Hypothyroidism in the elderly: diagnosis and management

Figures & data

Table 1 Prevalence of overt and subclinical hypothyroidism in elderly people

Reference	Place	Sample	Age of participants	Measurementsa	Prevalence (%)
Flatau et al^Citation19 cross-sectional	Israel Kibbutz members	751 (289 men and 462 men)	≥65 years Range: 65–92 years	TSH (>4.5 mIU/L), FT4 (14 to 28 pmol/L)	Overt and subclinical in men: 9.7% Overt and subclinical in women: 18.2% 38% of all hypothyroid subjects presented subclinical hypothyroidism
Cappola et al^Citation20 cohort study	US, community dwelling individuals	3233 (1307 men and 1926 women)	≥65 years	TSH (>4.5 mIU/L), FT4 (not informed)	Overt: 1.6% Subclinical: 15.0%
Gussekloo et al^Citation21 cohort study	The Netherlands, population based	558 (189 men and 369 women)	≥85 years	TSH (>4.8 mIU/L) FT4 (<13 pmol/L)	Overt: 7.0% Subclinical: 5.0%
Wilson et al^Citation22 cross-sectional	United Kingdom, community sample registered with 20 family practices	5960 (2892 men and 2980 women)	≥65 years	TSH (>5.5 mIU/L), FT4 (<9 pmol/L), FT3 (<3.5 pmol/L)	Overt: 0.4% (men 0.4% and women 0.4%) Subclinical: 2.9% (men 2.0% and women 3.7%)
Diaz-Olmos et al^Citation23	Brazil, women at workplace	314	≥40 years Mean age: 47.6 years	TSH (>4.0 mIU/L), FT4 (<10 pmol/L)	Overt: 3.5% Subclinical: 7.3%
Bensenor et al^Citation24 cross-sectional	Brazil population-based	1373 (538 men and 835 women)	≥65 years-old	TSH (>5.0 mIU/L), FT4 (<10 pmol/L)	Overt Men: 5.4% Women: 5.9% Subclinical Men: 6.1% Women: 6.7%

Abbreviations: TSH, thyrotropin or thyroid stimulating hormone; FT4, free-thyroxine; FT3, free-triiodothyronine.

Note:

a Measurements (cut-off points for diagnosis of overt hypothyroidism).

Table 2 Incidence of overt hypothyroidism in elderly people

Reference	Place	Sample	Age of participants	Measurementsa	Incidence (%)
Vanderpump et al^Citation2,b cohort study	United Kingdom	1877, population based	≥38 years	TSH (not informed), FT4 (not informed)	Overt Men: 0.6/1000 survivors/year Women: 3.5/1000 survivors/year
Gopinath et al^Citation25 cohort study	Australia	951, population based	≥55 years	TSH (>4.0 mIU/L), FT4 (<11.5 pmol/L)	Overt Men: 1.4%/5 year Women: 3.5%/5 year Subclinical Men: 0.7%/5 year Women: 2.5%/5 year

Notes:

a Measurements (cut-off for diagnosis of overt hypothyroidism);

b as there are few studies evaluating incidence of overt hypothyroidism in elderly people, this study was included; mean age was 58 years (range 38–93 years).

Abbreviations: TSH, thyrotropin or thyroid stimulating hormone; FT4, free-thyroxine.

Table 3 Unrecognized cases of overt hypothyroidism in elderly people at different scenarios

Reference	Place	Sample	Age of participants	Measurements	Frequency of unrecognized cases of overt hypothyroidism (%)
Primary care
Petersen et al^Citation40 cross-sectional	Sweden	1154, population based	≥50 years	TSH, FT4	Women: 1.3%
Bemben et al (Part 1)^Citation41 retrospective	US	283, retrospective analysis in a Department of Family Medicine	>60 years Range: 60–97 years	TSH, FT4	Men: 1.3% Women: 1.0%
Bensenor et al^Citation24 cross-sectional	Brazil	1373, population based	≥65 years	TSH, FT4	Men: 4.8% Women: 3.4%
Outpatient clinics
Nyström et al^Citation42 cross-sectional	Sweden	496, users of an outpatient clinic	≥50 years	TSH, FT4	Women: 2.2%
Ward
Nyström et al^Citation42 cross-sectional	Sweden	383, inpatients of emergency ward	≥50 years	TSH, FT4	Women: 1.3%
Emergency department
Chen et al^Citation43,a retrospective	Taiwan	54,756, hospital admissions at emergency department	Mean age: 75.8 ± 12.8 Range: 27–98 years	TSH, FT4	Overt: 0.1% (men 0.06%, women: 0.04%) Myxedema: 0.01% Only 21% of patients were admitted from the emergency room with an initial impression of primary overt hypothyroidism

Note:

a As there are no studies evaluating unrecognized cases of overt hypothyroidism in emergency department only in samples of elderly people, this study (age range 27–98 years) was included; however mean age of subjects was 75.8 ± 12.8 years.

Abbreviations: TSH, thyrotropin or thyroid stimulating hormone; FT4, free-thyroxine.

Table 4 Studies that estimated presence of symptoms in groups of subjects with overt and/or subclinical hypothyroidism compared to euthyroid subjects

Reference	Place	Sample	Age of participants	Symptoms	Frequency of symptoms
Cooper et al^Citation45 randomized clinical trial	US	14 receiving thyroxine and twelve receiving placebo	Mean age 55 years old	Symptoms of hypothyroidism	Symptoms improved in 57.1% in the active group and 25% in the placebo group; P < 0.05
Canaris et al^Citation44 cross-sectional	US	76 cases and 147 controls	Mean age 44.4 years (cases) and 45.8 years (controls) Range 19–86 years	Hoarse voice, deep voice, dry skin, coarse hair, cold sensitivity, tiredness, presence of puffy eyes, muscle cramps, muscle weakness, constipation, depression, slow thinking, poor memory, difficult for math, irregular menses, heavy menses	Hypothyroid: 30.2% Control: 16.5%; P < 0.0001 More frequent symptoms in hypothyroid patients: hoarse voice, dry skin, muscle cramps
Bemben et al (Part 2)^Citation46 retrospective	US	205 women and 78 men; 15.4% of men and 14.6% of women with subclinical hypothyroidism	≥60 years Range: 60–97 years	Clinical symptoms of hypothyroidism	No significant difference in the frequency of symptoms in subjects with subclinical hypothyroidism compared to subjects with normal thyroid function
Kong et al^Citation47 clinical trial	United Kingdom	Only women: 23 in the thyroxine group and 17 in placebo group	Mean age thyroxine group 53 (3) years; mean age in the placebo group 45 (4) years	Fatigue, weight gain, anxiety symptoms	Only a significant worsening of anxiety scores in the group receiving L-thyroxine
Engum et al^Citation48 cross-sectional	Norway	30,589 people; 745 men and women with subclinical hypothyroidism	40–89 years	Hospital Anxiety and Depression Scale	No association found between anxiety and depression symptoms and subclinical hypothyroidism
Grabe et al^Citation49 cross-sectional	Germany	3790, 18 cases of overt hypothyroidism, and 27 of subclinical hypothyroidism	Mean age overt hypothyroidism group 52.1 (14.2); mean age subclinical hypothyroidism group 51.9 (12.5); mean age euthyroid group 59.2 (46.9)	Zerrssen Complaint Scale	No difference in the number of symptoms and complaints in subjects with overt and subclinical hypothyroidism compared to euthyroid controls
Jorde et al^Citation50 clinical trial	Norway	36 subjects with subclinical hypothyroidism, and 33 controls	Mean age intervention group 61.6 ± 11.5 years; mean age placebo group 63 ± 12.4 years	14 tests of cognitive function, Beck Depression Inventory, General Health Questionnaire, questionnaire about symptoms of hypothyroidism	After 1 year of thyroxin there is no difference in the performance of cognitive tests, Beck Depression Inventory and in the frequency of hypothyroidism symptoms between the two groups; subjects with subclinical hypothyroidism scored significantly better than controls on the GHQ-30

Table 5 Results of clinical trials for treatment of subclinical hypothyroidism focusing on different outcomes

Reference	Place	Sample/follow-up	Age of participants	Results	Observations
Cooper et al^Citation45 randomized, placebo-controlled clinical trial	Boston, US	14 subjects in active group (4) and twelve in the placebo group (97% women); 1-year on LT4	Mean age 55 years	No difference between groups regarding symptoms of hypothyroidism	All patients included in the study presented subclinical hypothyroidism after treatment with Iodine-131 20 years earlier
Nyström et al^Citation67 randomized, double-blind, crossover trial	Gothenburg, Sweden	17 women; 6 months for placebo and 6 months for hormone	>50 years	No difference between groups regarding symptoms of hypothyroidism	All women diagnosed in a screening program
Jaeschke et al^Citation68 randomized, placebo-controlled clinical trial	Hamilton, Canada	32 subjects	>55 years	No difference between groups regarding symptoms of hypothyroidism	All subjects selected from an outpatient clinic in a community hospital
Meier et al^Citation69 randomized, placebo-controlled, double-blind clinical trial	Switzerland	63 women, 31 assigned to LT4 and 32 assigned to placebo; 48 weeks of follow-up	Mean age 58.6 (1.3) years	Results showed that physiological LT4 replacement in patients with subclinical hypothyroidism has a beneficial effect on low density lipoprotein cholesterol levels and clinical symptoms of hypothyroidism	Some patients included in the trial presented subclinical hypothyroidism after treatment with Iodine-131 20 years earlier. The proportion was similar in the active and the placebo group
Christ-Crain M et al^Citation70 randomized, double-blind, placebo-controlled trial	Basel, Switzerland	63 subjects with subclinical hypothyroidism (31 in the L-T4 group and 32 in the placebo group)	Mean age 57.5 ± 9.8 years	CRP values increases with progressive thyroid failure; supplementation of LT4 did not improve significantly CRP levels	Thyroid Research Unit of the Division of Endocrinology, Department of Medicine at the University Hospital, Basel
Iqbal et al^Citation71 randomized, placebo-controlled clinical trial	Norway	64 subjects with subclinical hypothyroidism; 32 assigned to LT4 and 32 assigned to placebo	62.0 (11.9) years in the LT4 group and 62.7 (12.4) years in the placebo group	Reduction in the levels of serum lipids in the group treated with LT4	Subjects with subclinical hypothyroidism selected from the 5143 subjects of the 5th Tromso Study
Razvi et al^Citation72 randomized placebo-controlled clinical trial	United Kingdom	150 subjects with subclinical hypothyroidism; 50 assigned to LT4 and 49 to placebo; 12 weeks of follow-up	Mean-age 53.8 (12.6) years	Subjects with subclinical hypothyroidism treated by LT4 presented a significant improvement in cardiovascular risk factors (Total cholesterol, LDL-cholesterol, waist to hip ratio, endothelial function) and symptoms of tiredness	Community-dwelling patients
Teixeira et al^Citation73 randomized double-blind, placebo-controlled clinical	Brazil	32 subjects: 18 in the LT4 group and 20 in the placebo group; 6 months follow-up	Mean age LT4 group 52.5 (10.1) years; mean age in the placebo group 46.6 (9.9) years	Reduction of serum lipids especially on the subgroup of subjects with antithyroid peroxidase antibodies, TSH > 8 IU/L, body mass index ≥25 kg/m^2 and in menopause	Endocrinology Outpatient Clinic, University Hospital Clementino Fraga Filho, Federal University of Rio de Janeiro
Teixeira et al^Citation74 randomized placebo-controlled clinical trial	Brazil	26 subjects: eleven receiving LT4 and 15 receiving placebo; 1-year follow-up	Mean age LT4 group 54.4 (9.0) years; mean age in the placebo group 48.1 (10.0) years	A significant lipid profile improvement occurred 1 year after L-T4 replacement therapy in the active group compared to placebo group	Endocrinology Outpatient Clinic, University Hospital Clementino Fraga Filho, Federal University of Rio de Janeiro
Nagasaki et al^Citation75 randomized placebo-controlled, double-blind clinical trial	Japan	95 women: 48 assigned to LT4 and 47 assigned to placebo; 5-month follow-up	Mean age in LT4 group 64.4 (2.6) years; mean age in placebo group 66.0 (3.0) years	Sustained normalization of thyroid function during LT4 replacement therapy significantly decreases brachial-ankle pulse wave velocity in female subclinical hypothyroid patients suggesting possible prevention of cardiovascular disease	Ninety-five consecutive patients with newly detected subclinical hypothyroidism due to chronic thyroiditis with antithyroglobulin or antithyroid peroxidase antibodies of the Osaka City University Hospital
Parle et al^Citation76 randomized, placebo-controlled double-blind clinical trial	England	94 subjects: 52 assigned to LT4 and 42 assigned to placebo; 1-year follow-up	≥65 years	Performance in cognitive tests did not improve in subjects treated for subclinical hypothyroidism compared to placebo	Patients with subclinical hypothyroidism were recruited from a community-based cross-sectional study describing the prevalence of thyroid dysfunction in the elderly identified by screening of thyroid function

Abbreviation: LT4, L-thyroxine.

Table 6 Progression of normal thyroid status to subclinical hypothyroidism and of subclinical hypothyroidism to overt hypothyroidism

Reference	Place	Age/follow-up	Antithyroid peroxidase	Evolution to overt disease	Observations
Parle et al^Citation77	United Kingdom	Mean age men 70.1 (6.1) years; mean age men women 70.7 (7.3) years	Incidence No information	TSH between 5–10 mIU/l/no antibodies: 2/28: 7.1% TSH between 5–10 mIU/l/positive antibodies: 5/27: 18.5% TSH > 10 mIU/L/no antibodies: 1/4: 25% TSH > 10 mIU/L/positive antibodies: 5/14: 35.7%	Evaluated progression of subclinical hypothyroidism to overt disease according to TSH and antithyroid antibodies levels
Vanderpump et al^Citation2	United Kingdom	86.2% of sample with >45 years	Incidence Women 45–54, 15.6% 55–64, 20.8% 65–74, 15.8% 75–84, 18.8% ≥85, 10.0% Total, 17.3 Men 45–54, 3.7% 55–64, 9.5% 65–74, 5.8% 75–84, 11.5% ≥85, 11.1% Total, 6.6	Women with only TSH > 6 mIU/L at baseline: OR, 8 (95% CI, 3–20) with only positive antithyroid antibodies at baseline: OR, 8 (95% CI, 5–15) with TSH > 6 mIU/L and positive antithyroid antibodies at baseline: 38 (95% CI, 22–65) with only TSH > 6 mIU/L at baseline: OR, 44 (95% CI, 19–104) with only positive antithyroid antibodies at baseline: OR, 25 (95% CI, 10–63) with TSH > 6 mIU/L and positive antithyroid antibodies at baseline: 173 (95% CI, 81–370)	Evaluated progression of subclinical hypothyroidism to overt disease
Gopinath et al^Citation25	Australia	≥55 years 5 years follow-up	No information	Subclinical hypothyroidism in women (using men as a reference): OR, 3.71 (95% CI, 1.05–13.11) TSH mIU/L (as a continuous variable): OR, 3.94 (95% CI, 2.21–7.04) Overt hypothyroidism in women (using men as a reference): 2.57 (95% CI, 1.01–6.54) TSH mIU/L (as a continuous variable): 4.13 (95% CI, 2.55–6.71) Fasting blood glucose (mmoL/L): 1.19 (95% CI, 1.00–1.42) BMI ≥ 30 kg/m^2 (using BMI < 30 kg/m^2 as a reference): 4.05 (1.74–9.41) White cell count (×10^9/l) as a continuous variable: 1.19 (1.01–1.40)	Evaluated progression of normal thyroid status to subclinical and overt hypothyroidism

Abbreviations: TSH, thyrotropin or thyroid stimulating hormone; FT4, free-thyroxine; OR, odds ratio; 95% CI, 95% confidence interval; BMI, body mass index.

Table 7 Incidence of cardiovascular events, death, and other outcomes in people with subclinical hypothyroidism in cohort studies

Reference	Place	Sample/follow-up	Age of participants	Results	Observations
van den Beld et al^Citation3	US	403 independent and ambulatory living men; follow-up of 4 years	73–94 years	Low FT4 was associated with a better 4-year survival	These results may reflect an adaptive mechanism to prevent excessive catabolism
Rodondi et al^Citation78	US	2730 men and women; follow-up of 4 years	70–79 years	In multivariate analysis using euthyroid subjects as the reference category, relative risk of congestive heart failure in subjects with TSH of 7.0–9.9 mIU/L was of 2.58 (95% CI, 1.19–5.60); and TSH ≥10.0 mIU/L, 3.26 (95% CI, 1.37–7.77)	Subclinical hypothyroidism was not associated with increased risk for coronary heart disease, stroke, peripheral artery disease, or cardiovascular or total mortality
Cappola et al^Citation20	US	3233 community-dwelling individuals; follow-up of 2 years	65 years or older	There was no difference in the cardiovascular or mortality outcomes in subjects with overt or subclinical hypothyroidism compared to euthyroid subjects	Individuals with subclinical hypothyroidism had an adjusted hazard ratio of 1.07 (95% CI, 0.90–1.28) for incident coronary heart disease
Kalra et al^Citation79	United Kingdom	131 elderly patients that underwent surgical treatment for hip fracture; 1-year follow-up	Mean age 82.0 (8.9) years Range 61–94 years	Presence of subclinical hypothyroidism (15%) did not affect 1-year mortality
Sgarbi et al^Citation80	Brazil	1110 Japanese-Brazilians; follow-up of 7.5 years	57 years (68.8% of the sample with age ≥50 years)	In multivariate analysis, subclinical hypothyroidism was associated to all-cause mortality (HR, 2.3; 95% CI, 1.2–4.4) but not with cardiovascular mortality, using euthyroid subjects as the reference category
Razvi et al^Citation81	United Kingdom	2376 community-dwelling subjects	Mean age 45.5 years	There is an association between incident ischemic coronary heart disease and ischemic heart disease mortality with subclinical hypothyroidism (HR, 1.76; 95% CI, 1.15–2.71 and HR 1.79; 95% CI, 1.02–3.56, respectively)	Subsequent treatment of subclinical hypothyroidism with L-thyroxine appears to attenuate ischemic heart disease morbidity and mortality
De Jongh et al^Citation82	The Netherlands	1219 subjects without thyroid diseases from a population-based cohort; follow-up of 10.7 years	65 years or older	Subclinical hypothyroidism was not associated with increased overall mortality risk (HR, 0.89; 95% CI, 0.59–1.35) using euthyroid subjects as the reference group	The study does not support disadvantageous effects of subclinical thyroid disorders on physical and cognitive function, depression, or mortality in an older population
Lee et al^Citation83	US	3567 US community dwelling adults; follow-up of 14 years	65 years or older	Men with subclinical hypothyroidism presented a higher risk of hip fracture compared to euthyroid men (OR, 2.45, 1.27–4.73); no relationship between subclinical hypothyroidism and hip fractures was observed in women

Abbreviations: F4, free-thyroxine; OR, odds ratio; 95% CI, 95% confidence interval; HR, hazard ratio.

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