Extra-Thyroidal Factors Impacting Thyroid Hormone Homeostasis
Brock McGregor, BSc, ND
PDF
HTML

Keywords

Hypothyroidism
Peripheral thyroid metabolism
Selenium
Thyroid
PDF
HTML

Abstract

Peripheral metabolism plays a significant role in maintaining thyroid hormone expression in local tissues. The thyroid secretes thyroxine (T4) at substantially greater levels than triiodothyronine (T3), relying on peripheral mechanisms to convert T4 to T3. Peripheral control is exerted through a number of pathways. These pathways include deiodination, facilitated by deiodinase enzymes, as well as conjugation and lipid peroxidation. Factors influencing any or all of the peripherally active pathways continue to be explored and may help explain why many patients continue to experience symptoms consistent with hypothyroidism, including low body temperature, even when their thyroid blood tests are normal. These factors include liver and kidney function as well as seasonal changes. Although non-thyroidal illness syndrome was originally defined as a condition occurring without direct thyroid function impact, there is evidence that the thyroid itself may alter T3 and T4 during illness via modified gene regulation in the presence of pro-inflammatory cytokines. There are also a number of lifestyle behaviors, including fasting, alcohol dependence, and smoking that have been shown to affect peripheral metabolism of thyroid hormones. Zinc affects both the synthesis and mode of action of action of thyroid hormones. For example, thyroid transcription factors, which are essential for modulation of gene expression, contain zinc at cysteine residues. Selenium is required for the selenocysteine moieties that confer the function of the deiodinase enzymes. Selenium supplementation has been shown to reduce anti-thyroid peroxidase antibodies and anti-thyroglobulin antibodies in patients with autoimmune thyroiditis. Selenium has been shown to increase the level of glutathione peroxidase, which contains selenocysteine. Both Withania somnifera and Commiphora mukul have been shown to improve hypothyroidism by elevating T3 levels and increasing T3:T4 ratios through peripheral metabolic pathways.

PDF
HTML

References

Kim B. Thyroid hormone as a determinant of energy expenditure and the basal metabolic rate. Thyroid. 2008; 18(2):141–144.
Silva JE. The thermogenic effect of thyroid hormone and its clinical implications. Ann Intern Med. 2003; 139(3):205–213.
Grimaldi D, Provini F, Pierangeli G, et al. Evidence of a diurnal thermogenic handicap in obesity. Chronobiol Int. 2014; 32:299–302.
Boelen A, Kwakkel J, Fliers E. Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection. Endocr Rev. 2011; 32(5):670–693.
Economidou F, Douka E, Tzanela M, Nanas S, Kotanidou A. Thyroid function during critical illness. Hormones (Athens). 2011; 10(2):117–124.
Warner MH, Beckett GJ. Mechanisms behind the non-thyroidal illness syndrome: an update. J Endocrinol. 2010; 205(1):1–13.
Moreau T, Manceau E. Headache in hypothyroidism. Prevalence and outcome under thyroid hormone therapy. Cephalalgia. 1998; 18(10):687–689.
Fallah R, Mirouliaei M. Frequency of subclinical hypothyroidism in 5- to 15-year-old children with migraine headache. J Ped End Met. 2012; 25(9–10):859–862.
Moline M, Zendall S. Evaluating and managing premenstrual syndrome. Medscape Womens Health, 2000; 5(2):1.
Kales A. Sleep disorders: recent findings in the diagnosis and treatment of disturbed sleep. N Engl J Med. 1974; 290(9):487–499.
Simon N, Blacker D. Hypothyroidism and hyperthyroidism in anxiety disorders revisited: new data and literature review. J Affect Disord. 2002; 69(1):209–217.
Kokkoris P, Pi-Sunyer F. Obesity and endocrine disease. Endocrinol Metab Clin North Am. 2003; 32(4):895–914.
Wheatley T, Edwards O. Mild hypothyroidism and oedema: evidence for increased capillary permeability to protein. Clin Endocrinol. 1983; 18(6):627–635.
Deodhar A, Fisher A. Fluid retention syndrome and fibromyalgia. Rheumatology. 1994; 33(6):576–582.
Harrison S. Diffuse hair loss: its triggers and management. Cleve Clin J Med. 2009; 76(6):361–367.
Cakir M, Samanci N. Musculoskeletal manifestations in patients; with thyroid disease. Clin Endocrinol. 2003; 59(2):162–167.
Olden K. Diagnosis of irritable bowel syndrome. Gastroenterology. 2002; 122(6):1701–1714.
Sintzel F, Mallaret M, Bougerol T. Potentializing of tricyclics and serotoninergics by thyroid hormones in resistant depressive disorders. Encephale. 2004; 30(3):267–275.
Jackson I. The thyroid axis and depression. Thyroid. 1998; 8(10):951–956.
Viera A. Managing hypoactive sexual desire in women. Medical Aspects Hum Sex. 2001; 1:7–13.
Verma I, Sood R, Juneja S, Kaur S. Prevalence of hypothyroidism in infertile women and evaluation of response of treatment for hypothyroidism on infertility. Int J Appl Basic Med Res. 2012; 2(1):17–19.
De Vries EM, Fliers E, Boelen A. The molecular basis of the non-thyroidal illness syndrome. J Endocrinol. 2015; 225(3):R67–R81.
Docter R, Ep K, de Jong M, Hennemann G. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf). 1993; 39:499–518.
Gärtner R. Selenium and thyroid hormone axis in critical ill states: an overview of conflicting view points. J Trace Elem Med Biol. 2009; 23(2):71–74.
Boelan A, Kwakkel J, Thijssen-Timmer D, Alkemade A, Fliers E, Wiersinga W. Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide induced acute illness in mice. J Endocrinol. 2004; 182:315–323.
Fliers E, Guldenaar S, Wiersinga W, Swaab D. Decreased hypothalamic thyrotropin-releasing hormone gene expression in patients with nonthyroidal illness. J Clin Endocrinol Metab. 1997; 82:4032–4036.
Bartalena L, Bogazzi F, Brogioni S, Grasso L, Martino E. Role of cytokines in the pathogenesis of the euthyroid sick syndrome. Eur J Endocrinol. 1998; 138:603–614.
Scanlon M, Toft A. Regulation of thyrotropin secretion. In: Braverman L, Utiger R, eds. The Thyroid8th Ed. 2005. pp. 234–253.
Maia A, Kim B, Huang S, Harney J, Larsen P. Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans. J Clin Invest. 2005; 15(9):2524–2533.
Farid NR, Szkudlinski MW. Minireview: structural and functional evolution of the thyrotropin receptor. Endocrinology. 2004; 145(9):4048–57.
Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev. 2002; 23(l):38–89.
Kohrle J. The deiodinase family: selenoenzymes regulating thyroid hormone availability and action. Cell Mol Life Sci. 2000; 57:1853–1863.
Kwakkel J, Fliers E, Boelen A. Illness-induced changes in thyroid hormone metabolism: focus on the tissue level. Neth J Med. 2011; 69(5):224–228.
Robbins J. Factors altering thyroid hormone metabolism. Env Heal Perspect. 1981; 38:65–70.
Kelly G. Peripheral metabolism of thyroid hormones: a review. Altern Med Rev. 2000; 5(4):306–333.
Kohrle J, Spanka M, Irmscher K, Hesch R. Flavonoid effects on transport, metabolism and action of thyroid hormones. Prog Clin Biol Res. 1988; 280:323–340.
Visser T. Pathways of thyroid hormone metabolism. Acta Med Austriaca. 1996; 23:10–16.
Malik R, Hodgson H. The relationship between the thyroid gland and the liver. Q J Med. 2002; 95(9):559–569.
Kano T, Kojima T, Takahashi T, Muto Y. Serum thyroid hormone levels in patients with fulminant hepatitis: usefulness of rT3 and the rT3/T3 ratio as prognostic indices. Gastroenterol Jpn. 1987; 22:344–53
Ohnhaus E, Studer H. A link between liver microsomal enzyme activity and thyroid hormone metabolism in man. Br J Clin Pharmacol. 1983; 15:71–76.
Basu G, Mohapatra A. Interactions between thyroid disorders and kidney disease. Indian J Endocrinol. 2012; 16(2):204–213.
Mohamedali M, Reddy Maddika S, Vyas A, Iyer V, Cheriyath P. Thyroid disorders and chronic kidney disease. Int J Nephrol. 2014; 2014:520281.
Lim V, Fang V, Katz A, Refetoff S. Thyroid dysfunction in chronic renal failure. A study of the pituitary thyroid axis and peripheral turnover kinetics of thyroxine and triiodothyronine. J Clin Invest. 1977; 60(3):522–534.
Omrani HR, Rahimi M, Nikseresht K. The effect of selenium supplementation on acute phase reactants and thyroid function tests in hemodialysis patients. Nephrourol Mon. 2015; 7(2):e24781.
Aoun EG, Lee MR, Haass-Koffler CL, et al. Relationship between the thyroid axis and alcohol craving. Alcohol Alcohol. 2014; 50(1):24–29.
Zoeller R, Fletcher D, Simonyl A, Rudeen P. Chronic ethanol treatment reduces the responsiveness of the hypothalamic-pituitary-thyroid axis to central stimulation. Alcohol Clin Exp Res. 1996; 20(5):954–960.
Knudsen N, Bülow I, Laurberg P, Perrild H, Ovesen L, Jørgensen T. Alcohol consumption is associated with reduced prevalence of goitre and solitary thyroid nodules. Clin Endocrinol (Oxf). 2001; 55(1):41–46.
da-Silva WS, Harney JW, Kim BW, et al. The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation. Diabetes. 2007; 56(3):767l76.
Simonides WS, Mulcahey MA, Redout EM, Muller A, Zuidwijk MJ, Visser TJ. Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease in rats. J Clin Invest. 2008; 118(3):975–983.
Boelen A, Wiersinga W, Fliers E. Fasting-induced changes in the hypothalamus-pituitary-thyroid axis. Thyroid. 2008; 18(2):123–129.
De Vries EM, van Beeren HC, Ackermans MT, Kalsbeek A, Fliers E, Boelen A. Differential effects of fasting vs. food restriction on liver thyroid hormone metabolism in male rats. J Endocrinol. 2015; 224(1):25–35.
Azizi F. Islamic fasting and thyroid hormones. Int J Endocrinol Metab. 2015; 13(2):14–16.
Nair R, Mahadevan S, Muralidharan RS, Madhavan S. Does fasting or postprandial state affect thyroid function testing? Indian J Endocrinol Metab. 2014; 18(5):705–707.
Do NV, Mino L, Merriam GR, et al. Elevation in serum thyroglobulin during prolonged Antarctic residence: effect of thyroxine supplement in the polar 3,5,3-triiodothyronine syndrome. J Clin Endocrinol Metab. 2004; 89:1529–1533.
Kim TH, Kim KW, Ahn HY, et al. Effect of seasonal changes on the transition between subclinical hypothyroid and euthyroid status. J Clin Endocrinol Metab. 2013; 98(8):3420–3429.
Dardente H, Hazlerigg DG, Ebling FJP. Thyroid hormone and seasonal rhythmicity. Front Endocrinol (Lausanne). 2014; 5:1–11.
Goto M, Matsuo H, Iigo M, Furuse M, Korf HW, Yasuo S. Melatonin-induced changes in the expression of thyroid hormone-converting enzymes in hypothalamus depend on the timing of melatonin injections and genetic background in mice. Gen Comp Endocrinol. 2013; 186:33–40.
Bauer M, Kurtz J, Winokur A, Phillips J, Rubin L, Marcus J. Thyroid function before and after 4-weeks light treatment in winter depressives and controls. Psychoneuroendocrinology. 1993; 18:437–443.
Lingjaerde O, Reichborn-Kjennerud T, Haug E. Thyroid function in seasonal affective disorder. J Affect Disord. 1995; 33(1):39–45.
Martiny K, Simonsen C, Lunde M, Clemmensen L, Bech P. Decreasing TSH levels in patients with Seasonal Affective Disorder (SAD) responding to 1 week of bright light therapy. J Affect Disord. 2004; 79(1–3):253–257.
Arnson Y, Shoenfeld Y, Amital H. Effects of tobacco smoke on immunity, inflammation and autoimmunity. J Autoimmun. 2010; 34:J258–65.
Vestergaard P. Smoking and thyroid disorders–a meta-analysis. Eur J Endocrinol. 2002; 146:153–161.
Wiersinga WM. Smoking and thyroid. Clin Endocrinol (Oxf). 2013; 79(2):145–151.
Jorde R, Sundsfjord J. Serum TSH levels in smokers and non-smokers. The 5th Tromso study. Exp Clin Endocrinol Diabetes. 2006; 114:343–347.
Asvold B, Bioro T, Nilsen T, Vatten LJ. Tobacco smoking and thyroid function: a population-based study. Arch Intern Med. 2007; 167:1428–1432.
Metsios G, Flouris A, Jamurtas A, et al. A brief exposure to moderate passive smoke increases metabolism and thyroid hormone secretion. J Clin Endocrinol Metab. 2007; 92:208–211.
Yorita Christensen KL. Metals in blood and urine, and thyroid function among adults in the United States 2007–2008. Int J Hyg Environ Health. 2013; 216(6):624–632.
Soldin O, O’Mara DM, Aschner M. Thyroid hormones and methylmercury toxicity. Biol Trace Elem Res. 2008; 126(1–3):1–12.
Holt R, Handley N. Essential Endocrinology and Diabetes. Malden, MA: John Wiley & Sons; 2012.
Nishida M, Yamamoto T, Yoshimura Y, Kawada J. Subacute toxicity of methylmercuric chloride and mercuric chloride on mouse thyroid. J Pharmacobiodyn. 1986; 9(4):331–338.
Mori K, Yoshida K, Hoshikawa S, et al. Effects of perinatal exposure to low doses of cadmium or methylmercury on thyroid hormone metabolism in metallothionein-deficient mouse neonates. Toxicology. 2006; 228(1):77–84.
Hammouda F, Messaoudi I, El Hani J, Baati T, Said K, Kerkeni A. Reversal of cadmium-induced thyroid dysfunction by selenium, zinc, or their combination in rat. Biol Trace Elem Res. 2008; 126(1–3):194–203.
Pavia Junior M, Paier B, Noli M, Hagmuller K, Zaninovich A. Evidence suggesting that cadmium induces a non-thyroidal illness syndrome in the rat. J Endocrinol. 1997; 154(1):113–117.
Lopez C, Pineiro A, Nunez N, Avagnina A, Villaamil E, Rose O. Thyroid hormone changes in males exposed to lead in the Buenos Aires area (Argentina). Pharmacol Res. 2000; 42(6):599–602.
Robins J, Cullen M, Connors B, Kayne R. Depressed thyroid indexes associated with occupational exposure to inorganic lead. Arch Intern Med. 1983; 143(2):220–224.
Singh B, Chandran V, Bandhu HK, et al. Impact of lead exposure on pituitary-thyroid axis in humans. Biometals. 2000; 13(2):187–192.
Tuppurainen M, Wagar G, Kurppa K, et al. Thyroid function as assessed by routine laboratory tests of workers with long-term lead exposure. Scand J Work Env Heal. 1988; 14(3):175–180.
Wu CY, Liu B, Wang HL, Ruan DY. Levothyroxine rescues the lead-induced hypothyroidism and impairment of long-term potentiation in hippocampal CA1 region of the developmental rats. Toxicol Appl Pharmacol. 2011; 256(2):191–197.
Duntas LH. The evolving role of selenium in the treatment of Graves’ disease and ophthalmopathy. J Thyroid Res. 2012; 2012:736161.
Eskes SA, Endert E, Fliers E, et al. Selenite supplementation in euthyroid subjects with thyroid peroxidase antibodies. Clin Endocrinol (Oxf). 2014; 80(3):444–451.
Turker O, Kumanlioglu K, Karapolat I, Dogan I. Selenium treatment in autoimmune thyroiditis: 9-month follow-up with variable doses. J Endocrinol. 2006; 190(1):151–156.
Boelen A, Platvoetter-Schiphorst M, Bakker O, Wiersinga W. The role of cytokines in the lipopolysaccharide-induced sick euthyroid syndrome in mice. J Endocrinol. 1995; 146:475–483.
Mahmoodianfard S, Vafa M, Golgiri F, et al. Effects of zinc and selenium supplementation on thyroid function in overweight and obese hypothyroid female patients: a randomized double-blind controlled trial. J Am Coll Nutr. 2015;(July):1–9.
Bonham M, O’Connor J, Alexander HD, et al. Zinc supplementation has no effect on circulating levels of peripheral blood leucocytes and lymphocyte subsets in healthy adult men. Br J Nutr. 2003; 89:695–703.
Gupta G, Rana A. Withania somnifera (Ashwagandha): a review. Pharmacogn Rev. 2007; 1:129–136.
Van der Hooft C, Hoekstra A, Winter A, de Smet P, Stricker B. Thyrotoxicosis following the use of Ashwagandha. Ned Tijdschr Geneeskd. 2005; 149:2637–2638.
Panda S, Kar A. Changes in thyroid hormone concentrations after administration of ashwagandha root extract to adult male mice. J Pharm Pharmacol. 1998; 50(9):1065–1068.
Panda S, Kar A. Withania somnifera and bauhinia purpurea in the regulation of circulating thyroid hormone concentrations in female mice. J Ethnopharmacol. 1999; 67:233–239.
Roy Chengappa K, Gannon J, Forrest P. Subtle changes in thyroid indices during a placebo-controlled study of an extract of Withania somnifera in persons with bipolar disorder. J Ayurveda Integr Med. 2014; 5(4):241.
Tripathi YB, Malhotra OP, Tripathi SN. Thyroid stimulating action of Z-guggulsterone obtained from Commiphora mukul. Planta Med. 1984; 50(l):78–80.
Singh AK, Tripathi SN, Prasad GC. Response of Commiphora mukul (guggulu) on melatonin induced hypothyroidism. Anc Sci Life. 1983; 3:85–90.
Panda S, Kar A. Guggulu (Commiphora mukul) potentially ameliorates hypothyroidism in female mice. Phyther Res. 2005; 19(1):78–80.
Panda S, Kar A. Gugulu (Commiphora mukul) induces triiodothyronine production: possible involvement of lipid peroxidation. Life Sci. 1999; 65(12):137–141.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY-NC-ND 4.0). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.