An update on non-thyroidal illness syndrome

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].”

What the sources say

• Disputed

  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.

  cites [69] Nicoloff JT, Fisher DA, Appleman MD Jr (1970) The role of glucocorticoids in the regulation of thyroid function in man. J Clin Invest 49(10):1922–1929. https://doi.org/10.1172/JCI106411 sourceExperimental — accuracy not yet measured
• ?Could not verify

  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)

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

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].”

What the sources say

• Supported

  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)

  cites [14] Alkemade A, Friesema EC, Unmehopa UA, Fabriek BO, Kuiper GG, Leonard JL, Wiersinga WM, Swaab DF, Visser TJ, Fliers E (2005) Neuroanatomical pathways for thyroid hormone feedback in the human hypothalamus. J Clin Endocrinol Metab 90(7):4322–4334 source

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].”

What the sources say

• ?Could not verify

  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)

  cites [15] Boelen A, Kwakkel J, Thijssen-Timmer DC, Alkemade A, Fliers E, Wiersinga WM (2004) Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice. J Endocrinol 182(2):315–323 sourceExperimental — accuracy not yet measured
• ?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 supported

  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)

  cites [22] Peeters RP, Wouters PJ, Kaptein E, van Toor H, Visser TJ, Van den Berghe G (2003) Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. J Clin Endocrinol Metab 88(7):3202–3211 sourceExperimental — accuracy not yet measured

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].”

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
• Supported

  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)

  cites [24] de Vries EM, van Beeren HC, Ackermans MT, Kalsbeek A, Fliers E, Boelen A (2015) Differential effects of fasting vs. food restriction on liver thyroid hormone metabolism in male rats. J Endocrinol 224(1):25–35. https://doi.org/10.1530/JOE-14-0533 source
• ?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

In the paper

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

What the sources say

• Partly supported

  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)

  cites [12] Mebis L, Debaveye Y, Ellger B, Derde S, Ververs EJ, Langouche L, Darras VM, Fliers E, Visser TJ, Van den BG (2009) Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness. Crit Care 13(5):R147 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Partly supported

  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)

  cites [12] Mebis L, Debaveye Y, Ellger B, Derde S, Ververs EJ, Langouche L, Darras VM, Fliers E, Visser TJ, Van den BG (2009) Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness. Crit Care 13(5):R147 sourceExperimental — accuracy not yet measured
• Supported

  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)

  cites [15] Boelen A, Kwakkel J, Thijssen-Timmer DC, Alkemade A, Fliers E, Wiersinga WM (2004) Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice. J Endocrinol 182(2):315–323 source
• ?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 supported

  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)

  cites [17] Boelen A, Kwakkel J, Wieland CW, St Germain DL, Fliers E, Hernandez A (2009) Impaired bacterial clearance in type 3 deiodinase-deficient mice infected with Streptococcus pneumoniae. Endocrinology 150(4):1984–1990. https://doi.org/10.1210/en.2008-1133 sourceExperimental — accuracy not yet measured
• ?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
• Supported

  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)

  cites [19] Boelen A, Kwakkel J, Wiersinga WM, Fliers E (2006) Chronic local inflammation in mice results in decreased TRH and type 3 deiodinase mRNA expression in the hypothalamic paraventricular nucleus independently of diminished food intake. J Endocrinol 191(3):707–714 source

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].”

What the sources say

• Supported

  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)

  cites [28] Kwakkel J, van Beeren HC, Ackermans MT, Platvoet-ter Schiphorst MC, Fliers E, Wiersinga WM, Boelen A (2009) Skeletal muscle deiodinase type 2 regulation during illness in mice. JEndocrinol 203(2):263–270 source
• ?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

In the paper

“In addition, DIO2 knockdown impairs macrophage phagocytosis while blunting the cytokine response upon stimulation with bacterial endotoxin [36, 37].”

What the sources say

• Supported

  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)

  cites [36] Kwakkel J, Surovtseva OV, de Vries EM, Stap J, Fliers E, Boelen A (2014) A novel role for the thyroid hormone-activating enzyme type 2 deiodinase in the inflammatory response of macrophages. Endocrinology 155(7):2725–2734. https://doi.org/10.1210/en.2013-2066 source
• Partly supported

  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)

  cites [37] van der Spek AH, Surovtseva OV, Jim KK, van Oudenaren A, Brouwer MC, Vandenbroucke-Grauls C, Leenen PJM, van de Beek D, Hernandez A, Fliers E, Boelen A (2018) Regulation of intracellular triiodothyronine is essential for optimal macrophage function. Endocrinology 159(5):2241–2252. https://doi.org/10.1210/en.2018-00053 sourceExperimental — accuracy not yet measured

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].”

What the sources say

• Partly supported

  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)

  cites [12] Mebis L, Debaveye Y, Ellger B, Derde S, Ververs EJ, Langouche L, Darras VM, Fliers E, Visser TJ, Van den BG (2009) Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness. Crit Care 13(5):R147 sourceExperimental — accuracy not yet measured
• ?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

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].”

What the sources say

• Supported

  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)

  cites [36] Kwakkel J, Surovtseva OV, de Vries EM, Stap J, Fliers E, Boelen A (2014) A novel role for the thyroid hormone-activating enzyme type 2 deiodinase in the inflammatory response of macrophages. Endocrinology 155(7):2725–2734. https://doi.org/10.1210/en.2013-2066 source

In the paper

“DIO2 is the main deiodinase present in macrophages and TRα1 is their dominant TR [36].”

What the sources say

• Partly supported

  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)

  cites [36] Kwakkel J, Surovtseva OV, de Vries EM, Stap J, Fliers E, Boelen A (2014) A novel role for the thyroid hormone-activating enzyme type 2 deiodinase in the inflammatory response of macrophages. Endocrinology 155(7):2725–2734. https://doi.org/10.1210/en.2013-2066 sourceExperimental — accuracy not yet measured

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].”

What the sources say

• Supported

  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)

  cites [48] Bloise FF, van der Spek AH, Surovtseva OV, Ortiga-Carvalho TM, Fliers E, Boelen A (2016) Differential effects of sepsis and chronic inflammation on diaphragm muscle fiber type, thyroid hormone metabolism, and mitochondrial function. Thyroid 26(4):600–609. https://doi.org/10.1089/thy.2015.0536 source

In the paper

“Liver TRα and TRβ expression in rodents decrease during acute illness [15, 39] but not during chronic inflammation and bacterial sepsis.”

What the sources say

• Partly supported

  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)

  cites [15] Boelen A, Kwakkel J, Thijssen-Timmer DC, Alkemade A, Fliers E, Wiersinga WM (2004) Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice. J Endocrinol 182(2):315–323 sourceExperimental — accuracy not yet measured
• ?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

In the paper

“Finally, DIO2 knockdown increases mortality in zebrafish embryos during pneumococcal meningitis, which can be restored by T3 administration during infection [37].”

What the sources say

• Supported

  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)

  cites [37] van der Spek AH, Surovtseva OV, Jim KK, van Oudenaren A, Brouwer MC, Vandenbroucke-Grauls C, Leenen PJM, van de Beek D, Hernandez A, Fliers E, Boelen A (2018) Regulation of intracellular triiodothyronine is essential for optimal macrophage function. Endocrinology 159(5):2241–2252. https://doi.org/10.1210/en.2018-00053 source

In the paper

“Acute inflammation in mice decreases muscle DIO3 [31] while chronic inflammation in the same species increases muscle DIO3.”

What the sources say

• Supported

  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)

  cites [31] Kwakkel J, Chassande O, van Beeren HC, Fliers E, Wiersinga WM, Boelen A (2010) Thyroid hormone receptor alpha modulates lipopolysaccharide-induced changes in peripheral thyroid hormone metabolism. Endocrinology 151(4):1959–1969. https://doi.org/10.1210/en.2009-1049 source

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].”

What the sources say

• Supported

  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)

  cites [41] Chamba A, Neuberger J, Strain A, Hopkins J, Sheppard MC, Franklyn JA (1996) Expression and function of thyroid hormone receptor variants in normal and chronically diseased human liver. J Clin Endocrinol Metab 81(1):360–367 source

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.”

What the sources say

• Partly supported

  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)

  cites [17] Boelen A, Kwakkel J, Wieland CW, St Germain DL, Fliers E, Hernandez A (2009) Impaired bacterial clearance in type 3 deiodinase-deficient mice infected with Streptococcus pneumoniae. Endocrinology 150(4):1984–1990. https://doi.org/10.1210/en.2008-1133 sourceExperimental — accuracy not yet measured

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].”

What the sources say

• Partly supported

  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)

  cites [59] Kwakkel J, Wiersinga WM, Boelen A (2006) Differential involvement of nuclear factor-kappaB and activator protein-1 pathways in the interleukin-1beta-mediated decrease of deiodinase type 1 and thyroid hormone receptor beta1 mRNA. J Endocrinol 189(1):37–44 sourceExperimental — accuracy not yet measured
• ?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

In the paper

“Diminished food intake plays an additional role as NTIS is associated with diminished appetite and nutritional intake [71–74].”

What the sources say

• Partly supported

  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)

  cites [71] Schutz P, Bally M, Stanga Z, Keller U (2014) Loss of appetite in acutely ill medical inpatients: physiological response or therapeutic target? Swiss Med Wkly 144:w13957. https://doi.org/10.4414/smw.2014.13957 sourceExperimental — accuracy not yet measured
• ?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

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].”

What the sources say

• Supported

  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)

  cites [15] Boelen A, Kwakkel J, Thijssen-Timmer DC, Alkemade A, Fliers E, Wiersinga WM (2004) Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice. J Endocrinol 182(2):315–323 source
• ?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

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].”

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
• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [64] de Vries EM, Nagel S, Haenold R, Sundaram SM, Pfrieger FW, Fliers E, Heuer H, Boelen A (2016) The role of hypothalamic NF-kappaB Signaling in the response of the HPT-Axis to acute inflammation in female mice. Endocrinology 157(7):2947–2956. https://doi.org/10.1210/en.2016-1027 source

In the paper

“the toleration of a nutritional deficit during the first week of critical illness resulted in fewer complications and accelerated recovery [91].”

What the sources say

• Supported

  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)

  cites [91] Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, Van Cromphaut S, Ingels C, Meersseman P, Muller J, Vlasselaers D, Debaveye Y, Desmet L, Dubois J, Van Assche A, Vanderheyden S, Wilmer A, Van den Berghe G (2011) Early versus late parenteral nutrition in critically ill adults. N Engl J Med 365(6):506–517. https://doi.org/10.1056/NEJMoa1102662 source

In the paper

“In the hypothalamus, D2 mRNA was strongly increased whereas preproTRH mRNA expression did not change after LPS.”

What the sources say

• Supported

  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)

  cites [15] Boelen A, Kwakkel J, Thijssen-Timmer DC, Alkemade A, Fliers E, Wiersinga WM (2004) Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice. J Endocrinol 182(2):315–323 source

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.”

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
• Supported

  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)

  cites [93] Gielen M, Mesotten D, Wouters PJ, Desmet L, Vlasselaers D, Vanhorebeek I, Langouche L, Van den Berghe G (2012) Effect of tight glucose control with insulin on the thyroid axis of critically ill children and its relation with outcome. J Clin Endocrinol Metab 97(10):3569–3576. https://doi.org/10.1210/jc.2012-2240 source

In the paper

“By contrast, the central lowering of T4 could be harmful (for review see Fliers et al., [83].”

What the sources say

• Supported

  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)

  cites [83] Fliers E, Bianco AC, Langouche L, Boelen A (2015) Thyroid function in critically ill patients. Lancet Diabetes Endocrinol 3(10):816–825. https://doi.org/10.1016/S2213-8587(15)00225-9 source

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].”

What the sources say

• Supported

  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)

  cites [87] Van den Berghe G (2014) Non-thyroidal illness in the ICU: a syndrome with different faces. Thyroid. https://doi.org/10.1089/thy.2014.0201 source

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.”

In the paper

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

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.”

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].”

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

In the paper

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

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.”

In the paper

“In theory, reduced cellular TH uptake by itself would cause tissue hypothyroidism, but this is generally not observed.”

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.”

In the paper

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

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.”

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

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].”

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

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].”

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

In the paper

“However, it is now generally accepted that serum rT3 may be normal or even reduced in some NTIS cases.”

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.”

In the paper

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

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.”

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.”

In the paper

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

In the paper

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

In the paper

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

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].”

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

In the paper

“Of note, both T3 and T2 are known to regulate mitochondrial activity in skeletal muscle [45, 46].”

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

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].”

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

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].”

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

In the paper

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

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.”

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.”

In the paper

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

In the paper

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

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].”

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

In the paper

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

In the paper

“Potential caveats include a clearly elevated TSH suggesting the presence of prior hypothyroidism.”

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].”

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

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].”

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

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.”

In the paper

“This may depend on disease type and severity, the need of prolonged vital support, and environmental factors including parenteral nutrition.”

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.”

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.”

In the paper

“Unfortunately at this stage we do not know whether this approach can improve clinical outcomes.”

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.”

In the paper

“It should be noted, however, that at this time, there is no direct evidence support this hypothesis.”

In the paper

“Moreover, use of anticonvulsants and glucocorticoids should be noted, since these agents can lower (F)T4.”

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.”

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.”

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.”

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.”

In the paper

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

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.”

In the paper

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

In the paper

“Furthermore, most studies used rather high doses of either T4 or T3, probably inducing further suppression of pituitary TSH release.”

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].”

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

In the paper

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

In the paper

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

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].”

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