Hypothyroidism in the older population
AbstractBackground. Both overt hypothyroidism as well as minor elevations of serum thyrotropin (TSH) levels associated with thyroid hormones within their respective reference ranges (termed subclinical hypothyroidism) are relatively common in older individuals. There is growing evidence that treatment of subclinical hypothyroidism may not be beneficial, particularly in an older person. These findings are relevant at a time when treatment with thyroid hormones is increasing and more than 10-15% of people aged over 80 years are prescribed levothyroxine replacement therapy.
Main body. The prevalence of hypothyroidism increases with age. However, the reference range for TSH also rises with age, as the population distribution of TSH concentration progressively rises with age. Furthermore, there is evidence to suggest that minor TSH elevations are not associated with important outcomes such as impaired quality of life, symptoms, cognition, cardiovascular events and mortality in older individuals. There is also evidence that treatment of mild subclinical hypothyroidism may not benefit quality of life and/or symptoms in older people. It is unknown whether treatment targets should be reset depending on the age of the patient. It is likely that some older patients with nonspecific symptoms and incidental mild subclinical hypothyroidism may be treated with thyroid hormones and could potentially be harmed as a result. This article reviews the current literature pertaining to hypothyroidism with a special emphasis on the older individual and assesses the risk/benefit impact of contemporary management on outcomes in this age group.
Conclusions. Current evidence suggests that threshold for treating mild subclinical hypothyroidism in older people should be high. It is reasonable to aim for a higher TSH target in treated older hypothyroid patients as their thyroid hormone requirements may be lower. In addition, age-appropriate TSH reference ranges should be considered in the diagnostic pathway of identifying individuals at risk of developing hypothyroidism. Appropriately designed and powered randomised controlled trials are required to confirm risk/benefit of treatment of subclinical hypothyroidism in older people. Until the results of such RCTs are available to guide clinical management international guidelines should be followed that advocate a conservative policy in the management of mild subclinical hypothyroidism in older individuals.
Keywords:hypothyroidism, elderly, ageing, TSH
Leng O., Razvi S. Hypothyroidism in the older population. Thyroid Research. 2019; 12: 2.
https://doi.org/10.1186/s13044-019-0063-3
References
1. Future of an Ageing Population. URL: https://www.ageing.ox.ac.uk/ files/Future_of_Ageing_Report.pdf (date of access December 10, 2018)
2. Canaris G.J., Manowitz N.R., Mayor G., Ridgway E.C. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000; 160: 526. URL: https://doi.org/10.1001/archinte.160.4.526
3. Ingoe L., Phipps N., Armstrong G., Rajagopal A., et al. Prevalence of treated hypothyroidism in the community: analysis from general practices in north-East England with implications for the United Kingdom. Clin Endocrinol. 2017; 87: 860-4. URL: https://doi.org/ 10.1111/cen.13440
4. Hadlow N.C., Rothacker K.M., Wardrop R., Brown S.J., et al. The relationship between TSH and free T 4 in a large population is complex and nonlinear and differs by age and sex. J Clin Endocrinol Metab. 2013; 98: 2936-43. URL: https://doi.org/10.1210/jc.2012-4223
5. Brown S.J., Bremner A.P., Hadlow N.C., Feddema P., et al. The log TSH-free T4 relationship in a community-based cohort is nonlinear and is influenced by age, smoking and thyroid peroxidase antibody status. Clin Endocrinol. 2016; 85: 789-96. URL: https://doi.org/10.1111/cen. 13107
6. Aggarwal N., Razvi S. Thyroid and aging or the aging thyroid? An evi-dencebased analysis of the literature. J Thyroid Res. 2013; 2013: 481287. URL: https://doi.org/10.1155/2013/481287
7. Jonklaas J., Razvi S. Reference intervals in the diagnosis of thyroid dysfunction - time to treat patients and not numbers. Lancet Diabetes Endocrinol. 2019. (in press)
8. Tunbridge W.M., Evered D.C., Hall R., Appleton D., et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol. 1977; 7: 481-93. URL: http://www.ncbi.nlm.nih.gov/pubmed/598014. (date of access December 2, 2018)
9. Sawin C.T., Castelli W.P., Hershman J.M., McNamara P., et al. The aging thyroid. Arch Intern Med. 1985; 145: 1386. URL: https://doi. org/10.1001/archinte.1985.00360080056006
10. Chaker L., van den Berg M.E., Niemeijer M.N., Franco O.H., et al. Thyroid function and sudden cardiac death. Circulation. 2016; 134: 71322. URL: https://doi.org/10.1161/CIRCULATI0NAHA.115.020789
11. Bensenor I.M., Goulart A.C., Lotufo P.A., Menezes P.R., et al. Prevalence of thyroid disorders among older people: results from the Sao Paulo Ageing & Health Study. Cad Saude Publica 2011; 27: 155-61. URL: http:// www.ncbi.nlm.nih.gov/pubmed/21340114. (date of access December 2, 2018)
12. Ceresini G., Lauretani F., Maggio M., Ceda G.P., et al. Thyroid function abnormalities and cognitive impairment in elderly people: results of the Invecchiare in chianti study. J Am Geriatr Soc. 2009; 57: 89-93. URL: https://doi.org/10.1111/j.1532-5415.2008.02080.x
13. Imaizumi M., Akahoshi M., Ichimaru S., Nakashima E., et al. Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab. 2004; 89: 3365-70. URL: https://doi. org/10.1210/jc.2003-031089
14. Cappola A.R., Fried L.P., Arnold A.M., Danese M.D., et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA. 2006; 295: 1033. URL: https://doi.org/10.1001/jama.295.9.1033
15. Rodondi N., Newman A.B., Vittinghoff E., de Rekeneire N., et al. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med. 2005; 165: 2460. URL: https:// doi.org/10.1001/archinte.165.21.2460
16. Gussekloo J., van E.E., de C.A.J.M., Meinders A.E., et al. Thyroid status, disability and cognitive function, and survival in old age. JAMA. 2004; 292: 2591. URL: https://doi.org/10.1001/jama.292.21.2591
17. Wilson S., Parle J.V., Roberts L.M., Roalfe A.K., et al. Prevalence of subclinical thyroid dysfunction and its relation to socioeconomic deprivation in the elderly: a community-based crosssectional survey. J Clin Endocrinol Metab. 2006; 91: 4809-16. URL: https://doi.org/10.1210/jc.2006-1557
18. Pearce S.H.S., Razvi S., Yadegarfar M.E., Martin-Ruiz C., et al. Serum thyroid function, mortality and disability in advanced old age: the Newcastle 85+ study. J Clin Endocrinol Metab. 2016; 101: 4385-94. URL: https://doi.org/10.1210/jc.2016-1935
19. van den Beld A.W., Visser T.J., Feelders R.A., Grobbee D.E., et al. Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J Clin Endocrinol Metab. 2005; 90: 6403-9. URL: https:// doi.org/10.1210/jc.2005-0872
20. De Jongh R.T., Lips P., Van Schoor N.M., Deeg D.J.H., et al. Endogenous subclinical thyroid disorders, physical and cognitivefunction, depression, and mortality in older individuals. Eur J Endocrinol. 2011; 165: 545-54. URL: https://doi.org/10.1530/EJE-11-0430
21. Surks M.I., Hollowell J.G. Age-specific distribution of serum thyrotropin and antithyroid antibodies in the U.S. population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab. 2007; 92: 4575-82. URL: https://doi.org/10.1210/jc.2007-1499
22. Kahapola-Arachchige K.M., Hadlow N., Wardrop R., Lim E.M., et al. Agespecific TSH reference ranges have minimal impact on the diagnosis of thyroid dysfunction. Clin Endocrinol. 2012; 77: 773-9. URL: https://doi.org/10.1111/j.1365-2265.2012.04463.x
23. Ceresini G., Ceda G.P., Lauretani F., Maggio M., et al. Thyroid status and 6-year mortality in elderly people living in a mildly iodine-deficient area: the aging in the chianti area study. J Am Geriatr Soc. 2013; 61: 868-74. URL: https://doi.org/10.1111/jgs.12267
24. Hansen P.S., Brix T.H., Sorensen T.I.A., Kyvik K.O., et al. Major genetic influence on the regulation of the pituitary-thyroid axis: a study of healthy Danish twins. J Clin Endocrinol Metab. 2004; 89: 1181-7. URL: https://doi.org/10.1210/jc.2003-031641
25. Garber J.R., Cobin R.H., Gharib H., Hennessey J.V., et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012; 22: 1200-35. URL: https://doi.org/10.1089/ thy.2012.0205
26. Okosieme O., Gilbert J., Abraham P., Boelaert K., et al. Management of primary hypothyroidism: statement by the British thyroid association executive committee. Clin Endocrinol. 2016; 84: 799-808. URL: https://doi.org/10.1111/cen.12824
27. Andersen S., Bruun N.H., Pedersen K.M., Laurberg P. Biologic variation is important for interpretation of thyroid function tests. Thyroid. 2003; 13: 1069-78. URL: https://doi.org/10.1089/105072503770867237
28. Baloch Z., Carayon P., Conte-Devolx B., Demers L.M., et al. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid. 2003; 13: 3-3. URL: https://doi.org/10.1089/105072503321086962
29. Jensen E., Petersen P.H., Blaabjerg O., Hansen P.S., et al. Establishment of a serum thyroid stimulating hormone (TSH) reference interval in healthy adults. The importance of environmental factors, including thyroid antibodies. Clin Chem Lab Med. 2004; 42: 824-32. URL: https:// doi.org/10.1515/CCLM.2004.136
30. Dickey R.A., Wartofsky L., Feld S. Optimal thyrotropin level: Normal ranges and reference intervals are not equivalent. Thyroid. 2005; 15: 1035-9. URL: https:// doi.org/10.1089/thy.2005.15.1035
31. Surks M.I., Goswami G., Daniels G.H. The thyrotropin reference range should remain unchanged. J Clin Endocrinol Metab. 2005; 90: 5489-96. URL: https://doi.org/10.1210/jc.2005-0170
32. Andersen S., Pedersen K.M., Bruun N.H., 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: 1068-72. URL: https://doi.org/10.1210/jcem.87.3.8165
33. Waring A.C., Harrison S., Samuels M.H., Ensrud K.E., et al. Thyroid function and mortality in older men: a prospective study. J Clin Endocrinol Metab. 2012; 97: 862-70. URL: https://doi.org/10.1210/jc.2011-2684
34. Bremner A.P., Feddema P., Leedman P.J., Brown S.J., et al. Age-related changes in thyroid function: a longitudinal study of a community-based cohort. J Clin Endocrinol Metab. 2012; 97: 1554-62. URL: https:// doi.org/10.1210/jc.2011-3020
35. Mammen J.S., McGready J., Ladenson P.W., Simonsick E.M. Unstable thyroid function in older adults is caused by alterations in both thyroid and pituitary physiology and is associated with increased mortality. Thyroid. 2017; 27: 1370-7. URL: https://doi.org/10.1089/thy.2017. 0211
36. Hollowell J.G., Staehling N.W., Flanders W.D., Hannon W.H., et al. Serum TSH, T 4, and thyroid antibodies in the United States population (1988 to 1994): National Health and nutrition examination survey (NHANES III). J Clin Endocrinol Metab. 2002; 87: 489-99. URL: https://doi. org/10.1210/jcem.87.2.8182
37. Vadiveloo T., Donnan P.T., Murphy M.J., Leese G.P. Age- and gender-specific TSH reference intervals in people with no obvious thyroid disease in Tayside, Scotland: the thyroid epidemiology, audit, and research study (TEARS). J Clin Endocrinol Metab. 2013; 98: 1147-53. URL: https:// doi.org/10.1210/jc.2012-3191
38. Wartofsky L., Dickey R.A. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab. 2005; 90: 5483-8. URL: https://doi.org/10.1210/jc.2005-0455
39. Vanderpump M.P.J., Tunbridge W.M.G., French J.M., Appleton D., et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham survey. Clin Endocrinol. 1995; 43: 55-68. URL: https://doi.org/10.1111/j.1365-2265.1995.tb01894.x
40. Walsh J.P., Bremner A.P., Feddema P., Leedman P.J., et al. Thyrotropin and thyroid antibodies as predictors of hypothyroidism: a 13-year, longitudinal study of a community-based cohort using current immunoassay techniques. J Clin Endocrinol Metab. 2010; 95: 1095-104. URL: https://doi.org/10.1210/jc.2009-1977
41. Razvi S., Ingoe L., Ryan V., Pearce S.H.S., et al. Study of optimal replacement of thyroxine in the elderly (SORTED) - results from the feasibility randomised controlled trial. Thyroid Res. 2016; 9: 5. URL: https:// doi.org/10.1186/s13044-016-0034-x
42. Boucai L., Hollowell J.G., Surks M.I. An approach for development of age-, gender-, and ethnicity-specific thyrotropin reference limits. Thyroid. 2011; 21: 5-11. URL: https://doi.org/10.1089/thy.2010.0092
43. Bensenor I., Lotufo P., Diaz-Olmos P.A. Hypothyroidism in the elderly: diagnosis and management. Clin Interv Aging. 2012; 7: 97. URL: https://doi.org/10.2147/CIA.S23966
44. Carle A., Pedersen I.B., Knudsen N., Perrild H., et al. Hypothyroid symptoms fail to predict thyroid insufficiency in old people: a population-based case-control study. Am J Med. 2016; 129: 1082-92. URL: https:// doi.org/10.1016/j.amjmed.2016.06.013
45. Doucet J., Trivalle C., Chassagne P., Perol M.-B., et al. Does age play a role in clinical presentation of hypothyroidism? J Am Geriatr Soc. 1994; 42: 984-6. URL: https://doi.org/10.1111/ j.1532-5415.1994.tb06592.x
46. Bahemuka M., Hodkinson H.M. Screening for hypothyroidism in elderly inpatients. Br Med J. 1975; 2: 601-3. URL: https://doi.org/10.1136/ bmj.2.5971.601
47. Lloyd W.H., Goldberg I.J. Incidence of hypothyroidism in the elderly. Br Med J. 1961; 2: 1256-9.
48. Ono Y., Ono S., Yasunaga H., Matsui H., et al. Clinical characteristics and outcomes of myxedema coma: analysis of a national inpatient database in Japan. J Epidemiol. 2017; 27: 117-22. URL: https:// doi.org/10.1016/j.je.2016.04.002
49. Jorde R., Waterloo K., Storhaug H., Nyrnes A., et al. Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment. J Clin Endocrinol Metab. 2006; 91: 145-53. URL: https://doi.org/10.1210/jc.2005-1775
50. Javed Z., Sathyapalan T. Levothyroxine treatment of mild subclinical hypothyroidism: a review of potential risks and benefits. Ther Adv Endocrinol Metab. 2016; 7: 12-23. URL: https://doi.org/10.1177/ 2042018815616543
51. Taylor P.N., Iqbal A., Minassian C., Sayers A., et al. Falling threshold for treatment of borderline elevated thyrotropin levels-balancing benefits and risks. JAMA Intern Med. 2014; 174: 32. URL: https://doi.org/10.1001/ jamainternmed.2013.11312
52. Razvi S., Jabbar A., Pingitore A., Danzi S., et al. Thyroid hormones and cardiovascular function and diseases. J Am Coll Cardiol. 2018; 71: 1781-96. URL: https://doi.org/10.1016/jjacc.2018.02.045
53. Biondi B., Cooper D.S. The clinical significance of subclinical thyroid dysfunction. Endocr Rev. 2008; 29: 76-131. URL: https://doi.org/ 10.1210/er.2006-0043
54. Ochs N., Auer R., Bauer D.C., Nanchen D., et al. Metaanalysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Ann Intern Med. 2008; 148: 832-45. URL: https:// doi.org/10.7326/0003-4819-148-11-200806030-00225
55. Razvi S., Shakoor A., Vanderpump M., Weaver J.U., et al. The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease: a meta-analysis. J Clin Endocrinol Metab. 2008; 93: 2998-3007. URL: https://doi.org/10.1210/jc.2008-0167
56. Jabbar A., Pingitore A., Pearce S.H.S., Zaman A., et al. Thyroid hormones and cardiovascular disease. Nat Rev Cardiol. 2016; 14: 39-55. URL: https://doi.org/10.1038/nrcardio.2016.174
57. Gencer B., Collet T.-H., Virgini V., Bauer D.C., et al. Subclinical thyroid dysfunction and the risk of heart failure events. Circulation. 2012; 126: 1040-9. URL: https://doi.org/10.1161/CIRCULATIONAHA.112.096024
58. Chaker L., Baumgartner C., den Elzen W.P.J., Ikram M.A., et al. Subclinical hypothyroidism and the risk of stroke events and fatal stroke: an individual participant data analysis. J Clin Endocrinol Metab. 2015; 100: 2181-91. URL: https://doi.org/10.1210/jc.2015-1438
59. Asher R. Myxoedematous madness. Br Med J. 1949; 2: 555-62.
60. Lansing R.W., Trunnell J.B. Electroencephalographic changes accompanying thyroid deficiency in Man1. J Clin Endocrinol Metab. 1963; 23: 470-80. URL: https://doi.org/10.1210/jcem-23-5-470
61. Ladenson P.W., Stakes J.W., Ridgway E.C. Reversible alteration of the visual evoked potential in hypothyroidism. Am J Med. 1984; 77: 1010-4. URL: https://doi.org/10.1016/0002-9343(84)90180-3
62. Osterweil D., Syndulko K., Cohen S.N., Pettier-Jennings P.D., et al. Cognitive function in non-demented older adults with hypothyroidism. J Am Geriatr Soc. 1992; 40: 325-35. URL: https://doi.org/10.1111/ j.1532-5415.1992.tb02130.x
63. Mennemeier M., Garner R.D., Heilman K.M. Memory, mood and measurement in hypothyroidism. J Clin Exp Neuropsychol. 1993; 15: 82231. URL: https://doi.org/10.1080/01688639308402598
64. Clarnette R.M., Patterson C.J. Hypothyroidism: does treatment cure dementia? J Geriatr Psychiatry Neurol. 1994; 7: 23-7. URL: http:// www.ncbi.nlm.nih.gov/pubmed/8192826 (date of access December 6, 2018)
65. Dugbartey A.T. Neurocognitive aspects of hypothyroidism. Arch Intern Med. 1998; 158: 1413-8. URL: https://doi.org/10.1001/ archinte.158.13.1413
66. Monzani F., Guerra P., Caracciol N., Pruneti C.A., et al. Subclinical hypothyroidism: neurobehavioral features and beneficial effect of l-thyroxine treatment. Clin Investig. 1993; 71: 367-71. URL: https:// doi.org/10.1007/BF00186625
67. Baldini I.M., Vita A., Mauri M.C., Amodei V., et al. Psychopathological and cognitive features in subclinical hypothyroidism. Prog Neu-ropsychopharmacol Biol Psychiatry. 1997; 21: 925-35. URL: https:// doi.org/10.1016/S0278-5846(97)00089-4
68. del Ser Quijano T., Delgado C., Martinez Espinosa S., Vazquez C. [Cognitive deficiency in mild hypothyroidism]. Neurologia (Barcelona, Spain). 2000; 15: 193-8.
69. Cook S.E., Nebes R.D., Halligan E.M., Burmeister L.A., et al. Memory impairment in elderly individuals with a mildly elevated serum TSH: the role of processing resources, depression and cerebrovascular disease. Aging Neuropsychol Cogn. 2002; 9: 175-83. URL: https:// doi.org/10.1076/anec.9.3.175.9610
70. Manciet G., Dartigues J.F., Decamps A., Gateau P.B., et al. The PA-QUID survey and correlates of subclinical hypothyroidism in elderly community residents in the south west of France. Age Ageing. 1995; 24: 235-41. URL: https://doi.org/10.1093/ ageing/24.3.235
71. Luboshitzky R., Oberman A.S., Kaufman N., Reichman N., et al. Prevalence of cognitive dysfunction and hypothyroidism in an elderly community population. Isr J Med Sci. 1996; 32: 60-5.
72. Park Y.J., Lee E.J., Lee Y.J., Choi S.H., et al. Subclinical hypothyroidism (SCH) is not associated with metabolic derangement, cognitive impairment, depression or poor quality of life (QoL) in elderly subjects. Arch Gerontol Geriatr. 2010; 50: e68-73. URL: https://doi.org/10.1016/ J.ARCHGER.2009.05.015
73. Jaeschke R., Guyatt G., Gerstein H., Patterson C., et al. Does treatment withl-thyroxine influence health status in middle-aged and older adults with subclinical hypothyroidism? J Gen Intern Med. 1996; 11: 744-9. URL: https://doi.org/10.1007/BF02598988
74. Nystrom E., Caidahl K., Fager G., Wikkelso C., et al. A double-blind cross-over 12-month study of L-thyroxine treatment of women with "subclinical" hypothyrodism. Clin Endocrinol. 1988; 29: 63-76. URL: https:// doi.org/10.1111/j.1365-2265.1988.tb00250.x
75. Parle J., Roberts L., Wilson S., Pattison H., et al. A randomized controlled trial of the effect of thyroxine replacement on cognitive function in community-living elderly subjects with subclinical hypothyroidism: the Birmingham elderly thyroid study. J Clin Endocrinol Metab. 2010; 95: 3623-32. URL: https://doi.org/10.1210/jc.2009-2571
76. Simonsick E.M., Newman A.B., Ferrucci L., Satterfield S., et al. Subclinical hypothyroidism and functional mobility in older adults. Arch Intern Med. 2009; 169: 2011-7. URL: https://doi.org/10.1001/archin-ternmed.2009.392
77. Nagata M., Suzuki A., Sekiguchi S., Ono Y., et al. Subclinical hypothyroidism is related to lower heel QUS in postmenopausal women. Endocr J. 2007; 54: 625-30. URL: https://doi.org/ 10.1507/END0CRJ.K06-201
78. Waring A.C., Harrison S., Fink H.A., Samuels M.H., et al. A prospective study of thyroid function, bone loss, and fractures in older men: the MrOS study. J Bone Miner Res. 2013; 28: 472-9. URL: https:// doi.org/10.1002/jbmr.1774
79. Lee J.S., Buzkova P., Fink H.A., Vu J., et al. Subclinical thyroid dysfunction and incident hip fracture in older adults. Arch Intern Med. 2010; 170: 1876-83. URL: https://doi.org/10.1001/ archinternmed.2010.424
80. Jansen S.W., Akintola A.A., Roelfsema F., van der Spoel E., et al. Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism. Sci Rep. 2015; 5: 11525. URL: https://doi.org/10.1038/srep11525
81. Buffenstein R. The naked mole-rat: a new long-living model for human aging research. J Gerontol A Biol Sci Med Sci. 2005; 60: 1369-77. URL: https://doi.org/10.1093/gerona/60.11.1369
82. Vergara M., Smith-Wheelock M., Harper J.M., Sigler R., et al. Hormone-treated snell dwarf mice regain fertility but remain long lived and disease resistant. J Gerontol A Biol Sci Med Sci. 2004; 59: 1244-50.
83. Rozing M.P., Houwing-Duistermaat J.J., Slagboom P.E., Beekman M., et al. Familial longevity is associated with decreased thyroid function. J Clin Endocrinol Metab. 2010; 95: 4979-84. URL: https://doi. org/10.1210/jc.2010-0875
84. Ceresini G., Marina M., Lauretani F., Maggio M., et al. Relationship between circulating thyroid-stimulating hormone, free thyroxine, and free triiodothyronine concentrations and 9-year mortality inEuthyroid elderly adults. J Am Geriatr Soc. 2016; 64: 553-60. URL: https:// doi.org/10.1111/jgs.14029
85. Yeap B.B., Alfonso H., Hankey G.J., Flicker L., et al. Higher free thyroxine levels are associated with all-cause mortality in euthyroid older men: the health in men study. Eur J Endocrinol. 2013; 169: 401-8. URL: https:// doi.org/10.1530/EJE-13-0306
86. Mammen J.S., McGready J., Oxman R., Chia C.W., et al. Thyroid hormone therapy and risk of thyrotoxicosis in community-resident older adults: findings from the Baltimore longitudinal study of aging. Thyroid. 2015; 25: 979-86. URL: https://doi.org/ 10.1089/thy.2015.0180
87. Razvi S., Korevaar T., Taylor P. Trends, determinants and associations of treated hypothyroidism in the United Kingdom, 2005-2014. Thyroid 2018; 2018: 0251. URL: https://doi.org/10.1089/thy.2018.0251
88. Samuels M.H., Schuff K.G., Carlson N.E., Carello P., et al. Health status, psychological symptoms, mood, and cognition in L-thyroxine-treated hypothyroid subjects. Thyroid. 2007; 17: 249-58. URL: https://doi.org/ 10.1089/thy.2006.0252
89. Rosenbaum R.L., Barzel U.S. Levothyroxine replacement dose for primary hypothyroidism decreases with age. Ann Intern Med. 1982; 96: 53-5. URL: https://doi.org/10.7326/0003-4819-96-1-53
90. Sawin C.T., Geller A., Wolf P.A., Belanger A.J., et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med. 1994; 331: 1249-52. URL: https://doi.org/10.1056/ NEJM199411103311901
91. Bauer D.C., Ettinger B., Nevitt M.C., Stone K.L. Risk for fracture in women with low serum levels of thyroid-stimulating hormone. Ann Intern Med. 2001; 134: 561-8. URL: https://doi.org/10.7326/0003-4819-134-7-200104030-00009
92. Flynn R.W., Bonellie S.R., Jung R.T., MacDonald T.M., et al. Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab. 2010; 95: 186-93. URL: https://doi.org/10.1210/ jc.2009-1625
93. Stott D.J., Rodondi N., Kearney P.M., Ford I., et al. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med. 2017; 376: 2534-44. URL: https://doi.org/10. 1056/NEJMoa1603825