1

To Treat or Not to Treat: Thyroxine for Subclinical Hypothyroidism

Elina Delgado, PharmD PGY2 Geriatric Pharmacy Resident

South Texas Veterans Health Care System The University of Texas at Austin College of Pharmacy

UT Health San Antonio

October 13, 2017

Objectives: 1. Distinguish subclinical hypothyroidism as a form of thyroid disease and the risk factors for

development2. Recognize the correlation between age and TSH level3. Describe health outcomes associated with subclinical hypothyroidism in the elderly4. Select optimal elderly candidates for treatment of subclinical hypothyroidism

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I. Thyroid Gland

A. Anatomy1 a. Highly vascular, ductless alveolar gland located in the anterior neck in front of the trachea b. 2 lobed gland (right and left) connected by the isthmus composed of varying cell types:

i. Follicular thyroid hormone synthesis ii. Endothelial provide the blood supply to the follicles

iii. Parafollicular (C cells) production of calcitonin iv. Fibroblasts, lymphocytes, and adipocytes

B. Thyroid Hormones2-4 a. Production

i. Thyroxine (T4) and triiodothyronine (T3) are produced from iodinated tyrosine residues within thyroglobulin (TG)

ii. T4 is secreted from the thyroid gland in about twentyfold excess over T3 iii. T4 is converted into T3 by varying versions of monodeiodinase enzymes located in

peripheral tissues, CNS, placenta, skin, etc. 1. The regulation of this conversion is affected by nutrition, non-thyroidal hormones,

ambient temperatures, drugs, and illness iv. The half-life of the two hormones differs: T4 about 7 days, T3 about 1 day

b. Regulation2-3

Figure 1. Regulation of Thyroid Hormone Synthesis2

i. The release of thyroid hormones is controlled by multiple mechanisms, including the hypothalamic-pituitary-thyroid (HPT) axis, iodine concentrations in the body, and free thyroxine

ii. About 99.5% of thyroid hormones are bound by three different proteins in the blood, thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin

1. Only unbound (free) thyroid hormone is responsible for regulation of thyroid-stimulating hormone (TSH)

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iii. Thyrotropin-Releasing Hormone (TRH) stimulates pulsatile TSH secretion that follows a circadian-rhythm, with peak concentrations occurring between midnight and 4 am

1. TRH synthesis and release can be impacted by other hormones, drugs, and leptin iv. Thyroid antibodies may be produced by lymphocytes and can cause hypo- or hyper-

thyroidism by stimulating or damaging the gland 1. Presence of antibodies is associated with autoimmune causes and are correlated to

high potential for progressive thyroid dysfunction c. Function3

i. Thyroid hormones have varying effects on tissue growth, brain maturation, increased calorigenesis and oxygen consumption, as well as effects on the heart, liver, kidneys, skeletal muscle, and skin

II. Hypothyroidism

A. Serum levels5 a. Normal values – Assay dependent

i. TSH: 0.4 to 4.5 mIU/L b. Overt hypothyroidism

i. Serum TSH above the upper limit of normal and low free thyroxine (fT4) c. Subclinical hypothyroidism (SH)

i. Serum TSH above the upper limit of normal and normal free thyroxine (fT4) ii. Sub-divided by mild (TSH 4.5–9.9 mIU/L) or severe (TSH ≥10 mIU/L)

B. Causes of hypothyroidism2 a. Autoimmune b. Iodine deficiency c. Pharmacologic – related to drugs such as lithium, amiodarone, and interferon alpha

Table 1. Risk Factors for Hypothyroidism Development6

Table 2. Signs and Symptoms Associated with Hypothyroidism7

C. Symptom assessment tools8 a. General quality of life

i. Short Form-36 (SF-36) ii. Nottingham Health Profile (NHP)

iii. General Health Questionnaire (GHQ) b. Disease Specific

i. Thyroid-related Quality-of-Life Patient Reported Outcome (ThyPRO) ii. Chronic Thyroid Questionnaire (CTQ)

Gender (female) Pregnancy Race and ethnicity (Caucasian) Iatrogenic factors Obesity Elderly age

Memory problems or slow thinking Muscle cramps/weakness Tiredness Dry skin Feeling colder Hoarseness of voice Puffy eyes Constipation/weight gain

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iii. The Underactive-Thyroid-Dependent Quality of Life Questionnaire (ThyDQoL) iv. Thyroid Symptom Questionnaire (TSQ)

III. Subclinical Hypothyroidism in the Literature

A. An in depth review of the subject reveals: a. Much of the evidence is from prospective cohort analyses reviewing all forms of thyroid

dysfunction b. Treatment with thyroxine was not protocalized or excluded (delineated throughout by *) c. Subset or sensitivity analyses were conducted to delineate if treatment influenced outcomes

(delineated throughout by †)

IV. Age and Subclinical Hypothyroidism

A. Hypothyroidism is most commonly seen in those age 50-70 years6,9 B. Natural rise in TSH has been associated with age ≥ 80 years C. Possible mechanisms of age-related increases in TSH6

a. Alteration in TSH set point due to diminished sensitivity of the pituitary to negative feedback b. Decrease in TSH biological activity c. Decrease in thyroid gland sensitivity to TSH

D. Framingham Study – Conducted in Framingham, MA to identify risk factors for development of cardiovascular disease10 a. During physical exams, thyroid nodules were found in about 3-4% of participants and spurred

the assessment of thyroid function (see Table 3)

Table 3. Summary of TSH Elevations by Age and Gender in the Framingham Trial*,10

Serum Level Age % of Women (N = 1260)

% of Men (N = 2139)

TSH 5-10 mIU/L 60-69 7.7% 2.5% 70-79 7.5% 3.6% 80-89 8.1% 7.9%

TSH > 10 mIU/L 60-69 5.7% 2.0% 70-79 7.3% 2.0% 80-89 3.8% 6.6%

E. Additional studies have reported an increased prevalence of SH in the elderly and females (see Table

4)

Table 4. Trials Reporting Prevalence of Subclinical Hypothyroidism in the Elderly11-14

Study N Prevalence of SH Comment

Cardiovascular Health Study*,11

3,594 12.8% (N = 459)

At 2 year follow up, no difference in SH when stratified for age (65-74 or ≥75)

NHANES III12

(population age ≥ 12) 16,533 4.3% Median TSH Concentration (mIU/L)

60-69 years: 1.79 70-79 years: 1.98 80+ years: 2.08

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Colorado Thyroid Disease Prevalence*,13

25,862 8.5% (N = 2067)

TSH increased with age in 21% of women and 16% of men 75 years of age or older

British Whickham14 2,779 Not reported TSH did not increase with age in men but markedly increased in women

V. Health Outcomes Associated with Subclinical Hypothyroidism in the Elderly15-17

A. Progression to overt hypothyroidism Table 5. Summary of Trials Examining Conversion of Subclinical to Overt Hypothyroidism11,14,18-21

Study N‡ Mean Age Rate of Progression

Tunbridge et al. (1977)14

139 47.1 TSH > 6 mIU/L was associated with an annual risk of 2.3% progression

Parle et al. (1991)18

94 ≥60 17.8% progressed to overt hypothyroidism More common in patients with an initial TSH > 10 mIU/L

Huber et al. (2002)19

82 (women

only)

51 28% developed overt hypothyroidism TSH 6-12 mIU/L: 3.3% annual incidence of progression TSH > 12 mIU/L: 11.4% annual incidence of progression

Diez et al. (2004)20

107 62 26.8% progressed to overt hypothyroidism Substantial progression in those with higher initial TSH (15.0–19.9 mIU/L)

Gussekloo et al. (2004)21

21 85 None progressed to overt disease (3 year follow up)

Somwaru et al. (2012)*,11

459 75 At 2 year follow-up: 56% remained subclinical, 35% reverted to euthyroid, 2% developed overt hypothyroidism

‡Number of subjects with SH not total subjects in the study B. Cardiovascular disease

a. Dyslipidemia i. Lipid-thyroid interactions (Appendix A)22

1. Induces hepatic expression of hydoxymethylglutaryl coenzyme A (HMG CoA) reductase increases cholesterol synthesis

2. Increases expression of cell surface LDL-C receptors 3. Regulates intestinal cholesterol absorption 4. Increases cholesteryl ester transfer protein (CETP) concentrations 5. Increases hepatic lipase concentrations

ii. The association between SH with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, lipoprotein(a), and triglycerides (TG) has not been established23

1. Varying trials have had conflicting results, possibly due to study size or patient demographics and baseline characteristics

iii. Levothyroxine therapy in patients with underlying SH and hyperlipidemia has also had conflicting evidence

1. A 2007 Cochrane review found no significant improvement associated with treatment of SH24

2. SH treatment vs. simvastatin vs. placebo only showed a significant decrease in TC, TG, and LDL correlated with simvastatin therapy25

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b. Thyroid hormones and the cardiovascular system3 i. Triiodothyronine has varying functions within cardiac myocytes (Appendix B)26

1. Stimulates transcription of sarcoplasmic reticulum Ca2+ ATPase 2. Increases expression of the more rapidly contractile α isoform of myosin heavy chain 3. Expression of different isoforms of the Na+-K+ ATPase genes 4. Increases expression of α-adrenergic receptors 5. Decreases the concentration of the inhibitory G protein Gi α 6. Increases the rate of depolarization and repolarization of the sinoatrial node 7. Increases the number of β-adrenergic receptors in heart

ii. Cardiovascular heart disease (CHD)27-29 1. Conflicting results for the risk of myocardial infarct (MI), ischemic heart disease (IHD),

heart failure (HF), and death in elderly patients 2. Severe SH has been associated with an increased risk of CHD and death (see Table 6)

Table 6. Results of Meta-analyses Examining Relationship Between SH and CHD30-31

Study N Age Range

TSH value range for SH

Outcome with SH

Meta-analysis Razvi et al. (2008)*,30

Total: 1,085,841 SH: 126,590

42-85 2.8-10 mIU/L Age ≥ 65: No difference in IHD risk or CV death

Meta-analysis Rodondi et al. (2010) †,31

Total: 55,287 SH: 3,450

46-85 4.5-20 mIU/L - TSH >10 mIU/L: significantly greater risk of CHD event and CHD death - Age 65–79: greater risk of CHD death and total death - Age ≥80: no greater risk of CHD event or death

3. SH in patients ≥ 85 showed reduced risk of cardiovascular and overall mortality (see

Table 7)21,32

Table 7. Summary of the Leiden 85+ and Newcastle 85+ Studies Study Gussekloo et al. (2004)21 Pearce et al. (2016)†,32

Design Prospective, observational cohort study

Prospective, observational cohort study

Statistics Cox regression models adjusted for age, disability and health status

Kaplan-Meier plots were used to assess the mortality risk of thyroid dysfunction

Patient Demographics N = 558 • Female (N = 369, 66%) • Independent living (N = 458, 82%) • Euthyroid (N = 472, 85%) • Mild SH (N = 25, 4%), • Severe SH (N = 5, < 1%)

N = 643 • Male (N = 270, 42%) • Living in care home (N = 56, 8.7%) • Euthyroid (N = 534, 83.1%) • SH (N = 19, 2.9%)

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Outcomes Increased TSH levels were associated with decreased all-cause mortality and cardiovascular related mortality

Results trended toward decreased mortality in males and females with hypothyroidism (overt & subclinical)

4. In participants age ≥ 70 years there was no statistically significant difference in

incidence of IHD events, cerebrovascular accidents, or death (circulatory, IHD, or any cause) between LT4-treated and untreated groups (See Table 8)33

Table 8. Trial Overview Examining SH Treatment and CHD Outcomes33

Citation Razvi S, Weaver JU, Butler TJ, Pearce SH. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. Arch Intern Med. 2012;172(10):811-7.

Objective Determine the cardiac benefits of treated subclinical hypothyroidism Methods

Study Design Prospective cohort study Inclusion criteria

• Records available through United Kingdom General Practitioner Research Database (GPRD)

• Age ≥ 40 years with first increased serum thyrotropin levels of 5.01 to 10.00 mIU/L and normal serum free thyroxine (fT4) levels (0.7-1.9 ng/dL)

Exclusion criteria

• Current use of levothyroxine or anti-thyroid drugs • Use of amiodarone, lithium, or one year of corticosteroids • History of ischemic heart disease or cerebrovascular disease

Intervention Levothyroxine treatment initiated for subclinical hypothyroid treatment Outcomes Primary (change in baseline to 12 months):

- Fatal and nonfatal ischemic heart disease Secondary

- Fatal and nonfatal cerebrovascular disease - All-cause and cause-specific mortality - New-onset atrial fibrillation

Statistical Analysis

• Cohorts separated into two cohorts, age 40-70 years and ≥ 70 years • Cox proportional hazard models utilized to assess significance of primary outcomes • Separate Cox analyses completed – one with adjustment for cardiovascular risk and

one only for age and sex • 2 sided P values

Results

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Baseline Characteristics

Age 40-70 years Age ≥ 70 years Characteristics Not

treated (N = 1459)

Treated (N = 1634)

P-value

Not treated (N = 823)

Treated (N = 819)

P-value

Age mean, y 55.9 55.9 .75 79.89 79.37 .12 Female (%) 1204

(82.5) 1428 (87.4) < 0.001 622 (75.6) 693

(84.6) < 0.001

SBP mean, mmHg

136.45 135.23 .09 149.37 149.37 .99

DBP mean, mmHg

80.97 80.91 .88 81.1 81.56 .39

TSH, mIU/L 6.32 6.74 < 0.001 6.32 6.77 < 0.001

Outcomes Age 40-70 years Outcome Untreated

(N = 1459), N (%) Treated (N = 1634), N (%)

Multivariate Adjusted, HR (95% CI)

Fatal and nonfatal IHD events

97 (6.6) 68 (4.2) 0.61 (0.39-0.95)

All-cause mortality 94 (6.4) 55 (3.4) 0.36 (0.19-0.66)

Death due to circulatory diseases‡

38 (2.4) 23 (1.4) 0.54 (0.37-0.92)

Age ≥70 years

Outcome Untreated (N = 1459), N (%)

Treated (N = 1634), N (%)

Multivariate Adjusted, HR (95% CI)

Fatal and nonfatal IHD events

88 (10.7) 104 (12.7) 0.99 (0.59-1.33)

All-cause mortality 333 (40.5) 288 (35.2) 0.71 (0.56-1.08) Death due to circulatory diseases‡

116 (18.3) 134 (17.1) 0.91 (0.56-1.46)

‡Circulatory events include IHD, CVA, and PVD

• Age and sex adjusted HR (95% CI) results were the same as above Author’s Conclusions

Levothyroxine therapy significantly decreased fatal and nonfatal IHD events and mortality for adults 40-70 years of age but not for those age ≥70 years

Critique Strengths • Community dwelling participants

• Randomly selected by TSH level • Baseline cardiovascular risk factors not significantly different between cohorts

Limitations • Baseline TSH levels significantly different in both age groups and predominantly female

• Subclinical hypothyroidism population limited to those with TSH of 5.01 to 10.00 mIU/L and only one abnormal level

• Initiation of levothyroxine therapy was not standardized and unclear TSH levels achieved

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• Unclear if patients had symptoms at baseline • Baseline TSH levels were low

iii. Heart Failure (HF) – See Table 9

Table 9. Summary of Trials Examining Impact of SH on HF34-37

Study N Mean Age TSH value range for SH

Outcome with SH

Rodondi et al. (2008)†,34

Total: 3,044 SH: 474

72.6 4.5–20 mIU/L

Greater risk of HF event with TSH ≥ 10 mIU/L

Nanchen et al. (2012)†,35

Total: 5,245 SH: 199

75 > 4.5 mIU/L

No greater risk of HF but increased risk of HF hospitalization with TSH ≥ 10 mIU/L

Gencer et al. (2012)†,36

Total: 25,390 SH: 2,068

70 4.5–19.9 mIU/L

TSH ≥ 10 mIU/L: significantly greater risk of HF

Hayahi et al. (2016)37

Total: 274 SH: 58

70 4.5–19.9 mIU/L

Increased adverse CV events in ADHF

C. Cognitive Impairment

a. Thyroid hormones regulate gene expression in the adult stratum3 i. Affected genes can impair neurotransmitter systems in hypothyroidism leading to cognitive

abnormalities b. Aside from cognitive impairment, studies have looked at an association between SH and

psychiatric disorders, neurologic disorders, depression, and dementia9 c. 2015 and 2016 meta-analyses have evaluated the evidence for an association between SH and

cognitive function, Mini-Mental State Exam (MMSE), dementia, executive function, and memory (see Table 10)38-40

Table 10. Results of Meta-analyses Examining Relationship Between SH and Cognitive Impairment38-40

Meta-Analysis Akintola et al. (2015)38 Pasqualetti et al. (2015)*,39

Rieben (2106)†,40

Number of studies included

15 13 11

Age Range > 60-85 50.3-81.2 68-85 TSH range 3.6-10 mIU/L 5.5-12 mIU/L > 4 mIU/L Outcomes assessed

MMSE, executive function, and memory

Cognitive function, MMSE, and dementia

MMSE and dementia

Results No association between SH and worse performance in MMSE, executive function, and memory

Association between SH and cognitive alterations or dementia seen in those age ≤ 75 years

SH was not found to be associated with dementia or faster decline of MMSE

d. The Health ABC study was published September 2017 and results showed no correlation

between SH and dementia or cognitive decline in those age 70-79 years old (see Table 11) 41

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Table 11. Trial Overview Examining Relationship Between SH and Dementia or Cognitive Decline41 Citation Aubert C, Bauer D, de Costa BR, et al. The association between subclinical thyroid

dysfunction and dementia: the Health, Aging and Body Composition (Health ABC) Study [published online ahead of print Aug 29, 2017]. Clin Endocrinol. doi: 10.1111/cen.13458.

Objective Assess the correlation between subclinical hypothyroidism and the development of dementia or cognitive decline

Methods Study Design Prospective cohort study Inclusion criteria

• Health, Aging, and Body Composition (Health ABC) study participants • Modified Mini-Mental State (3MS) at Year 1 visit (baseline visit of Health ABC)

and at least at one follow-up visit • TSH measured at year 2

Exclusion criteria

• Pre-existing dementia, thyroid dysfunction, or life-threatening cancer • Prescribed anti-thyroid medications or amiodarone • Individuals who had difficulty with activities of daily living, could not walk a

quarter of a mile, could not climb 10 steps without resting • High probability of geographical relocation in the initial 3 years of the study

Outcomes Primary: - Incident-adjudicated dementia

Secondary: - Change in Modified Mini-Mental State score

Statistical Analysis

• Two-sided, 0.05 level of significance utilized for all statistical tests conducted • Multivariable Cox regression model was utilized to examine study outcomes • Results adjusted for confounders significantly associated with dementia and SH • Second analysis adjusted for confounders associated with increased

cardiovascular risk • Fractional polynomials utilized to assess the non-linear association between

TSH and dementia Results

Baseline Characteristics

Characteristic Euthyroidism (N = 2163), N (%)

Subclinical hypothyroidism (N = 315), N (%)

P-value

Age, years 75.1 (2.9) 75.3 (2.7) 0.34 Women 1095 (50.7) 175 (55.6) .10 Race 1284 (59.4) 236 (74.9) < 0.001 3MS 90.4 (8.1) 91.7 (7.1) 0.01

Outcomes Primary: Subclinical hypothyroidism was not associated with dementia • 574 (22.4%) total participants developed dementia; 493 (85.9%) euthyroid and

61 (10.6%) SH • Adjusted HR = 0.91, 95% CI = 0.70-1.19 Secondary: No difference in adjusted 3MS score mean change • HR = −0.01, 95% CI = −0.98-0.95 When adjusted for cardiovascular risk, results were unchanged

Author’s Conclusions

Subclinical hypothyroidism is not associated with dementia or decreased cognitive performance

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Critique Strengths • Community-dwelling patients within the United States

• Prospective with 10-year follow up • Accounted for factors such as cardiovascular health, decrease functional

capacity, etc. • Validated dementia assessment utilized (3MS)

Limitations • Classification of thyroid status was based upon one TSH level • Actual patient TSH levels unknown at baseline • T4 was not measured for all patients • 3MS and TSH measured at different time points

e. Treatment of SH has not been shown to have a clear effect on cognitive function42

D. Musculoskeletal and Functional Capacity a. Thyroid hormones play a role in hematopoiesis, bone remodeling, and musculature3

i. Increase the 2,3-diphosphoglycerate content of erythrocytes 1. ↑ O2 dissociation from hemoglobin and ↑ O2 availability to tissues

ii. Stimulate bone turnover 1. ↑ bone resorption and, to a lesser degree, bone formation

iii. Regulate protein turnover in muscles, speed of muscle contraction and relaxation b. Bone Health – See Table 12

Table 12. Results of Meta-analyses Examining Relationship Between SH and Bone Fractures43-45

Meta-Analysis Blum et al. (2015)†,43 Yan et al. (2016)†,44 Yang et al. (2017)†,45

Number of studies included

13 5 19

Age (mean or range) 64 60-76 37.5−85 TSH range 4.50 to 19.99 mIU/L > 4.0 mIU/L > 3.5 mIU/L Outcomes assessed Hip fracture, fractures

of any location, nonspine, and clinical spine fractures

Fracture Fractures of any location, hip fractures, spine fractures, and non-spine fractures

Results (as reported by author)

No association between SH and fracture risks

No association between SH and incidence of fractures

SH associated with risk of hip, any location, and forearm fractures

c. Functional Capacity – See Table 13

Table 13. Summary of Trials Examining Impact of SH on Functional Capacity46-51

Study N Age (mean or

range)

Outcomes

Reuters et al. (2009)46

Total: 68 SH: 44

Unknown Cramps, weakness, and altered manual muscle testing more prevalent in SH population

Simonsick et al. (2009)†,47

Total: 2290 SH: 262

74.6 Mild SH (TSH 4.5-6.99 mIU/L) was associated with faster usual and rapid gait speed. A higher percent of

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participants with SH had good cardiorespiratory fitness and reported walking ease

Moon et al. (2010)48

Total: 797 SH: 136

≥65 SH was not associated with a difference in muscle mass, muscle strength, or physical activities/performances

Virgini et al. (2014)49

Total: 5182 SH: 919

75.2 No difference between euthyroid and SH participants on functional capacity assessed by Barthel Index (BI; p = 0.15) and Instrumental Activites of Daily Living (IADL; p = 0.47) scores

Lankhaar et al. (2014)†,50

Total: 1379 SH: 173

16-80+ Meta-analysis: Insufficient evidence to assess the impact of SH on physical training

Bano et al. (2016)51

Total: 2645

59.6 Clinical and subclinical hypothyroidism associated with worse global gait

E. Possible complications with limited evidence in SH

a. Renal Function b. Diabetes c. Obesity

VI. Treatment of Subclinical Hypothyroidism

A. Screening8 a. Prior to initiating medication therapy, thyroid panel should be re-checked in 3 months or more

B. Treatment52 a. Levothyroxine therapy – Synthetic T4

i. Adults > 50 without cardiac disease: 25-50 mcg daily; adjust at 6-8 weeks increments ii. Adults > 50 with cardiac disease: 12.5-25 mcg daily; adjust at 6-8 weeks increments

C. Guideline Recommendations for Treatment a. American Association of Clinical Endocrinologists/American Thyroid Association

(AACE/ATA) Clinical Practice Guidelines5 i. Patients with a TSH > 10 mIU/L should be treated

ii. TSH levels between the upper limit of a given laboratory’s reference range and 10 mIU/L should be considered for treatment if patients have one of the following:

1. Symptoms suggestive of hypothyroidism 2. Positive thyroid peroxidase antibody (TPOAb) 3. Evidence of atherosclerotic cardiovascular disease, heart failure, or associated risk

factors for these diseases iii. American Thyroid Association (ATA) suggests raising the target serum TSH to 4-6 mIU/L in

people age 70 to 80 years b. American Academy of Family Physicians53

i. Consider initiation of levothyroxine in SH (defined as TSH > 5.5 mIU/L) if: 1. TSH > 10 mIU/L 2. Increased thyroid peroxidase antibody titer 3. Patient has symptoms of hypothyroidism

c. European Thyroid Association (ETA) Guideline (see Figure 2)17

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Figure 2. ETA’s Stepwise Approach to Subclinical Hypothyroidism Treatment17

VII. Clinical Question

Table 14. Trial Overview Examining Relationship Between SH Treatment and Quality of Life54

Citation Scott D, Rodondi N, Kearney P, Ford I, et al. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med. 2017; 376:2534-2544.

Objective Clinical benefits of thyroxine treatment in subclinical hypothyroidism Methods

Study Design Multicenter, randomized, double-blind, parallel-group, placebo controlled trial Inclusion criteria

• Community-dwelling patients aged ≥ 65 years old • Subclinical hypothyroidism (SH) – defined as persistently elevated TSH levels (≥

4.6 and ≤ 19.9 mIU/L) and free thyroxine (fT4) in reference range measured on at least two occasions 3 months or more apart

Age ≤ 70

Serum TSH < 10

Hypothyroid symptoms

Yes: 3-month trial of LT4 then

reassess

No: Observe and repeat TFT in 6

months

Serum TSH ≥ 10

Treat with LT4

Age > 70

Serum TSH < 10

Observe and repeat TFT in 6

months

Serum TSH ≥ 10

Consider LT4 if clear symptoms of

hypothyroidism or high vascular

risk

SH Elderly Treat?

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Exclusion criteria

• Current use of levothyroxine, anti-thyroid drugs, amiodarone or lithium • Thyroid surgery or radio-iodine within 12 months • Grade IV NYHA heart failure • Clinical diagnosis of dementia • Hospitalization for major illness/elective surgery or acute coronary syndrome

(MI or unstable angina) within 4 weeks • Acute myocarditis or acute pancarditis • Untreated adrenal insufficiency • Terminal illness • Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency

or glucose-galactose malabsorption

Intervention Levothyroxine 50 mcg by mouth daily (25 mcg in subjects < 50 kg or known coronary heart disease) vs. placebo

Outcomes Primary (change in baseline to 12 months): - Thyroid-Related Quality-of-Life Patient-Reported Outcome measure

(ThyPRO) Hypothyroid Symptoms score - Tiredness score

Secondary - Health-related quality of life - Comprehensive thyroid-related quality of life - Hand-grip strength - Executive cognitive function - Blood pressure - Weight, body-mass index, waist circumference - Activities of daily living - Fatal and nonfatal cardiovascular events

Statistical Analysis

• For 80% power to be achieved, 540-750 participants needed • P value split between each test (0.025) • Time to first event Cox regression analysis based upon intention to treat • Analysis of covariate (ANCOVA) used for continuous variables

Results Baseline Characteristics

• N = 737 (L-thyroxine = 368, placebo = 369) • Mean age, y: L-thyroxine 74.0±5.8, placebo 74.0±6.8 • Female sex, %: L-thyroxine 53.8, placebo 53.7 • White race, %: L-thyroxine 98.4, placebo 98.1 • Hypertension, %: L-thyroxine 52.2, placebo 50.0 • TSH, mIU/L: L-thyroxine 6.41±2.01, placebo 6.38±2.01 • Hypothyroid symptom score: L-thyroxine 17.5±18.8, placebo 16.9±17.9 • Tiredness score: L-thyroxine 25.9±20.6, placebo 25.5±20.3

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Outcomes Primary: Variable Levothyroxine

Group (N = 320) [baseline]

Placebo Group (N = 318) [baseline]

P-value

Hypothyroid Symptoms score (ThyPRO)

16.6±16.9 [17.5±18.8]

16.7±17.5 [16.9±17.9]

0.99

Tiredness score 28.7±20.2 [25.9±20.6]

28.6±19.5 [25.5±20.3]

0.77

Secondary: Variable Levothyroxine

Group (N = 320) Placebo Group (N = 318)

P-value

EQ-SD score 0.833±0.212 0.853±0.191 0.05 EQ VAS score 77.3±15.6 77.4±13.7 0.18

Hand-grip strength, kg

27.5±10.5 27.1±11.2 0.84

Systolic BP, mmHg Diastolic BP, mmHg

138.3±18.7 72.8±11.4

138.4±17.8 73.5±11.1

0.90 0.93

Body-mass index 27.9±5.1 27.7±4.6 0.89 Waist circumference, cm

98.0±13.2 96.8±13.1 0.34

Author’s Conclusions

Treatment of subclinical hypothyroidism provided no symptomatic benefits

Critique Strengths • Community dwelling participants

• Randomly selected by TSH level • Large range of secondary endpoints

Limitations • Dosing guides provide lower initial doses in the elderly • Relatively healthy, white population • Initial TSH, ThyPRO, and Tiredness score • Thyroid antibody levels not measured • Variance in number of initial patients enrolled and amount at follow-up

VIII. Conclusion

A. Decision to initiate treatment should be patient specific B. Variables to consider prior to starting levothyroxine therapy

a. Patient’s life expectancy and co-morbid conditions b. Medication adherence c. Symptomatology

C. Recommendations for patients ≥ 65 years old a. Confirm subclinical hypothyroid diagnosis with 2 thyroid panels, 3-6 months apart b. Assess patient’s symptom status and rule out differential diagnoses c. If TSH ≥ 10 mIU/L, initiate treatment if:

i. Pt is symptomatic ii. History of CHD

iii. Positive thyroid peroxidase antibody (TPOAb)

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iv. Life expectancy > 1 year d. If TSH 6-10 mIU/L, initiate treatment if:

i. Pt is symptomatic ii. History of CHD

e. If treatment is initiated, titrate to goal TSH of 4-6 mIU/L i. If symptoms continue once at goal, consider re-evaluation of treatment

f. If treatment is not initiated, monitor yearly or if patient becomes symptomatic

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IX. References

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Appendices

Appendix A: Effects of thyroid hormone on cholesterol metabolism22

Appendix B: Effects of triiodothyronine (T3) on cardiomyocytes26