This series of meta-analyses were aimed to elucidate the impact of hypothyroidism on low-grade systemic inflammation and oxidative stress assessed by C-reactive protein (CRP) and malondialdehyde (MDA) respectively; and to evaluate the effect of levothyroxine replacement therapy (LRT) on those outcomes.
PubMed database and the key studies references were searched prior to March 3, 2020. Data on serum or plasma CRP and MDA levels in SHT (subclinical) and/or OHT (overt) hypothyroid patients and controls were extracted to compute overall standardized mean differences (SMD) by the random-effects model.
A total of 93 studies were entered into analyses and ten main meta-analyses were performed. OHT (SMD = 0.72 [0.39; 1.04], k = 35), SHT (SMD = 1.58 [0.78; 2.38], k = 56) and even mild SHT (TSH < 10 mU/L, SMD = 2.19 [0.02; 4.37], k = 13) proved to have a detrimental effect on CRP levels. LRT showed a favorable effect on CRP levels, particularly in OHT (SMD = −0.30 [−0.57; −0.02], k = 17). Increased levels of MDA were also found, especially in OHT (SMD = 2.49 [0.66; 4.31], k = 13). LRT may also improve MDA levels; however future studies would further validate the advantageous effect of LRT in hypothyroidism. Heterogeneity primarily originated from different study designs and geographic locations.
Overall, these meta-analyses reveal that screening for hs-CRP and MDA in hypothyroid patients as simple biomarkers of low-grade systemic inflammation and oxidative stress may become a useful tool to identify those at increased risk who may benefit most from early interventions.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Data are available from PubMed.
Analyses were executed in R versión 3.6.3 by using meta, metafor and dmetar R packages. Scrips are available under request.
levothyroxine replacement therapy
standardized mean difference
thyrotropin or thyroid-stimulating hormone
C.G. Roberts, P.W. Ladenson, Hypothyroidism. Lancet 363, 793–803 (2004). https://doi.org/10.1016/S0140-6736(04)15696-1
B. Biondi, A.R. Cappola, D.S. Cooper, Subclinical hypothyroidism. JAMA 322, 153 (2019). https://doi.org/10.1001/jama.2019.9052
F. Magri, L. Chiovato, L. Croce, M. Rotondi, Thyroid hormone therapy for subclinical hypothyroidism. Endocrine 66, 27–34 (2019). https://doi.org/10.1007/s12020-019-02039-z
N. Gong, C. Gao, X. Chen, Y. Fang, L. Tian, Endothelial function in patients with subclinical hypothyroidism: a meta-analysis. Horm. Metab. Res. 51, 691–702 (2019). https://doi.org/10.1055/a-1018-9564
K. Yao, T. Zhao, L. Zeng, J. Yang, Y. Liu, Q. He, X. Zou, Non-invasive markers of cardiovascular risk in patients with subclinical hypothyroidism: a systematic review and meta-analysis of 27 case control studies. Sci. Rep. 8, 4579 (2018). https://doi.org/10.1038/s41598-018-22897-3
N. Gao, W. Zhang, Y. Zhang, Q. Yang, S. Chen, Carotid intima-media thickness in patients with subclinical hypothyroidism: a meta-analysis. Atherosclerosis 227, 18–25 (2013). https://doi.org/10.1016/j.atherosclerosis.2012.10.070
Y. Zhou, Y. Chen, X. Cao, C. Liu, C. Liu, Y. Xie, Association between plasma homocysteine status and hypothyroidism: a meta-analysis. Int. J. Clin. Exp. Med. 7, 4544–4553 (2014)
R. Marfella, F. Ferraraccio, M.R. Rizzo, M. Portoghese, M. Barbieri, C. Basilio, R. Nersita, L.I. Siniscalchi, F.C. Sasso, I. Ambrosino, M. Siniscalchi, L. Maresca, C. Sardu, G. Amato, G. Paolisso, C. Carella, Innate immune activity in plaque of patients with untreated and L-thyroxine-treated subclinical hypothyroidism. J. Clin. Endocrinol. Metab. 96, 1015–1020 (2011). https://doi.org/10.1210/jc.2010-1382
M.B. Pepys, G.M. Hirschfield, C-reactive protein: a critical update. J. Clin. Investig. 111, 1805–1812 (2003). https://doi.org/10.1172/JCI18921
S. Kaptoge, E. Di Angelantonio, G. Lowe, M.B. Pepys, S.G. Thompson, R. Collins, J. Danesh, R.W. Tipping, C.E. Ford, S.L. Pressel, G. Walldius, I. Jungner, A.R. Folsom, L. Chambless, C.M. Ballantyne, D. Panagiotakos, C. Pitsavos, C. Chrysohoou, C. Stefanadis, M.W. Knuiman, U. Goldbourt, M. Benderly, D. Tanne, P. Whincup, S.G. Wannamethee, R.W. Morris, S. Kiechl, J. Willeit, A. Mayr, G. Schett, N. Wald, S. Ebrahim, D. Lawlor, J. Yarnell, J. Gallacher, E. Casiglia, V. Tikhonoff, P.J. Nietert, S.E. Sutherland, D.L. Bachman, J.E. Keil, M. Cushman, B.M. Psaty, R. Tracy, A. Tybjærg-Hansen, B.G. Nordestgaard, J. Zacho, R. Frikke-Schmidt, S. Giampaoli, L. Palmieri, S. Panico, D. Vanuzzo, L. Pilotto, A.G. De La Cámara, J.A. Gómez Gerique, L. Simons, J. McCallum, Y. Friedlander, F.G.R. Fowkes, A. Lee, J. Taylor, J.M. Guralnik, C.L. Phillips, R.B. Wallace, D.G. Blazer, K.T. Khaw, H. Brenner, E. Raum, H. Müller, D. Rothenbacher, J.H. Jansson, P. Wennberg, A. Nissinen, C. Donfrancesco, K. Harald, P. Jousilahti, E. Vartiainen, M. Woodward, R.B. D’Agostino, P.A. Wolf, R.S. Vasan, E.J. Benjamin, E.M. Bladbjerg, T. Jørgensen, V. Salomaa, J. Jespersen, R. Dankner, A. Chetrit, F. Lubin, A. Rosengren, L. Wilhelmsen, G. Lappas, H. Eriksson, C. Björkelund, L. Lissner, C. Bengtsson, P. Cremer, D. Nagel, R.S. Tilvis, T.E. Strandberg, Y. Kiyohara, H. Arima, Y. Doi, T. Ninomiya, B. Rodriguez, J. Dekker, G. Nijpels, C.D.A. Stehouwer, E. Rimm, J.K. Pai, S. Sato, H. Iso, A. Kitamura, H. Noda, J.T. Salonen, K. Nyyssönen, T.P. Tuomainen, J.A. Laukkanen, D.J.H. Deeg, M.A. Bremmer, T.W. Meade, J.A. Cooper, B. Hedblad, G. Berglund, G. Engström, W.M.M. Verschuren, A. Blokstra, S. Shea, A. Döring, W. Koenig, C. Meisinger, H.B. Bueno-De-Mesquita, L.H. Kuller, G. Grandits, R. Selmer, A. Tverdal, W. Nystad, R.F. Gillum, M. Mussolino, S. Hankinson, J.E. Manson, C. Knottenbelt, K.A. Bauer, K. Davidson, S. Kirkland, J. Shaffer, M.R. Korin, Y. Naito, I. Holme, H. Nakagawa, K. Miura, P. Ducimetiere, X. Jouven, G. Luc, C.J. Crespo, M.R. Garcia-Palmieri, P. Amouyel, D. Arveiler, A. Evans, J. Ferrieres, H. Schulte, G. Assmann, C.J. Packard, N. Sattar, R.G. Westendorp, B.M. Buckley, B. Cantin, B. Lamarche, J.P. Després, G.R. Dagenais, E. Barrett-Connor, D.L. Wingard, R.R. Bettencourt, V. Gudnason, T. Aspelund, G. Sigurdsson, B. Thorsson, M. Trevisan, J. Witteman, I. Kardys, M.M.B. Breteler, A. Hofman, H. Tunstall-Pedoe, R. Tavendale, B.V. Howard, Y. Zhang, L. Best, J. Umans, Y. Ben-Shlomo, G. Davey-Smith, A. Onat, I. Njølstad, E.B. Mathiesen, M.L. Løchen, T. Wilsgaard, E. Ingelsson, S. Basu, T. Cederholm, L. Byberg, J.M. Gaziano, M. Stampfer, P.M. Ridker, H. Ulmer, G. Diem, H. Concin, A. Tosetto, F. Rodeghiero, S. Wassertheil-Smoller, M. Marmot, R. Clarke, A. Fletcher, E. Brunner, M. Shipley, J. Buring, J. Shepherd, S. Cobbe, I. Ford, M. Robertson, Y. He, A. Marin Ibañez, E.J.M. Feskens, M. Walker, S. Watson, S. Erqou, S. Lewington, L. Pennells, P.L. Perry, K.K. Ray, N. Sarwar, M. Alexander, A. Thompson, I.R. White, A.M. Wood, C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 375, 132–140 (2010). https://doi.org/10.1016/S0140-6736(09)61717-7
J. Danesh, J.G. Wheeler, G.M. Hirschfield, S. Eda, G. Eiriksdottir, A. Rumley, G.D.O. Lowe, M.B. Pepys, V. Gudnason, C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N. Engl. J. Med. 350, 1387–1397 (2004). https://doi.org/10.1056/NEJMoa032804
M. Christ-Crain, C. Meier, M. Guglielmetti, P.R. Huber, W. Riesen, J.-J. Staub, B. Müller, Elevated C-reactive protein and homocysteine values: cardiovascular risk factors in hypothyroidism? A cross-sectional and a double-blind, placebo-controlled trial. Atherosclerosis 166, 379–386 (2003). https://doi.org/10.1016/S0021-9150(02)00372-6
M. Frisard, E. Ravussin, Energy metabolism and oxidative stress: impact on the metabolic syndrome and the aging process. Endocrine 29, 27–32 (2006). https://doi.org/10.1385/ENDO:29:1:27
M.F. Walter, R.F. Jacob, B. Jeffers, M.M. Ghadanfar, G.M. Preston, J. Buch, R.P. Mason, Serum levels of thiobarbituric acid reactive substances predict cardiovascular events in patients with stable coronary artery disease. J. Am. Coll. Cardiol. 44, 1996–2002 (2004). https://doi.org/10.1016/j.jacc.2004.08.029
W. He, S. Li, J. Zhang, J. Zhang, K. Mu, X. Li, Effect of levothyroxine on blood pressure in patients with subclinical hypothyroidism: a systematic review and meta-analysis. Front. Endocrinol. 9 (2018). https://doi.org/10.3389/fendo.2018.00454
X. Li, Y. Wang, Q. Guan, J. Zhao, L. Gao, The lipid-lowering effect of levothyroxine in patients with subclinical hypothyroidism: a systematic review and meta-analysis of randomized controlled trials. Clin. Endocrinol. 87, 1–9 (2017). https://doi.org/10.1111/cen.13338
B. Swaid, B. Kheiri, S. Sundus, M. Shah Miran, T. Haykal, Y. Zayed, G. Bachuwa, The effect of levothyroxine treatment in individuals with subclinical hypothyroidism on surrogate markers of atherosclerosis: a meta-analysis of randomized controlled trials. J. Community Hosp. Intern. Med. Perspect. 9, 305–309 (2019). https://doi.org/10.1080/20009666.2019.1625704
A.L. Burgueño, Y.R. Juarez, A.M. Genaro, M.L. Tellechea, Systematic review and meta-analysis on the relationship between prenatal stress and metabolic syndrome intermediate phenotypes. Int. J. Obes. 44, 1–12 (2020). https://doi.org/10.1038/s41366-019-0423-z
M.L. Tellechea, C.J. Pirola, The impact of hypertension on leukocyte telomere length: a systematic review and meta-analysis of human studies. J. Hum. Hypertens. 31, 99–105 (2017). https://doi.org/10.1038/jhh.2016.45
G.J. Blake, P.M. Ridker, Inflammatory bio-markers and cardiovascular risk prediction. J. Intern. Med. 252, 283–294 (2002). https://doi.org/10.1046/j.1365-2796.2002.01019.x
C. Zhu, J. Gao, F. Mei, L. Lu, D. Zhou, S. Qu, Reduction in thyroid-stimulating hormone correlated with improved inflammation markers in Chinese patients with morbid obesity undergoing laparoscopic sleeve gastrectomy. Obes. Surg. 29, 3954–3965 (2019). https://doi.org/10.1007/s11695-019-04063-4
P.S. Tayde, N.M. Bhagwat, P. Sharma, B. Sharma, P.P. Dalwadi, A. Sonawane, A. Subramanyam, M. Chadha, P.K. Varthakavi, Hypothyroidism and depression: are cytokines the link? Indian. J. Endocrinol. Metab. 21, 886–892 (2017). https://doi.org/10.4103/ijem.IJEM_265_17
E.E. Türemen, B. Çetinarslan, T. Şahin, Z. Cantürk, I. Tarkun, Endothelial dysfunction and low grade chronic inflammation in subclinical hypothyroidism due to autoimmune thyroiditis. Endocr. J. 58, 349–354 (2011). https://doi.org/10.1507/endocrj.K10E-333
S. Taddei, N. Caraccio, A. Virdis, A. Dardano, D. Versari, L. Ghiadoni, E. Ferrannini, A. Salvetti, F. Monzani, Low-grade systemic inflammation causes endothelial dysfunction in patients with Hashimoto’s thyroiditis. J. Clin. Endocrinol. Metab. 91, 5076–5082 (2006). https://doi.org/10.1210/jc.2006-1075
J.J. Díez, A. Hernanz, S. Medina, C. Bayón, P. Iglesias, Serum concentrations of tumour necrosis factor-alpha (TNF-α) and soluble TNF-α receptor p55 in patients with hypothyroidism and hyperthyroidism before and after normalization of thyroid function. Clin. Endocrinol. 57, 515–521 (2002). https://doi.org/10.1046/j.1365-2265.2002.01629.x
J.H. Gómez-Zamudio, V. Mendoza-Zubieta, A. Ferreira-Hermosillo, M.A. Molina-Ayala, A. Valladares-Sálgado, F. Suárez-Sánchez, J. de Jesús Peralta-Romero, M. Cruz, High thyroid-stimulating hormone levels increase proinflammatory and cardiovascular markers in patients with extreme obesity. Arch. Med. Res. 47, 476–482 (2016). https://doi.org/10.1016/j.arcmed.2016.10.007
A.P. Weetman, A.M. McGregor, Autoimmune thyroid disease: further developments in our understanding. Endocr. Rev. 15, 788–830 (1994). https://doi.org/10.1210/edrv-15-6-788
C.X. Gao, B. Yang, Q. Guo, L.H. Wei, L.M. Tian, High thyroid-stimulating hormone level is associated with the risk of developing atherosclerosis in subclinical hypothyroidism. Horm. Metab. Res. 47, 220–224 (2015). https://doi.org/10.1055/s-0034-1394370
T.T. Antunes, A. Gagnon, M.L. Langille, A. Sorisky, Thyroid-stimulating hormone induces interleukin-6 release from human adipocytes through activation of the nuclear factor-κB pathway. Endocrinology 149, 3062–3066 (2008). https://doi.org/10.1210/en.2007-1588
Y.-J. Zhang, W. Zhao, M.-Y. Zhu, S.-S. Tang, H. Zhang, 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 121, 488–493 (2013). https://doi.org/10.1055/s-0033-1347266
T.T. Antunes, A. Gagnon, A. Bell, A. Sorisky, Thyroid-stimulating hormone stimulates interleukin-6 release from 3T3-L1 adipocytes through a cAMP-protein Kinase A pathway. Obes. Res. 13, 2066–2071 (2005). https://doi.org/10.1038/oby.2005.256
A. Gagnon, M.L. Langille, S. Chaker, T.T. Antunes, J. Durand, A. Sorisky, TSH signaling pathways that regulate MCP-1 in human differentiated adipocytes. Metabolism 63, 812–821 (2014). https://doi.org/10.1016/j.metabol.2014.02.015
M. Whetsell, E.U. Bagriacik, G.S. Seetharamaiah, B.S. Prabhakar, J.R. Klein, Neuroendocrine-induced synthesis of bone marrow-derived cytokines with inflammatory immunomodulating properties. Cell. Immunol. 192, 159–166 (1999). https://doi.org/10.1006/cimm.1998.1444
A. Dardano, L. Ghiadoni, Y. Plantinga, N. Caraccio, A. Bemi, E. Duranti, S. Taddei, E. Ferrannini, A. Salvetti, F. Monzani, Recombinant human thyrotropin reduces endothelium-dependent vasodilation in patients monitored for differentiated thyroid carcinoma. J. Clin. Endocrinol. Metab. 91, 4175–4178 (2006). https://doi.org/10.1210/jc.2006-0440
R.C. Marchiori, L.A.F. Pereira, A.A. Naujorks, D.L. Rovaris, D.F. Meinerz, M.M.M.F. Duarte, J.B.T. Rocha, Improvement of blood inflammatory marker levels in patients with hypothyroidism under levothyroxine treatment. BMC Endocr. Disord. 15 (2015). https://doi.org/10.1186/s12902-015-0032-3
N. Nanda, Z. Bobby, A. Hamide, Inflammation and oxidative stress in hypothyroids: Additive effects on cardiovascular risk. Indian J. Physiol. Pharmacol. 55, 351–356 (2011)
A. Haribabu, V.S. Reddy, C. Pallavi, A.R. Bitla, A. Sachan, P. Pullaiah, V. Suresh, P.V.L.N.S. Rao, M.M. Suchitra, Evaluation of protein oxidation and its association with lipid peroxidation and thyrotropin levels in overt and subclinical hypothyroidism. Endocrine. 44, 152–157 (2013). https://doi.org/10.1007/s12020-012-9849-y
N. Nanda, Z. Bobby, A. Hamide, Association of thyroid stimulating hormone and coronary lipid risk factors with lipid peroxidation in hypothyroidism. Clin. Chem. Lab. Med. 46 (2008). https://doi.org/10.1515/CCLM.2008.139
V.S. Reddy, S. Bukke, K. Mahato, V. Kumar, N.V. Reddy, M. Munikumar, B. Vodelu, A meta-analysis of the association of serum ischaemia-modified albumin levels with human hypothyroidism and hyperthyroidism. Biosci. Rep. 37 (2017). https://doi.org/10.1042/BSR20160268
K.A. Metwalley, H.S. Farghaly, K. Saad, H.A.K. Othman, Oxidative status in children and adolescents with autoimmune thyroiditis. Clin. Exp. Med. 16, 571–575 (2016). https://doi.org/10.1007/s10238-015-0386-x
A. Aydogdu, E.Y. Karakas, E. Erkus, I.H. Altiparmak, E. Savik, T. Ulas, T. Sabuncu, Epicardial fat thickness and oxidative stress parameters in patients with subclinical hypothyroidism. Arch. Med. Sci. 13, 383–389 (2017). https://doi.org/10.5114/aoms.2017.65479
L.J. Lakshmi, E. Mohapatra, D. Zephy, S. K., Serum lipids and oxidative stress in hypothyroidism. J. Adv. Res. Biol. Sci. 5, 63–66 (2013)
A.N. Torun, S. Kulaksizoglu, M. Kulaksizoglu, B.O. Pamuk, E. Isbilen, N.B. Tutuncu, Serum total antioxidant status and lipid peroxidation marker malondialdehyde levels in overt and subclinical hypothyroidism. Clin. Endocrinol. 70, 469–474 (2009). https://doi.org/10.1111/j.1365-2265.2008.03348.x
M.J. Cheserek, G.R. Wu, A. Ntazinda, Y.H. Shi, L.Y. Shen, G.W. Le, Association between thyroid hormones, lipids and oxidative stress markers in subclinical hypothyroidism. J. Med. Biochem. 34, 323–331 (2015). https://doi.org/10.2478/jomb-2014-0044
Y. Chen, G. Wu, M. Xu, The effect of l-thyroxine substitution on oxidative stress in early-stage diabetic nephropathy patients with subclinical hypothyroidism: a randomized double-blind and placebo-controlled study. Int. Urol. Nephrol. 50, 97–103 (2018). https://doi.org/10.1007/s11255-017-1756-y
G. Baskol, H. Atmaca, F. Tanriverdi, M. Baskol, D. Kocer, F. Bayram, Oxidative stress and enzymatic antioxidant status in patients with hypothyroidism before and after treatment. Exp. Clin. Endocrinol. Diabetes. 115, 522–526 (2007). https://doi.org/10.1055/s-2007-981457
H. Erdamar, H. Demirci, H. Yaman, M.K. Erbil, T. Yakar, B. Sancak, S. Elbeg, G. Biberoǧlu, I. Yetkin, The effect of hypothyroidism, hyperthyroidism, and their treatment on parameters of oxidative stress and antioxidant status. Clin. Chem. Lab. Med. 46, 1004–1010 (2008). https://doi.org/10.1515/CCLM.2008.183
S.V. Reddy, M.M. Suchitra, V. Pradeep, S. Alok, V. Suresh, A.R. Bitla, P.V.L.N. Srinivasa Rao, Ischemia-modified albumin levels in overt and subclinical hypothyroidism. J. Endocrinol. Investig. 38, 885–890 (2015). https://doi.org/10.1007/s40618-015-0283-x
S. Mutlu, A. Parlak, U. Aydogan, A. Aydogdu, B. Soykut, C. Akay, K. Saglam, A. Taslipinar, The effect of levothyroxine replacement therapy on lipid profile and oxidative stress parameters in patients with subclinical hypothyroid. Arch. Pharm. Res. (2013). https://doi.org/10.1007/s12272-013-0227-y
M.L.T. is member of the National Scientific and Technical Research Council (CONICET).
Conflict of interest
The author declares no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Tellechea, M.L. Meta-analytic evidence for increased low-grade systemic inflammation and oxidative stress in hypothyroid patients. Can levothyroxine replacement therapy mitigate the burden?. Endocrine 72, 62–71 (2021). https://doi.org/10.1007/s12020-020-02484-1
- Low-grade inflammation
- Oxidative stress
- C-reactive protein