Download PDF
Horm Metab Res 2017; 49(02): 95-102
DOI: 10.1055/s-0042-119211
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Tumor Necrosis Factor-α is Inversely Related to Free Thyroxine in Euthyroid Subjects Without Diabetes

L. J. N. van Tienhoven-Wind
1   Department of Endocrinology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
,
R. P. F. Dullaart
1   Department of Endocrinology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
› Author Affiliations
Further Information

Publication History

received 02 June 2016

accepted 29 September 2016

Publication Date:
10 November 2016 (online)

Also available at
    Permissions and Reprints

Abstract

Lower thyroid functional status within the euthyroid range may confer increased atherosclerosis susceptibility, as evidenced by increased intima media thickness and coronary artery calcification. Associations of lower thyroid functional status with pro-atherogenic (inflammatory) biomarkers may also extend into the euthyroid range. Here we established relationships of plasma tumor necrosis factor-α (TNF-α) with thyroid stimulating hormone (TSH) and free thyroxine (free T4) in euthyroid subjects with and without Type 2 diabetes mellitus (T2DM). Fasting TSH, free T4, and TNF-α were measured in 81 nondiabetic subjects and in 73 T2DM subjects with Type 2 diabetes mellitus (T2DM; insulin using subjects were excluded) with TSH and free T4 levels each within the institutional reference ranges. TSH was similar and free T4 was slightly higher in T2DM (p<0.016). Plasma TNF-α was increased in T2DM (p=0.007). In nondiabetic subjects, TNF-α was correlated inversely with free T4 (r=−0.254, p=0.022), whereas such a relationship was absent in T2DM subjects (r=0.058, p=0.63). Multivariable linear regression analysis showed that in nondiabetic subjects TNF-α remained inversely associated with free T4 after adjustment for age and sex (β=−0.243, p=0.032) and additionally for thyroid autoantibodies (β=−0.251, p=0.027), contrasting the lack of relationship in T2DM subjects (interaction: p=0.053). In T2DM subjects, TNF-α was also unrelated to free T4 taking account of possible confounders, as well as after exclusion of subjects using metformin or antihypertensive medication. In conclusion, higher levels of TNF-α relate to lower free T4. Low-normal thyroid function could influence pro-inflammatory pathways. This relationship appears to be disturbed in T2DM.

Key words

tumor necrosis factor-α - thyroid function - Type 2 diabetes mellitus
 

  • References

  • 1 Andersen S, Pedersen KM, Bruun NH, Laurberg P. Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab 2002; 87: 1068-1072
    CrossrefPubMedGoogle Scholar
  • 2 Taylor PN, Razvi S, Pearce SH, Dayan CM. Clinical review: A review of the clinical consequences of variation in thyroid function within the reference range. J Clin Endocrinol Metab 2013; 98: 3562-3571
    CrossrefPubMedGoogle Scholar
  • 3 Walsh JP. Setpoints and susceptibility: Do small differences in thyroid function really matter?. Clin Endocrinol 2011; 75: 158-159
    CrossrefPubMedGoogle Scholar
  • 4 Dullaart RP, de Vries R, Roozendaal C, Kobold AC, Sluiter WJ. Carotid artery intima media thickness is inversely related to serum free thyroxine in euthyroid subjects. Clin Endocrinol (Oxf) 2007; 67: 668-673
    CrossrefPubMedGoogle Scholar
  • 5 Takamura N, Akilzhanova A, Hayashida N, Kadota K, Yamasaki H, Usa T, Nakazato M, Maeda T, Ozono Y, Aoyagi K. Thyroid function is associated with carotid intima-media thickness in euthyroid subjects. Atherosclerosis 2009; 204: e77-e81
    CrossrefPubMedGoogle Scholar
  • 6 Park HJ, Kim J, Han EJ, Park SE, Park CY, Lee WY, Oh KW, Park SW, Rhee EJ. Association of low baseline free thyroxin levels with progression of coronary artery calcification over four years in euthyroid subjects: The Kangbuk Samsung Health Study. Clin Endocrinol (Oxf) 2016; 84: 889-895
    CrossrefPubMedGoogle Scholar
  • 7 Zhang Y, Kim BK, Chang Y, Ryu S, Cho J, Lee WY, Rhee EJ, Kwon MJ, Rampal S, Zhao D, Pastor-Barriuso R, Lima JA, Shin H, Guallar E. Thyroid hormones and coronary artery calcification in euthyroid men and women. Arterioscler Thromb Vasc Biol 2014; 34: 2128-2134
    CrossrefPubMedGoogle Scholar
  • 8 Åsvold BO, Vatten LJ, Bjøro T, Bauer DC, Bremner A, Cappola AR, Ceresini G, den Elzen WP, Ferrucci L, Franco OH, Franklyn JA, Gussekloo J, Iervasi G, Imaizumi M, Kearney PM, Khaw KT, Maciel RM, Newman AB, Peeters RP, Psaty BM, Razvi S, Sgarbi JA, Stott DJ, Trompet S, Vanderpump MP, Völzke H, Walsh JP, Westendorp RG, Rodondi N. Thyroid Studies Collaboration . Thyroid function within the normal range and risk of coronary heart disease: an individual participant data analysis of 14 cohorts. JAMA Intern Med 2015; 175: 1037-1047
    CrossrefPubMedGoogle Scholar
  • 9 van Tienhoven-Wind LJ, Dullaart RP. Low-normal thyroid function and the pathogenesis of common cardio-metabolic disorders. Eur J Clin Invest 2015; 45: 494-503
    CrossrefPubMedGoogle Scholar
  • 10 Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 1998; 97: 2007-2011
    CrossrefPubMedGoogle Scholar
  • 11 Christ-Chrain M, Meier C, Guglielmetti M, Huber PR, Riesen W, Staub JJ, Müller B. Elevated C-reactive protein and homocysteine values: cardiovascular risk factors in hypothyroidism? A cross-sectional and a double-blind, placebo-controlled trial. Atherosclerosis 2003; 16: 379-386
    PubMedGoogle Scholar
  • 12 Kvetny J, Heldgaard PE, Bladbjerg EM, Gram J. Subclinical hypothyroidism is associated with a low-grade inflammation, increased triglyceride levels and predicts cardiovascular disease in males below 50 years. Clin Endocrinol (Oxf) 2004; 61: 232-238
    CrossrefPubMedGoogle Scholar
  • 13 Tuzcu A, Bahceci M, Gokalp D, Tuzun Y, Gunes K. Subclinical hypothyroidism may be associated with elevated high-sensitive c-reactive protein (low grade inflammation) and fasting hyperinsulinemia. Endocr J 2005; 52: 89-94
    CrossrefPubMedGoogle Scholar
  • 14 Luboshitzky R, Herer P. Cardiovascular risk factors in middle-aged women with subclinical hypothyroidism. Neuro Endocrinol Lett 2004; 25: 262-266
    PubMedGoogle Scholar
  • 15 Hueston WJ, King DE, Geesey ME. Serum biomarkers for cardiovascular inflammation in subclinical hypothyroidism. Clin Endocrinol (Oxf) 2005; 63: 582-587
    CrossrefPubMedGoogle Scholar
  • 16 Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev 2008; 29: 76-131
    CrossrefPubMedGoogle Scholar
  • 17 Beutler B. TNF, immunity and inflammatory disease: lessons of the past decade. J Investig Med 1995; 43: 227-235
    PubMedGoogle Scholar
  • 18 Kleinbongard P, Heusch G, Schulz R. TNFalpha in atherosclerosis, myocardial ischemia/reperfusion and heart failure. Pharmacol Ther 2010; 127: 295-314
    CrossrefPubMedGoogle Scholar
  • 19 Ridker PM, Rifai N, Pfeffer M, Sacks F, Lepage S, Braunwald E. Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Circulation 2000; 101: 2149-2153
    CrossrefPubMedGoogle Scholar
  • 20 Skoog T, Dichtl W, Boquist S, Skoglund-Andersson C, Karpe F, Tang R, Bond MG. de Faire U, Nilsson J, Eriksson P, Hamsten A. Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Eur Heart J 2002; 23: 376-383
    CrossrefPubMedGoogle Scholar
  • 21 Hajje G, Saliba Y, Itani T, Moubarak M, Aftimos G, Farès N. Hypothyroidism and its rapid correction alter cardiac remodeling. PLoS One 2014; 9: e109753
    CrossrefPubMedGoogle Scholar
  • 22 Pontikides N, Krassas GE. Basic endocrine products of adipose tissue in states of thyroid dysfunction. Thyroid 2007; 17: 421-431
    CrossrefPubMedGoogle Scholar
  • 23 Marfella R, Ferraraccio F, Rizzo MR, Portoghese M, Barbieri M, Basilio C, Nersita R, Siniscalchi LI, Sasso FC, Ambrosino I, Siniscalchi M, Maresca L, Sardu C, Amato G, Paolisso G, Carella C. Innate immune activity in plaque of patients with untreated and L-thyroxine-treated subclinical hypothyroidism. J Clin Endocrinol Metab 2011; 96: 1015-1020
    CrossrefPubMedGoogle Scholar
  • 24 Qin B, Anderson RA, Adeli K. Tumor necrosis factor-alpha directly stimulates the overproduction of hepatic apolipoprotein B100-containing VLDL via impairment of hepatic insulin signaling. Am J Physiol Gastrointest Liver Physiol. 2008; 294: G1120-G1129
    CrossrefPubMedGoogle Scholar
  • 25 Qin B, Dawson H, Anderson RA. Elevation of tumor necrosis factor-alpha induces the overproduction of postprandial intestinal apolipoprotein B48-containing very low-density lipoprotein particles: evidence for related gene expression of inflammatory, insulin and lipoprotein signaling in enterocytes. Exp Biol Med (Maywood) 2010; 235: 199-205
    CrossrefPubMedGoogle Scholar
  • 26 Fernandez-Real JM, Ricart W. Insulin resistance and chronic cardiovascular inflammatory syndrome. Endocr Rev 2003; 24: 278-301
    CrossrefPubMedGoogle Scholar
  • 27 Ramana KV, Tammali R, Reddy AB, Bhatnagar A, Srivastava SK. Aldose reductase-regulated tumor necrosis factoralpha production is essential for high glucose-induced vascular smooth muscle cell growth. Endocrinology 2007; 148: 4371-4384
    CrossrefPubMedGoogle Scholar
  • 28 Jostel A, Ryder WD, Shalet SM. The use of thyroid function tests in the diagnosis of hypopituitarism: definition and evaluation of the TSH Index. Clin Endocrinol (Oxf) 2009; 71: 529-534
    CrossrefPubMedGoogle Scholar
  • 29 Dietrich JW, Landgrafe-Mende G, Wiora E, Chatzitomaris A, Klein HH, Midgley JE, Hoermann R. Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research. Front Endocrinol (Lausanne) 2016; 9 7: 57
    PubMedGoogle Scholar
  • 30 Selvin S. Statistical analysis of epidemiological data. New York: Oxford University Press; 1996
    Google Scholar
  • 31 Türemen EE, Çetinarslan B, Şahin T, Cantürk Z, Tarkun İ. Endothelial dysfunction and low grade chronic inflammation in subclinical hypothyroidism due to autoimmune thyroiditis. Endocr J 2011; 58: 349-354
    CrossrefPubMedGoogle Scholar
  • 32 Zhang YJ, Zhao W, Zhu MY, Tang SS, Zhang H. Thyroid-stimulating hormone induces the secretion of tumor necrosis factor-α from 3T3-L1 adipocytes via a protein kinase A-dependent pathway. Exp Clin Endocrinol Diabetes 2013; 121: 488-493
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Wolf M, Hansen N, Greten H. Interleukin 1 beta, tumor necrosis factor-alpha and interleukin 6 decrease nuclear thyroid hormone receptor capacity in a liver cell line. Eur J Endocrinol 1994; 131: 307-312
    CrossrefPubMedGoogle Scholar
  • 34 Pantos C, Xinaris C, Mourouzis I, Kokkinos AD, Cokkinos DV. TNF-alpha administration in neonatal cardiomyocytes is associated with differential expression of thyroid hormone receptors: a response prevented by T3. Horm Metab Res 2008; 40: 731-734
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Cesari M, Penninx BW, Newman AB, Kritchevsky SB, Nicklas BJ, Sutton-Tyrrell K, Rubin SM, Ding J, Simonsick EM, Harris TB, Pahor M. Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation 2003; 108: 2317-2322
    CrossrefPubMedGoogle Scholar
  • 36 Jovinge S, Hamsten A, Tornvall P, Proudler A, Båvenholm P, Ericsson CG, Godsland I, de Faire U, Nilsson J. Evidence for a role of tumor necrosis factor alpha in disturbances of triglyceride and glucose metabolism predisposing to coronary heart disease. Metabolism 1998; 47: 113-118
    CrossrefPubMedGoogle Scholar
  • 37 Nilsson J, Jovinge S, Niemann A, Reneland R, Lithell H. Relation between plasma tumor necrosis factor-alpha and insulin sensitivity in elderly men with non-insulin-dependent diabetes mellitus. Arterioscler Thromb Vasc Biol 1998; 18: 1199-1202
    CrossrefPubMedGoogle Scholar
  • 38 Gruppen EG, Connelly MA, Otvos JD, Bakker SJ, Dullaart RP. A novel protein glycan biomarker and LCAT activity in metabolic syndrome. Eur J Clin Invest 2015; 45: 850-859
    CrossrefPubMedGoogle Scholar
  • 39 van Tienhoven-Wind L, Dullaart RP. Low normal thyroid function as a determinant of increased large very low density lipoprotein particles. Clin Biochem 2015; 48: 489-494
    CrossrefPubMedGoogle Scholar
  • 40 van Tienhoven-Wind LJ, Perton FG, Dullaart RP. Pre-β-HDL formation relates to high-normal free thyroxine in type 2 diabetes mellitus. Clin Biochem 2016; 49: 41-46
    CrossrefPubMedGoogle Scholar
  • 41 van Tienhoven-Wind LJ, Dullaart RP. Low-normal thyroid function and novel cardiometabolic biomarkers. Nutrients 2015; 7: 1352-1377
    CrossrefPubMedGoogle Scholar
  • 42 Dullaart RP, de Vries R, Kwakernaak AJ, Perton F, Dallinga-Thie GM. Increased large VLDL particles confer elevated cholesteryl ester transfer in diabetes. Eur J Clin Invest 2015; 45: 36-44
    CrossrefPubMedGoogle Scholar
  • 43 Triolo M, Kwakernaak AJ, Perton FG, de Vries R, Dallinga-Thie GM, Dullaart RP. Low normal thyroid function enhances plasma cholesteryl ester transfer in Type 2 diabetes mellitus. Atherosclerosis 2013; 228: 466-471
    CrossrefPubMedGoogle Scholar
  • 44 Ferri N, Ruscica M. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and metabolic syndrome: insights on insulin resistance, inflammation, and atherogenic dyslipidemia. Endocrine 2016 [Epub ahead of print]
    PubMed
  • 45 Kwakernaak AJ, Lambert G, Dullaart RP. Plasma proprotein convertase subtilisin-kexin type 9 is predominantly related to intermediate density lipoproteins. Clin Biochem 2014; 47: 679-682
    CrossrefPubMedGoogle Scholar
  • 46 Miyazaki Y, Pipek R, Mandarino LJ, DeFronzo RA. Tumor necrosis factor alpha and insulin resistance in obese type 2 diabetic patients. Int J Obes Relat Metab Disord 2003; 27: 88-94
    CrossrefPubMedGoogle Scholar
  • 47 Kabadi UM. Impaired pituitary thyrotroph function in uncontrolled type II diabetes mellitus: normalization on recovery. J Clin Endocrinol Metab 1984; 59: 521-525
    CrossrefPubMedGoogle Scholar
  • 48 Vigersky RA, Filmore-Nassar A, Glass AR. Thyrotropin suppression by metformin. J Clin Endocrinol Metab 2006; 91: 225-227
    CrossrefPubMedGoogle Scholar
  • 49 Díez JJ, Iglesias P. Relationship between serum thyrotropin concentrations and metformin therapy in euthyroid patients with type 2 diabetes. Clin Endocrinol 2013; 78: 505-511
    CrossrefPubMedGoogle Scholar
  • 50 Wang F, Tan Y, Wang C, Zhang X, Zhao Y, Song X, Zhang B, Guan Q, Xu J, Zhang J, Zhang D, Lin H, Yu C, Zhao J. Thyroid-stimulating hormone levels within the reference range are associated with serum lipid profiles independent of thyroid hormones. J Clin Endocrinol Metab 2012; 97: 2724-2731
    CrossrefPubMedGoogle Scholar
  • 51 Koh KK, Son JW, Ahn JY, Jin DK, Kim HS, Choi YM, Kim DS, Jeong EM, Park GS, Choi IS, Shin EK. Comparative effects of diet and statin on NO bioactivity and matrix metalloproteinases in hypercholesterolemic patients with coronary artery disease. Arterioscler Thromb Vasc Biol 2002; 22: e19-e23
    CrossrefPubMedGoogle Scholar