Abstracts
To assess studies that evaluate the relation between serum thyrotropin concentration, very old subjects, and their events. We searched the PubMed, SciELO, and LILACS databases for articles published between 2004 and 2012. Our search was restricted to studies involving humans aged 65 years or older, and written in English, Spanish, or Portuguese. Studies that evaluated the association between elevated serum thyrotropin concentration among elderly subjects with subclinical hypothyroidism were chosen since at least in part they included a subpopulation of individuals aged 80 years and above. Thirteen studies were selected. No significant increase in risk of cardiovascular events, coronary heart disease, or total mortality was observed. Elevated thyrotropin concentration was associated with longevity. More randomized controlled trials are required to better define the potential benefits of elevated thyrotropin concentration in this oldest old population, hormone replacement, and longevity.
Hypothyroidism; Aged; 80 and over
Avaliar os artigos que consideram a relação entre a concentração da tirotropina sérica, indivíduos muito idosos e seus eventos. Foram selecionados artigos do PubMed, SciELO e LILACS publicados entre 2004 e 2012, que consideraram uma população ≥65 anos, escritos em inglês, espanhol ou português. Os estudos que avaliaram a associação entre níveis séricos elevados de tirotropina sérica e idosos com hipotireoidismo subclínico foram escolhidos, desde que incluíssem uma subpopulação com 80 anos ou mais. Treze estudos foram selecionados. Não houve associação significante entre maior risco de eventos cardiovasculares, doença coronariana ou mortalidade. A concentração elevada de tirotropina sérica foi associada à longevidade. Mais estudos randomizados controlados são necessários para o melhor entendimento do potencial benefício da elevação de concentração da tirotropina sérica nos longevos, reposição hormonal e longevidade.
Hipotireoidismo; Idosos de 80 anos ou mais; Longevidade
INTRODUCTION
Subclinical hypothyroidism is a laboratory diagnosis(
11 Peeters RP. Thyroid hormones and aging. Hormones (Athens).
2008;7(1):28-35. Review.
) defined by an abnormally high serum thyrotropin (TSH) level associated
with a normal plasma concentration of free thyroxin (fT4).(
22 Gussekloo J, van Exel E, Craen AJ, Meinders AE, Frölich M, Western
RG. Thyroid status, disability and cognitive function and survival in old age.
JAMA. 2004;292(21):2591-9.
3 Brabant G, Beck-Peccoz P, Jarzab B, Laurberg P, Orgiazzi J, Szabolcs
I, et al. Is there a need to redefine the upper normal limit of TSH? Eur J
Endocrinol. 2006;154(5):633-7. Review.
-
44 Laurberg P, Andersen S, Carlé A, Karmisholt J, Knudsen N, Pedersen
IB. The TSH upper reference limit: where are we at? Nat Rev Endocrinol.
2011;7(4):232-9. Review.
) It is common among elderly individuals and its prevalence increases
with age, affecting 6% of population between 70 and 79 years and 10% of individuals
above 80 years of age.(
55 Surks MI, Hollowell JG. Age specific distribution of serum
thyrotropin and antithyroid antibodies in the US population: implications for
the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab.
2007;92(12):4575-82.
,
66 Biondi B. Should we treat all subjects with subclinical thyroid
disease the same way? Eur J Endocrinol. 2008;159(3):343-5.
) The prevalence of subclinical hypothyroidism is lower in blacks
compared with whites, in women over the age of 80 years, and in populations with
iodine deficiency.(
11 Peeters RP. Thyroid hormones and aging. Hormones (Athens).
2008;7(1):28-35. Review.
)
Subclinical thyroid dysfunction has been associated with several negative clinical outcomes such as hypercholesterolemia, atherosclerosis,( 77 Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A, Maisonneuve P, Sgarbi JA, Khaw KT, Vanderpump MP, Newman AB, Cornuz J, Franklyn JA, Westendorp RG, Vittinghoff E, Gussekloo J; Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010;304(12):1365-74. ) coronary heart disease events and mortality,( 22 Gussekloo J, van Exel E, Craen AJ, Meinders AE, Frölich M, Western RG. Thyroid status, disability and cognitive function and survival in old age. JAMA. 2004;292(21):2591-9. , 77 Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A, Maisonneuve P, Sgarbi JA, Khaw KT, Vanderpump MP, Newman AB, Cornuz J, Franklyn JA, Westendorp RG, Vittinghoff E, Gussekloo J; Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010;304(12):1365-74. ) cognitive impairment,( 22 Gussekloo J, van Exel E, Craen AJ, Meinders AE, Frölich M, Western RG. Thyroid status, disability and cognitive function and survival in old age. JAMA. 2004;292(21):2591-9. , 88 Parle J, Roberts L, Wilson S, Pattison H, Roalfe A, Haque MS, et al. A randomized controlled trial of the effect of thyroxin replacement on cognitive function in community-living elderly subjects with subclinical hypothyroidism: the Birmingham Elderly Thyroid study. J Clin Endocrinol Metab. 2010;95(8):3623-32. , 99 Hogervorst E, Huppert F, Matthews FE, Brayne C. Thyroid function and cognitive decline in the MRC Cognitive Function and Ageing Study. Psychoneuroendocrinology. 2008;33(7):1013-22. ) depression,( 1010 Chueire VB, Romaldini JH, Ward L. Subclinical hypothyroidism increases the risk for depression in the elderly. Arch Gerontol Geriatr. 2007;44(1):21-8. ) disability,( 22 Gussekloo J, van Exel E, Craen AJ, Meinders AE, Frölich M, Western RG. Thyroid status, disability and cognitive function and survival in old age. JAMA. 2004;292(21):2591-9. ) lower physical function,( 1111 Van den Beld A, Visser TJ, Feelders RA, Grobbee DE, Lamberts SW. Thyroid hormone concentrations, disease, physical function and mortality in elderly men. J Clin Endocrinol Metab. 2005;90(12):6403-9. ) and risk of progression to overt hypothyroidism.( 1212 Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev. 2008;29(1):76-131. Review. )
Serum TSH concentration increases slightly in very old healthy
individuals,(
1313 Peeters RP. Thyroid function and longevity: new insights into an old
dilemma. J Clin Endocrinol Metab. 2009;94(12):4658-60.
) regardless of the presence of antithyroid antibodies(
55 Surks MI, Hollowell JG. Age specific distribution of serum
thyrotropin and antithyroid antibodies in the US population: implications for
the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab.
2007;92(12):4575-82.
,
1414 Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I. Extreme
longevity is associated with increased serum thyrotropin. J Clin Endocrinol
Metab. 2009;94(4):1251-4.
) and along with an age-dependent decline in serum free and total
triiodothyronine (T3), suggesting that some very elderly individuals may have an
altered set point of the hypothalamic-pituitary-thyroid axis.(
44 Laurberg P, Andersen S, Carlé A, Karmisholt J, Knudsen N, Pedersen
IB. The TSH upper reference limit: where are we at? Nat Rev Endocrinol.
2011;7(4):232-9. Review.
) Despite a likely increase in serum reverse triiodothyronine (rT3) with
age,(
1111 Van den Beld A, Visser TJ, Feelders RA, Grobbee DE, Lamberts SW.
Thyroid hormone concentrations, disease, physical function and mortality in
elderly men. J Clin Endocrinol Metab. 2005;90(12):6403-9.
) free and total serum thyroxin (T4) concentrations remain unchanged,
complicating the interpretation of these measurements since concomitant chronic
illnesses and use of medications are often present in this population. It is
possible that the decrease in thyroid function and metabolic rate(
1111 Van den Beld A, Visser TJ, Feelders RA, Grobbee DE, Lamberts SW.
Thyroid hormone concentrations, disease, physical function and mortality in
elderly men. J Clin Endocrinol Metab. 2005;90(12):6403-9.
) may be adaptive mechanisms to prevent catabolism and reduce damage to
DNA by reactive oxygen species.(
1313 Peeters RP. Thyroid function and longevity: new insights into an old
dilemma. J Clin Endocrinol Metab. 2009;94(12):4658-60.
) Furthermore, reports have demonstrated that centenarians(
1414 Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I. Extreme
longevity is associated with increased serum thyrotropin. J Clin Endocrinol
Metab. 2009;94(4):1251-4.
) and their offspring have higher serum TSH levels, characterizing a
heritable phenotype.(
1515 Aztmon G, Barzilai N, Surks MI, Gabriely I. Genetic predisposition
to elevated serum thyrotropin is associated with exceptional longevity. J Clin
Endocrinol Metab. 2009;94(12):4768-75.
16 Rozing MP, Houwing-Duistermaat JJ, Slagboom PE, Beekman M, Frölich
M, de Craen AJ, et al. Familial longevity is associated with decreased thyroid
function. J Clin Endocrinol Metab. 2010;95(11):4979-84.
-
1717 Corsonello A, Montesanto A, Berardelli M, De Rango F, Dato S, Mari
V, et al. A cross-section analysis of FT3 age-related changes in a group of old
and oldest-old subjects, including centenarians’ relatives, shows that a
down-regulated thyroid function has a familial component and is related to
longevity. Age Ageing. 2010;39(6):723-7.
)
Despite this evidence, the hypothesis that some degree of physiological decrease in thyroid activity at a tissue level may favor effects in oldest old subjects remains uncertain.
OBJECTIVE
To assess studies that evaluated the relation between elevated serum thyrotropin concentrations in mild hypothyroidism and comorbidities in individuals aged over 80 years.
METHODS
This review was conducted at the Department of Geriatrics and Gerontology, Universidade Federal de São Paulo, and approved by the local Research Ethics Committee. We searched the PubMed, Scientific Electronic Library Online (SciELO), and LILACS databases for articles published between 2004 and 2012, and performed the last survey in April 2013. To conduct the search, we used the following combinations of keywords: “subclinical hypothyroidism” OR “mild hypothyroidism” WITH “oldest old” OR “very old” OR “80 and over” or “centenarians” OR “longevity”. Our search was restricted to studies involving humans aged 65 years or older, and written in English, Spanish, or Portuguese. Studies evaluating the association between elevated serum TSH levels among elderly subjects with subclinical hypothyroidism were included, since at least in part, they included a subpopulation of individuals aged 80 years and more. We excluded studies that lacked this information and studies on non-thyroidal diseases or low-T3 syndrome. Some of these studies did not exclude patients with overt hypothyroidism. We made no restrictions regarding study design or sample size.
RESULTS
Our search identified 192 studies (Figure 1).
Twenty-eight irrelevant studies were excluded for not covering the association
between subclinical hypothyroidism and the oldest old (n=21) or not clearly
considering the oldest old population (n=9). Thirteen studies were selected and
classified according to the Oxford Centre for Evidence-Based Medicine Levels of
Evidence.(
1818 Phillips B, Ball C, Sackett D, Badenoch D, Straus S, Haynes S, et
al. Oxford Centre for Evidence-based Medicine − Levels of Evidence (March 2009).
Nuffield Department of Primary Care Health Sciences; 2009 Available from:
http://www.cebm.net/index.aspx?o=1025
http://www.cebm.net/index.aspx?o=1025...
) Three studies were conducted in the Netherlands,(
22 Gussekloo J, van Exel E, Craen AJ, Meinders AE, Frölich M, Western
RG. Thyroid status, disability and cognitive function and survival in old age.
JAMA. 2004;292(21):2591-9.
,
1111 Van den Beld A, Visser TJ, Feelders RA, Grobbee DE, Lamberts SW.
Thyroid hormone concentrations, disease, physical function and mortality in
elderly men. J Clin Endocrinol Metab. 2005;90(12):6403-9.
,
1616 Rozing MP, Houwing-Duistermaat JJ, Slagboom PE, Beekman M, Frölich
M, de Craen AJ, et al. Familial longevity is associated with decreased thyroid
function. J Clin Endocrinol Metab. 2010;95(11):4979-84.
) one in the United Kingdom,(
99 Hogervorst E, Huppert F, Matthews FE, Brayne C. Thyroid function and
cognitive decline in the MRC Cognitive Function and Ageing Study.
Psychoneuroendocrinology. 2008;33(7):1013-22.
) one in Italy,(
1717 Corsonello A, Montesanto A, Berardelli M, De Rango F, Dato S, Mari
V, et al. A cross-section analysis of FT3 age-related changes in a group of old
and oldest-old subjects, including centenarians’ relatives, shows that a
down-regulated thyroid function has a familial component and is related to
longevity. Age Ageing. 2010;39(6):723-7.
) four in the United States,(
55 Surks MI, Hollowell JG. Age specific distribution of serum
thyrotropin and antithyroid antibodies in the US population: implications for
the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab.
2007;92(12):4575-82.
,
1414 Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I. Extreme
longevity is associated with increased serum thyrotropin. J Clin Endocrinol
Metab. 2009;94(4):1251-4.
,
1515 Aztmon G, Barzilai N, Surks MI, Gabriely I. Genetic predisposition
to elevated serum thyrotropin is associated with exceptional longevity. J Clin
Endocrinol Metab. 2009;94(12):4768-75.
,
1919 Spencer CA, Hollowell JG, Kazarosyan M, Braverman LE. National
Health and Nutrition Examination Survey III thyroid-stimulating hormone
(TSH)-thyroperoxidase antibody relationships demonstrate that TSH upper
reference limits may be skewed by occult thyroid dysfunction. J Clin Endocrinol
Metab. 2007;92(11):4236-40.
) and three in Brazil.(
2020 Duarte GC, Tomimori EK, Camargo RY, Rubio IG, Wajngarten M,
Rodrigues AG, et al. The prevalence of thyroid dysfunction in elderly cardiology
patients with mild excessive iodine intake in the urban area of São Paulo.
Clinics. 2009;64 (2):135-42.
21 Benseñor IM, Goulart AC, Lotufo PA, Menezes PR, Scazufca M.
Prevalence of thyroid disorders among older people: results from the São Paulo
Ageing & Health Study. Cad. Saúde Pública.
2011;27(1):155-61.
-
2222 Tonial R, Rosa LA, Rosa MI, Basso FO, Argente JS. Prevalência de
hipotireoidismo em residentes das seis instituições para idosos do município de
Criciúma – SC. Arq Catarinenses Med. 2007;36(4):37-41.
) One of the studies included subpopulations from various
countries,(
77 Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP,
Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A, Maisonneuve P, Sgarbi
JA, Khaw KT, Vanderpump MP, Newman AB, Cornuz J, Franklyn JA, Westendorp RG,
Vittinghoff E, Gussekloo J; Thyroid Studies Collaboration. Subclinical
hypothyroidism and the risk of coronary heart disease and mortality. JAMA.
2010;304(12):1365-74.
) (Chart 1). The total number of
subjects enrolled in the studies varied from 109(
2222 Tonial R, Rosa LA, Rosa MI, Basso FO, Argente JS. Prevalência de
hipotireoidismo em residentes das seis instituições para idosos do município de
Criciúma – SC. Arq Catarinenses Med. 2007;36(4):37-41.
) to 55,287 individuals.(
77 Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP,
Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A, Maisonneuve P, Sgarbi
JA, Khaw KT, Vanderpump MP, Newman AB, Cornuz J, Franklyn JA, Westendorp RG,
Vittinghoff E, Gussekloo J; Thyroid Studies Collaboration. Subclinical
hypothyroidism and the risk of coronary heart disease and mortality. JAMA.
2010;304(12):1365-74.
) In studies that have considered the length of follow-up, the average
time varied from 2(
99 Hogervorst E, Huppert F, Matthews FE, Brayne C. Thyroid function and
cognitive decline in the MRC Cognitive Function and Ageing Study.
Psychoneuroendocrinology. 2008;33(7):1013-22.
) to 20 years.(
77 Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP,
Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A, Maisonneuve P, Sgarbi
JA, Khaw KT, Vanderpump MP, Newman AB, Cornuz J, Franklyn JA, Westendorp RG,
Vittinghoff E, Gussekloo J; Thyroid Studies Collaboration. Subclinical
hypothyroidism and the risk of coronary heart disease and mortality. JAMA.
2010;304(12):1365-74.
) Different reference values of TSH were adopted, with the minimum
reference ranging from 0.27 to 0.5mIU/L, and the maximum ranging from 4.0 to 5.6
mIU/L.
Two selected studies were multicenter trials. One was a longitudinal epidemiological study( 99 Hogervorst E, Huppert F, Matthews FE, Brayne C. Thyroid function and cognitive decline in the MRC Cognitive Function and Ageing Study. Psychoneuroendocrinology. 2008;33(7):1013-22. ) involving six centers in England and Wales evaluating the association between cognitive decline, assessed by the Mini-Mental State Examination (MMSE), and high TSH levels in elderly individuals. The other included 11 prospective cohorts from different countries (United States, Australia, Europe, Brazil and Japan) and showed an increased risk of coronary heart disease and coronary heart disease mortality in individuals with TSH concentrations of 10mIU/L or above.( 77 Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A, Maisonneuve P, Sgarbi JA, Khaw KT, Vanderpump MP, Newman AB, Cornuz J, Franklyn JA, Westendorp RG, Vittinghoff E, Gussekloo J; Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010;304(12):1365-74. ) However, when the analysis included only individuals aged 80 years and more, no significant increase in risk of cardiovascular events, coronary heart disease, or total mortality was observed.( 77 Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A, Maisonneuve P, Sgarbi JA, Khaw KT, Vanderpump MP, Newman AB, Cornuz J, Franklyn JA, Westendorp RG, Vittinghoff E, Gussekloo J; Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010;304(12):1365-74. )
Some of the cross-sectional and longitudinal population-based studies recognized that
the upper limits of serum TSH levels could have been skewed by individuals with
occult autoimmune thyroid dysfunction and negative serum thyroperoxidase antibody
(aTPO),(
1414 Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I. Extreme
longevity is associated with increased serum thyrotropin. J Clin Endocrinol
Metab. 2009;94(4):1251-4.
) whereas others considered the results to overestimate thyroid
hypofunction since no age-specific range for TSH was adopted, with the possibility
of identifying healthy individuals as having subclinical thyroid
disease.(
55 Surks MI, Hollowell JG. Age specific distribution of serum
thyrotropin and antithyroid antibodies in the US population: implications for
the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab.
2007;92(12):4575-82.
) Despite these facts, most studies confirmed that serum TSH is elevated
in this population, increases gradually with age,(
2121 Benseñor IM, Goulart AC, Lotufo PA, Menezes PR, Scazufca M.
Prevalence of thyroid disorders among older people: results from the São Paulo
Ageing & Health Study. Cad. Saúde Pública.
2011;27(1):155-61.
) and that this finding is very common in the population over 80 years of
age.(
1414 Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I. Extreme
longevity is associated with increased serum thyrotropin. J Clin Endocrinol
Metab. 2009;94(4):1251-4.
) Elevated TSH was associated with longevity, especially in the oldest
old,(
22 Gussekloo J, van Exel E, Craen AJ, Meinders AE, Frölich M, Western
RG. Thyroid status, disability and cognitive function and survival in old age.
JAMA. 2004;292(21):2591-9.
,
1414 Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I. Extreme
longevity is associated with increased serum thyrotropin. J Clin Endocrinol
Metab. 2009;94(4):1251-4.
,
1919 Spencer CA, Hollowell JG, Kazarosyan M, Braverman LE. National
Health and Nutrition Examination Survey III thyroid-stimulating hormone
(TSH)-thyroperoxidase antibody relationships demonstrate that TSH upper
reference limits may be skewed by occult thyroid dysfunction. J Clin Endocrinol
Metab. 2007;92(11):4236-40.
) extended to family members,(
1616 Rozing MP, Houwing-Duistermaat JJ, Slagboom PE, Beekman M, Frölich
M, de Craen AJ, et al. Familial longevity is associated with decreased thyroid
function. J Clin Endocrinol Metab. 2010;95(11):4979-84.
,
1717 Corsonello A, Montesanto A, Berardelli M, De Rango F, Dato S, Mari
V, et al. A cross-section analysis of FT3 age-related changes in a group of old
and oldest-old subjects, including centenarians’ relatives, shows that a
down-regulated thyroid function has a familial component and is related to
longevity. Age Ageing. 2010;39(6):723-7.
) and could be correlated with better survival.(
88 Parle J, Roberts L, Wilson S, Pattison H, Roalfe A, Haque MS, et al.
A randomized controlled trial of the effect of thyroxin replacement on cognitive
function in community-living elderly subjects with subclinical hypothyroidism:
the Birmingham Elderly Thyroid study. J Clin Endocrinol Metab.
2010;95(8):3623-32.
) Results from cross-sectional clinical studies have reported higher
prevalence of both subclinical and overt hypothyroidism in oldest old
subjects.(
2121 Benseñor IM, Goulart AC, Lotufo PA, Menezes PR, Scazufca M.
Prevalence of thyroid disorders among older people: results from the São Paulo
Ageing & Health Study. Cad. Saúde Pública.
2011;27(1):155-61.
22 Tonial R, Rosa LA, Rosa MI, Basso FO, Argente JS. Prevalência de
hipotireoidismo em residentes das seis instituições para idosos do município de
Criciúma – SC. Arq Catarinenses Med. 2007;36(4):37-41.
-
2323 Mooradian AD. Subclinical hypothyroidism in the elderly: to treat or
not to treat? Am J Ther. 2011;18(6):477-86.
)
DISCUSSION
Different studies have suggested that the thyroid gland undergoes anatomical and physiological changes with time, providing evidence that its function declines with age.
A meta-analysis demonstrated that cardiovascular events and mortality in patients with subclinical hypothyroidism were restricted to those younger than 65 years of age.( 2424 Ochs N, Auer R, Bauer DC, Nanchen D, Gussekloo J, Cornuz J, et al. Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Ann Intern Med. 2008;148(11):832-45. , 2525 Razvi S, Shakoor A, Vanderpump M, Weaver JU, Pearce SH. The influence of age on relationship between subclinical hypothyroidism and ischemic heart disease: a meta-analysis. J Clin Endocrinol. Metab. 2008;93(8):2998-3007. ) In contrast, it showed no association between a higher risk of coronary events or mortality and elevated TSH for individuals aged 80 years or more.( 77 Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A, Maisonneuve P, Sgarbi JA, Khaw KT, Vanderpump MP, Newman AB, Cornuz J, Franklyn JA, Westendorp RG, Vittinghoff E, Gussekloo J; Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010;304(12):1365-74. ) A possible explanation for this discrepancy may be that participants with subclinical hypothyroidism included in these studies already had preexisting comorbidity factors (such as dyslipidemia and endothelial dysfunction), or even cardiovascular disease, and by becoming exposing to more serious or fatal outcomes before the age of 80 years, increased their risks for cardiovascular events.( 2626 Mariotti S. Mild hypothyroidism and ischemic heart disease: is age the answer? J Clin Endocrinol Metab. 2008;93(8):2969-71. ) Thus, those who survived would have a higher chance of getting old. It is unclear why inadequately high TSH would be associated with lower mortality( 22 Gussekloo J, van Exel E, Craen AJ, Meinders AE, Frölich M, Western RG. Thyroid status, disability and cognitive function and survival in old age. JAMA. 2004;292(21):2591-9. ) and longevity. It is possible that a lower metabolic rate and fluctuating concentration of serum TSH may be represented by early signs of thyroid hypoechogenicity on ultrasound,( 2727 Rosário PW, Bessa B, Valadão MM, Purisch S. Natural history of mild subclinical hypothyroidism: prognostic value of ultrasound. Thyroid. 2009;19(1):9-12. , 2828 Shin DY, Kim EK, Lee EJ. Role of ultrasonography in outcome prediction in subclinical hypothyroid patients treated with levothyroxine. Endocr J. 2010; 57(1):15-22. ) decreased fT4, increased rT3, and altered pituitary set point,( 1414 Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I. Extreme longevity is associated with increased serum thyrotropin. J Clin Endocrinol Metab. 2009;94(4):1251-4. , 2323 Mooradian AD. Subclinical hypothyroidism in the elderly: to treat or not to treat? Am J Ther. 2011;18(6):477-86. ) as has been documented in centenarians, and could possibly denote adaptive metabolic processes to prevent excessive catabolism.( 1111 Van den Beld A, Visser TJ, Feelders RA, Grobbee DE, Lamberts SW. Thyroid hormone concentrations, disease, physical function and mortality in elderly men. J Clin Endocrinol Metab. 2005;90(12):6403-9. , 2323 Mooradian AD. Subclinical hypothyroidism in the elderly: to treat or not to treat? Am J Ther. 2011;18(6):477-86. ) Indeed, relatives of the oldest old tended to repeat this laboratorial finding( 1616 Rozing MP, Houwing-Duistermaat JJ, Slagboom PE, Beekman M, Frölich M, de Craen AJ, et al. Familial longevity is associated with decreased thyroid function. J Clin Endocrinol Metab. 2010;95(11):4979-84. , 1717 Corsonello A, Montesanto A, Berardelli M, De Rango F, Dato S, Mari V, et al. A cross-section analysis of FT3 age-related changes in a group of old and oldest-old subjects, including centenarians’ relatives, shows that a down-regulated thyroid function has a familial component and is related to longevity. Age Ageing. 2010;39(6):723-7. ) showing down-regulation of thyroid hormones due to genetic predisposition( 1515 Aztmon G, Barzilai N, Surks MI, Gabriely I. Genetic predisposition to elevated serum thyrotropin is associated with exceptional longevity. J Clin Endocrinol Metab. 2009;94(12):4768-75. ) and benefiting from a longer life span.( 22 Gussekloo J, van Exel E, Craen AJ, Meinders AE, Frölich M, Western RG. Thyroid status, disability and cognitive function and survival in old age. JAMA. 2004;292(21):2591-9. , 1111 Van den Beld A, Visser TJ, Feelders RA, Grobbee DE, Lamberts SW. Thyroid hormone concentrations, disease, physical function and mortality in elderly men. J Clin Endocrinol Metab. 2005;90(12):6403-9. , 1515 Aztmon G, Barzilai N, Surks MI, Gabriely I. Genetic predisposition to elevated serum thyrotropin is associated with exceptional longevity. J Clin Endocrinol Metab. 2009;94(12):4768-75. , 1717 Corsonello A, Montesanto A, Berardelli M, De Rango F, Dato S, Mari V, et al. A cross-section analysis of FT3 age-related changes in a group of old and oldest-old subjects, including centenarians’ relatives, shows that a down-regulated thyroid function has a familial component and is related to longevity. Age Ageing. 2010;39(6):723-7. )
Elderly patients with subclinical thyroid disease had worse overall results in the MMSE. The association between overt hypothyroidism and cognitive impairment is well established, and there are cases described of secondary dementia due to thyroid dysfunction.( 99 Hogervorst E, Huppert F, Matthews FE, Brayne C. Thyroid function and cognitive decline in the MRC Cognitive Function and Ageing Study. Psychoneuroendocrinology. 2008;33(7):1013-22. ) In contrast, some controversial studies have reported an inverse association between high TSH and memory function( 99 Hogervorst E, Huppert F, Matthews FE, Brayne C. Thyroid function and cognitive decline in the MRC Cognitive Function and Ageing Study. Psychoneuroendocrinology. 2008;33(7):1013-22. ) or even no association at all when considering the elderly aged over 85 years.( 22 Gussekloo J, van Exel E, Craen AJ, Meinders AE, Frölich M, Western RG. Thyroid status, disability and cognitive function and survival in old age. JAMA. 2004;292(21):2591-9. ) A similar observation has been made with depression. While some studies report worsening of mood with subclinical hypothyroidism,( 1010 Chueire VB, Romaldini JH, Ward L. Subclinical hypothyroidism increases the risk for depression in the elderly. Arch Gerontol Geriatr. 2007;44(1):21-8. ) others have not confirmed this association.( 2929 Kim JM, Stewart R, Kim SY, Bae KY, Yang SJ, Kim SW, et al. Thyroid stimulating hormone, cognitive impairment and depression in an older Korean population. Psychiatry Investig. 2010;7(4):264-9. , 3030 Freitas AC, Campolina AG, Ribeiro RL, Kitadai FT. Comparação de função cognitiva e depressão em pacientes hipotiroideos subclínicos com eutiroidianos e hipotiroideos em tratamento, acima de 65 anos. Rev Bras Clin Med. 2009;7:89-94. )
The studies selected showed no evidence that reduced thyroid function had a positive association with disability( 22 Gussekloo J, van Exel E, Craen AJ, Meinders AE, Frölich M, Western RG. Thyroid status, disability and cognitive function and survival in old age. JAMA. 2004;292(21):2591-9. ) or lower physical function.( 1111 Van den Beld A, Visser TJ, Feelders RA, Grobbee DE, Lamberts SW. Thyroid hormone concentrations, disease, physical function and mortality in elderly men. J Clin Endocrinol Metab. 2005;90(12):6403-9. )
The literature lacks information on the risks of mildly elevated TSH levels on health both in the general population and in the oldest old individuals. Abnormal concentrations of TSH are often found in these elderly individuals and are associated with a prolonged life span, although the exact mechanism for that remains unclear.
Maybe the use of age-specific reference values could offer a more reliable TSH distribution, more representative of the elderly population. This could be an opportunity to redefine the upper limit of normal for serum TSH, at least for the very elderly population.( 3131 Boucai L, Hollowell JG, Surks MI. An approach for development of age-, gender-, and ethnicity-specific thyrotropin reference limits. Thyroid. 2011;21(1):5-11. )
Targets for TSH level during levothyroxine replacement therapy tend to be individualized and should be adjusted to around 6mIU/L in individuals older than 70 years.( 66 Biondi B. Should we treat all subjects with subclinical thyroid disease the same way? Eur J Endocrinol. 2008;159(3):343-5. ) Although it seems that levothyroxine replacement is unlikely to benefit and may even be harmful,( 1212 Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev. 2008;29(1):76-131. Review. , 1313 Peeters RP. Thyroid function and longevity: new insights into an old dilemma. J Clin Endocrinol Metab. 2009;94(12):4658-60. ) treatment should be administered to patients considered at high risk for cardiovascular disease (diabetes mellitus, diastolic dysfunction or hypertension, atherosclerosis, smokers) with TSH greater than 10mIU/L and to those with antithyroid antibodies and/or positive ultrasound findings who may progress to overt hypothyroidism.( 66 Biondi B. Should we treat all subjects with subclinical thyroid disease the same way? Eur J Endocrinol. 2008;159(3):343-5. , 1212 Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev. 2008;29(1):76-131. Review. , 3232 Sgarbi JA, Teixeira PF, Maciel LM, Mazeto GM, Vaisman M, Montenegro Junior RM, et al. Consenso brasileiro para abordagem clínica e tratamento do hipotiroidismo subclínico em adultos: recomendações do Departamento de Tireoide da Sociedade Brasileira de Endocrinologia e Metabologia. Arq Bras Endocrinol Metab. 2013;57(3):166-83. )
CONCLUSION
Current clinical implications and treatment recommendations for oldest old individuals with subclinical hypothyroidism are still unclear. With the gradual expansion of the age group of very old individuals, more randomized controlled trials are required to better define the potential benefits of thyroid hormone replacement for this population.
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Publication Dates
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Publication in this collection
24 Mar 2015 -
Date of issue
Jan-Mar 2015
History
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Received
7 July 2013 -
Accepted
28 June 2014