper
“In the hypothalamus, D2 mRNA was strongly increased whereas preproTRH mRNA expression did not change after LPS.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of the hypothalamus vs. peripheral mechanisms in the fall of serum T3 and T3?
What the sources say
- Supportedcites [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 Hypothalamus results report that preproTRH mRNA did not change compared with controls 1–24 hours after LPS, while D2 mRNA increased significantly threefold, peaking at 6–8 hours. These findings directly support the claim in LPS-treated mice. (LLM, conf=0.95)
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The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of reduced caloric intake?
What the sources say
- Not checked — no full text of the sourcecites [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
- Supportedcites [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
The Discussion (page not supplied) states that tight glucose control targeted age-normal fasting levels, improved survival and reduced morbidity in critically ill children, while further lowering T3 and raising rT3. It describes this as aggravated peripheral thyroid hormone inactivation and a fasting-like response. (LLM, conf=0.94)
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In the paper
“By contrast, the central lowering of T4 could be harmful (for review see Fliers et al., [83].”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of reduced caloric intake?
What the sources say
- Supportedcites [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
The ‘Pathogenesis of NTIS > Role of nutrition’ passage states verbatim that central lowering of T4 could be harmful. It presents this as a possibility, matching the citing sentence’s qualification. (LLM, conf=0.95)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“These responses include increased tissue expression of monocarboxylate transporters, upregulation of type-2 deiodinase activity, and increased sensitivity at the receptor level [87].”
§ An update on non-thyroidal illness syndrome > Remaining questions > Is thyroid hormone signaling disrupted during prolonged NTIS?
What the sources say
- Supportedcites [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
In “Prolonged critical illness,” the paper reports increased MCT-8 expression and D2 expression and activity in peripheral tissues. It also describes a receptor-isoform measure as a surrogate for thyroid hormone sensitivity and summarizes these changes as adaptations during prolonged critical illness; the receptor-level response is therefore supported as an inferred change, not a direct sensitivity measurement. (LLM, conf=0.89)
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Introduction
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“A healthy liver predominantly expresses DIO1, with very low DIO3 expression.”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Abstract
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In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > TH transporters
What the sources say
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In mice, muscle TH transporter expression is low during acute inflammation and bacterial sepsis but remains unchanged during chronic inflammation.”
§ An update on non-thyroidal illness syndrome > Introduction > TH transporters
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Abstract
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In theory, reduced cellular TH uptake by itself would cause tissue hypothyroidism, but this is generally not observed.”
§ An update on non-thyroidal illness syndrome > Introduction > TH transport and metabolism
hedgeddirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Abstract
boosted- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Once elevated, rT3 does not increase much more in patients with more severe illness.”
§ An update on non-thyroidal illness syndrome > Introduction
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Introduction > TH transport and metabolism
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > Tissue and organ specific responses
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“MCT8 and OATP1C1 are of crucial importance for the regulation of TH activity in the brain and thus for brain development [2].”
§ An update on non-thyroidal illness syndrome > Introduction > TH transport and metabolism
What the sources say
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, it is now generally accepted that serum rT3 may be normal or even reduced in some NTIS cases.”
§ An update on non-thyroidal illness syndrome > Introduction
hedged- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Abstract
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Hypothalamic MCT10 and OATP1C1 expression increases during critical illness in experimental animals while hypothalamic MCT8 mRNA expression does not change.”
§ An update on non-thyroidal illness syndrome > Introduction > TH transporters
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Introduction
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Introduction > TH transport and metabolism
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Prolonged illness in rabbits results in markedly increased MCT10 expression while MCT8 mRNA expression does not change.”
§ An update on non-thyroidal illness syndrome > Introduction > TH transporters
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“TH action is determined by intracellular T3 concentration and TR status.”
§ An update on non-thyroidal illness syndrome > Introduction > TH action
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This may result in a coordinated breakdown of both T4 and T3, finally leading to increased intracellular T2 levels.”
§ An update on non-thyroidal illness syndrome > Introduction > TH action
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > TH action
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Of note, both T3 and T2 are known to regulate mitochondrial activity in skeletal muscle [45, 46].”
§ An update on non-thyroidal illness syndrome > Introduction > TH action
What the sources say
- Not checked — no full text of the sourcecites [45] Harper ME, Seifert EL (2008) Thyroid hormone effects on mitochondrial energetics. Thyroid 18(2):145–156 source
- Not checked — no full text of the sourcecites [46] Moreno M, Lombardi A, Silvestri E, Lanni A, Goglia F (2008) Metabolic effects of thyroid hormone derivatives. Thyroid 18(2):239–253 source
boosteddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > TH action
What the sources say
- Not checked — no full text of the sourcecites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“DIO3 is also expressed in human neutrophils [34] and present in intracellular granules involved in bacterial killing and in neutrophil extracellular traps (NETs) [34].”
§ An update on non-thyroidal illness syndrome > Introduction > Type 1, type 2 and type 3 deiodinases
What the sources say
- Not checked — no full text of the sourcecites [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
plain- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“These findings are in line with chronic inflammation mouse and rat models.”
§ An update on non-thyroidal illness syndrome > Introduction > TH action
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The determination of rT3 is, however, not routinely available in many hospitals and does not reliably distinguish between hypothyroidism and NTIS.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Finding positive anti thyroid peroxidase (TPO) antibody titers supports the diagnosis of primary hypothyroidism but does not prove it.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“If both T3 and T4 are very low a potentially fatal outcome may be assumed.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Potential caveats include a clearly elevated TSH suggesting the presence of prior hypothyroidism.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > Mechanism of altered TH metabolism
What the sources say
- Not checked — no full text of the sourcecites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This may depend on disease type and severity, the need of prolonged vital support, and environmental factors including parenteral nutrition.”
§ An update on non-thyroidal illness syndrome > Conclusion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of the hypothalamus vs. peripheral mechanisms in the fall of serum T3 and T3?
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of reduced caloric intake?
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Unfortunately at this stage we do not know whether this approach can improve clinical outcomes.”
§ An update on non-thyroidal illness syndrome > Remaining questions > Is thyroid hormone signaling disrupted during prolonged NTIS?
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of the hypothalamus vs. peripheral mechanisms in the fall of serum T3 and T3?
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It should be noted, however, that at this time, there is no direct evidence support this hypothesis.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of reduced caloric intake?
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Moreover, use of anticonvulsants and glucocorticoids should be noted, since these agents can lower (F)T4.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No solid data are available to answer the question if the neuroendocrine changes in prolonged critical illness are harmful and should be treated.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of the hypothalamus vs. peripheral mechanisms in the fall of serum T3 and T3?
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Remaining questions > Is thyroid hormone signaling disrupted during prolonged NTIS?
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and that the inactivation of T4–rT3 and T3–T2, as part of the fasting response, might be a beneficial adaptation during acute illness.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of reduced caloric intake?
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Peripheral mechanisms related to macronutrient restriction occur already in the acute phase in critical illness and appear beneficial.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of the hypothalamus vs. peripheral mechanisms in the fall of serum T3 and T3?
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The net result of altered tissue TH metabolism may be beneficial or maladaptive, dependent on disease duration and severity.”
§ An update on non-thyroidal illness syndrome > Conclusion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Furthermore, most studies used rather high doses of either T4 or T3, probably inducing further suppression of pituitary TSH release.”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of reduced caloric intake?
What the sources say
- Not checked — no full text of the sourcecites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Critical illness is associated with loss of appetite and poor nutritional intake.”
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of reduced caloric intake?
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Whether the observed changes in critically ill patients defined as NTIS are beneficial or deleterious is currently unknown.”
§ An update on non-thyroidal illness syndrome > Conclusion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > Differential diagnosis and clinical implications
What the sources say
- Not checked — no full text of the sourcecites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.”
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?
The cited source says what the claim attributes to it.
In the citing paper
“TH measurement is also required to complement TSH measurement in a number of clinical situations (Table 2) such as pregnancy,60 intercurrent illness when TSH can be suppressed (the nonthyroidal illness syndrome61,62), and the initial treatment of hypo-63 or hyperthyroidism64 as the response of the pituitary-thyroid axis can be delayed after a change in thyroid status.57”
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ An update on non-thyroidal illness syndrome > Remaining questions > What is the relative role of reduced caloric intake?
“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].”
§ An update on non-thyroidal illness syndrome > Introduction > TH transport and metabolism
“type 3 deiodinase (DIO3) which catalyzes only inner-ring monodeiodination (converting its preferred substrate T3 into T2 but also T4 into rT3 thereby inactivating TH) [8].”
Citations
Cites
Early versus late parenteral nutrition in critically ill adults
Casaer, M. P., Mesotten, D., Hermans, G., Wouters, P. J., Schetz, M., Meyfroidt, G., Van Cromphaut, S., Ingels, C., Meersseman, P., Muller, J., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1102662 · Cited by 1,696
Deiodinases: implications of the local control of thyroid hormone action
Bianco, A. C., & Kim, B. W. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29812 · Cited by 845
Chan, J. L., Heist, K., DePaoli, A. M., Veldhuis, J. D., & Mantzoros, C. S. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17490 · Cited by 697
Vlasselaers, D., Milants, I., Desmet, L., Wouters, P. J., Vanhorebeek, I., van den Heuvel, I., Mesotten, D., Casaer, M. P., Meyfroidt, G., Ingels, C., et al. (2009) · The Lancet · doi:10.1016/s0140-6736(09)60044-1 · Cited by 554
Peeters, R. P., Wouters, P. J., Kaptein, E., van Toor, H., Visser, T. J., & Van den Berghe, G. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-022013 · Cited by 452
Thyroid function in critically ill patients
Fliers, E., Bianco, A. C., Langouche, L., & Boelen, A. (2015) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(15)00225-9 · Cited by 441
Self-citationHennemann, G., Docter, R., Friesema, E. C. H., de Jong, M., Krenning, E. P., & Visser, T. J. (2001) · Endocrine Reviews · doi:10.1210/edrv.22.4.0435 · Cited by 394
Mechanisms of thyroid hormone receptor-specific nuclear and extra nuclear actions
Bassett, J. H. D., Harvey, C. B., & Williams, G. R. (2003) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2003.10.033 · Cited by 392
Minireview: Thyroid Hormone Transporters: The Knowns and the Unknowns
Visser, W. E., Friesema, E. C. H., & Visser, T. J. (2011) · Molecular Endocrinology · doi:10.1210/me.2010-0095 · Cited by 390
Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans
Luiza Maia, A. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25083 · Cited by 360
Cited by
Sorted by citations
Deiodinases control local cellular and systemic thyroid hormone availability
Köhrle, J., & Frädrich, C. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.09.024 · Cited by 133
Van Uytfanghe, K., Ehrenkranz, J., Halsall, D., Hoff, K., Loh, T. P., Spencer, C. A., Köhrle, J., & ATA Thyroid Function Tests Writing Group (2023) · Thyroid® · doi:10.1089/thy.2023.0169 · Cited by 100
“…number of clinical situations (Table 2) such as pregnancy, 60 intercurrent illness when TSH can be suppressed (the nonthyroidal illness syndrome 61,62 ), and the initial treatment of hypo-63 or hyperthyroidism 64 as the response of the pituitary-thyroid axis can be delayed after a change in…”
BackgroundCOVID-19 and thyroid function: What do we know so far?
Rossetti, C. L., Cazarin, J., Hecht, F., Beltrão, F. E. D. L., Ferreira, A. C. F., Fortunato, R. S., Ramos, H. E., & de Carvalho, D. P. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1041676 · Cited by 86
Hypothyroidism: The difficulty in attributing symptoms to their underlying cause
Jansen, H. I., Boelen, A., Heijboer, A. C., Bruinstroop, E., & Fliers, E. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1130661 · Cited by 74
Self-citationThyroid hormone system disrupting chemicals
Köhrle, J., & Frädrich, C. (2021) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2021.101562 · Cited by 72
Metadata
- 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
- Published
- 2020-12-15
- Volume
- 44
- Issue
- 8
- Pages
- 1597-1607
- ISSN
- 0391-4097 (ISSN-L)
- 1720-8386
- PMC
- PMC8285315
- OpenAlex
- W3112055569
- Semantic Scholar
- d7f0ff8bc65037551ff01b95625ed1c4dafc3647
- Cited by
- 218
- References
- 95
- Citations by year
- 2026: 51 · 2025: 40 · 2024: 49 · 2023: 39 · 2022: 27 · 2021: 12
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Endocrinological Investigation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (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.
A language model drew the claims from the paper on 2026-10-08, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-08 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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