SUBCLINICAL THYROID DISEASE Kina M. Merwin McDougall Endocrinology PGY4

Objectives • To define subclinical thyroid dysfunction• To review the clinical implications of subclinical dysfunction• To outline recommendations for therapy per guidelines

The Spectrum of Thyroid Dysfunction

TSH

FT4

Euthyroidism

Overt

Hypothyroidism

Mild Overt

Thyrotoxicosis

Mild

Definitions• Subclinical Hypothyroidism: serum TSH concentration

above the statistically defined upper limit of the reference range when serum free T4 is within its reference range

• Subclinical Hyperthyroidism: serum TSH concentration below the statistically defined lower limit of the reference range when serum free T4 is within its reference range

• Entirely a biochemical diagnosis

Type TSH fT4 SymptomsHyper Low Normal Not necessaryHypo High Normal Not necessary

Impact of Subclinical Thyroid Dysfunction

• Incidence (conservative estimate)• 5% of women • 3% of men• 0.5% undiagnosed overt thyroid disease

• Consequences• Subclinical hyperthyroidism:

• All cause & coronary heart disease mortality• Atrial fibrillation• Decreased bone density

• Subclinical Hypothyroidism• Coronary artery disease• Congestive heart failure

Thyroid Screening Recommendations• ATA: all individuals > 35 and every 5 years thereafter• AACE: preconception & 1st Trimester of pregnancy• ACP: females > 50 with at least one symptom• AAFP: avoid screening asymptomatic patients < 60• Canadian Task Force on Periodic Health Examination

• peri/menopausal women with at least one symptom• US Preventative Services Task Force:

• 2004: Insufficient evidence to recommend for or against screening• 2015: Insufficient evidence to recommend for or against screening

• Lack of studies on subclinical hyperthyroidism since 2004• Conflicting results from several studies of subclinical hypothyroidism

TSH Screening Pitfalls

• Diurnal variation• lowest in evening

• highest in very early morning

• NHANES III TSH subsets• Slightly lower for African Americans

• Slightly higher for Mexican Americans

• Naturally rises with age• For every 10yr increase after age 39,

TSH increases by 0.3mIU/L

TSH Screening Pitfalls

• No reference range in ill or convalescing patients• Sick Euthyroid• Adrenal insufficiency elevates TSH

• Reference range different in each trimester of pregnancy

• Elevation in thyroid hormone resistance• Assay interference:

• heterophile/interfering antibodies• Rheumatoid factor

• Medication interference

• Get free hormone levels prior to diagnosing or treating

When are antibodies indicated?

• Depends on clinical presentation• Any patient with goitre• Other autoimmune diseases • Chromosomal abnormalities (e.g. Down Syndrome)• Medications: lithium, interferon alpha, amiodarone

• Antibodies directed to TSH-receptor (TSHR)• Pregnant women with history of Graves’: determines risk of

neonatal thyrotoxicosis• Subclinical hyperthyroidism: helps determine underlying cause• Overt hyperthyroidism: confirms diagnosis if suspicion for Graves

• Antibodies to thyroid peroxidase (TPO)• Subclinical hypothyroidism: predicts progression• Not a diagnostic requirement in overt hypothyroidism

SUBCLINICAL HYPERTHYROIDISM

Subclinical Hyperthyroidism • Prevalence: ~ 1%

• More common in women and elderly• Causes:

• Toxic Multi-Nodular Goiter (most common)• Graves Disease • Solitary autonomously functioning nodule• Various forms of thyroiditis• Excessive thyroid hormone replacement

• UpToDate: 25% of pts on LT4 have low TSH• 5.8% have TSH <0.1

• Remember the TSH pitfalls: • corticosteroid therapy• non-thyroidal illness

Subclinical Hyperthyroidism• Risk Factors

• Presence of goitre• History of thyroid disease• Family history of thyroid disease• Smoking• Living in area with mild to moderate iodine

deficiency• Intake of iodine-containing substances

• Amiodarone• IV contrast• Kelp/Seaweed• Calcium from sea shells• Iodine supplements

Clinical Symptoms and Signs• Similar to overt hyperthyroidism

• less severe and less specific• Young and middle-aged

• Adrenergic over-activity and palpitations• Elderly

• Symptoms and signs often masked• Remember to check if on beta-blockade

Clinical Implications of Untreated Subclinical Hyperthyroidism• Progression to overt hyperthyroidism• Adverse cardiac endpoints• Atrial fibrillation• Neuropsychiatric symptoms• Reduced bone mineral density• Fractures

Progression to Overt Hyperthyroidism• Frequency of progression uncertain

• Variable potential risk of progression to overt hyperthyroidism • ATA: 0.5% and 1% per year• Framingham: in adults >60 years with a TSH <0.1 mU/L, 4.3% progressed to

overt hyperthyroidism after four years• UpToDate: 40 - 60% have normal values within weeks to a year

• Progression varies with initial TSH and inciting cause• Less frequent at higher TSH levels• New Zealand: 96 patients with endogenous TSH <0.25 mU/L

progressed to overt disease at 8% at one year and 26% at five years. • At five years, overt hyperthyroidism was seen in

• 9% of Graves patients• 21% of nodular goiter patients• 61% of autonomous nodule patients

Possible Subclinical Hyper Cardiac Dysfunction

• Consistent cardiac findings• Sinus tachycardia • Atrial fibrillation • Premature atrial complexes • No evidence of ventricular arrhythmias• Risk of heart failure• Risk of nonfatal cardiovascular disease

• Possible cardiac risks• Increased cardiac contractility• Increased LV mass• Possible diastolic dysfunction & risk of heart failure• Reduced exercise tolerance

Cardiac Outcomes in Sub. Hyperthyroidism

• Atrial Fibrillation• 1994 study found a 2.8-fold risk of AFib in people > 60 years• 2006 study confirmed tendency to Afib in people > 65 years

• Cardiovascular Mortality - variable results:• 2008 meta-analysis of 5 population studies showed no

relationship between SHyper and all-cause mortality/CV death• 2008 Meta-analysis of 7 cohort studies showed relative increase

in CV mortality of 41%• Mathematical modelling suggests mortality risk increases above age

60 especially in men

Sawin CT et al. 1994. N Engl J Med 331:1249–1252.Cappola AR et al. 2006. JAMA 295:1033–1041Ochs N et al. 2008 Ann Intern Med 148:832–845.Haentjens P et al. 2008 Eur J Endocrinol 159:329–341.

Mortality in Sub. Hyperthyroidism

• Data on the effects of SH on mortality are conflicting• 2008 meta-analysis suggested that all-cause mortality risk in SH

progressively increases with age. • Another 2008 meta-analysis, however, did not find a statistically

significant increase in mortality in SH• 2012 study again found mildly increased all-cause mortality

Haentjens P et al. 2008 Eur J Endocrinol 159:329–341.Ochs N et al. 2008 Ann Intern Med 148:832–845Collet TH et al. 2012 Ann Intern Med 172:799-809

Neuropsychiatric Effects• Very conflicting data on mood, depression and anxiety• Conflict on association between SHyper & dementia in older

people (population or cohort cross-sectional studies) • England 2006: subclinical thyroid dysfunction not associated with

depression, anxiety, or cognition• Frammingham 2008: women (but not men) with TSH < 0.1 (or >2.1) had

a 2.39 increased risk of Alzheimer disease compared with the middle tertile

• Italy 2009: pts age >65 with TSH <0.46 associated with cognitive dysfunction

• Scotland 2011: persistent endogenous TSH <0.4 associated with an increased risk of dementia

• USA 2014: Women with exogenously suppressed TSH do not have central nervous system dysfunction including no dementia

Vadiveloo et alJ Clin Endocrinol Metab. 2011;96(5):1344.Samuels et al. J Clin Endocrinol Metab. 2014 Mar;99(3):843-51.

Roberts et al. Ann Intern Med. 2006;145(8):573.Tan et al. Arch Intern Med. 2008;168(14):1514.Ceresini et al J Am Geriatr Soc. 2009;57(1):89.

Musculoskeletal Effects• Bone mineral density

• In SHyper caused by exogenous LT4 therapy, no effects on BMD in premenopausal women or men

• In postmenopausal women LT4 may accelerate bone turnover particularly cortical bone• Depends on severity of TSH suppression and dietary Ca intake

• In endogenous SHyper , suppressed TSH likely reduces BMD regardless of gender and menopausal state• Depends on duration of disease and associated risk factors

• Fractures• Overt hyperthyroidism known risk for fractures• In SHyper, no definitive evidence showing increased risk

Surks et al. JAMA 2004; 291:228-38

ATA 2011 GuidelinesSubclinical Hyperthyroidism Management• Ensure persistence with repeat TSH at 3 - 6 months

• May spontaneously resolve, especially if TSH >0.1• Treatment controversial due to lack of trial data to

show benefit• Expert consensus that benefit sufficient to warrant

therapy in older individuals with TSH <0.1mU/L• Based on studies with an increased rate of atrial fibrillation and altered

skeletal health• Insufficient data for/against treatment in younger

persons or premenopausal women with TSH <0.1mU/L

Subclinical Hyperthyroidism: When to Treat

FACTOR TSH (<0.1 mU/L) TSH (0.1–0.5 mU/L)

Age > 65 Yes Consider treating

Age<65 with Heart disease Osteoporosis MenopausalHyperthyroid symptoms

YESYESConsider TreatingYES

Consider Treating NOConsider TreatingConsider Treating

Age < 65 Consider Treating NO

ATA guidelines: How to treat• Treatment similar to the treatment of overt hyperthyroidism• Radioactive iodine appropriate for many patients

• Particularly older patients with TMNG • In subclinical Graves, long-term ATD therapy reasonable

alternative• Risks to benefits discussion required

• Younger patients with subclinical Graves may remit without therapy, therefore observation reasonable

• Elderly patients with no symptoms or evidence of complications can also be observed• Treatment with beta-adrenergic blockade may be enough to

control the cardiovascular-related morbidity, especially AFib• Goal of therapy is to render the patient euthyroid with a

normal TSH

Avoid Overtreatment of Hypothyroidism• Titrate replacement LT4 dose to TSH of 0.5 - 4.0• Subclinical hyperthyroidism unavoidable when thyroid

hormone given to suppress TSH secretion• Minimize adverse effects with the lowest dose of LT4 necessary to

meet goal• Consider measuring TSH, free T4, and T3 every six months

• Patients >65 years of age• Patients with risk factors for cardiac arrhythmias• Postmenopausal women with or at risk for osteoporosis

Results of therapy in Sub. Hyperthyroid

• No studies show therapy prevents atrial fibrillation or decreases mortality• Uncontrolled study showed improvement in symptoms with beta

blockers

• Improvement in BMD in nonrandomized controlled trials of antithyroid drugs or radioactive iodine

• Increase in muscle mass and muscle strength in middle-aged women in one uncontrolled study

.

Faber J et al. 1998 Clin Endocrinol (Oxf ) 48:285–290.Brennan MD et al. 2006 Thyroid 16:375–380

Subclinical hyperthyroidism outcomes

Summary

• Subclinical hyperthyroidism• Affect on cardiac parameters such as HR, LV mass• Strong association with Afib when TSH <0.1 mIU/L• Possible association with dementia• Exogenous SHyper post-menopause and endogenous

SHyper are associated with reduced BMD• definitive evidence lacking for association with fractures

• Consider treating when • TSH <0.1 mIU/L & age >65

• <65 with comorbidities

SUBCLINICAL HYPOTHYROIDISM

Subclinical Hypothyroidism (SCH)

• Definition• Serum TSH above upper reference limit in combination

with normal free thyroxine (fT4)• Thyroid function stable for weeks to months• Hypothalamic–pituitary–thyroid axis normal • No recent or ongoing severe illness

Etiology • Primary >99%

• Autoimmune – Hashimoto’s thyroiditis• Thyroiditis – subacute, painless, postpartum• Inadequate thyroid replacement therapy for overt hypothyroidism

• Poor absorption or compliance• Iatrogenic – hemi-thyroidectomy or radiation• Drug induced

• Amiodarone, Lithium, Interferon

• Thyroid infiltration • Hemochromatosis, amyloidosis, sarcoidosis, AIDS

• Central hypothyroidism • TSH receptor mutations

SCH Epidemiology• Prevalence: 4-12%

• NHANES III 4.3%• British General Practice Study 6%• Colorado Health Fair Study 10%• Rotterdam Study 11.8%

• Increases with age• Up to 20% in women > 60y• Controversial if actually indicative of disease

Subclinical Hypothyroidism

• Risk factors: • Family history of thyroid disease• Postpartum thyroiditis• Previous hyperthyroidism• Previous head and neck cancer treated with radiation• Previous hyperthyroidism treated with RAIA• Type 1 diabetes mellitus

• 10% develop chronic thyroiditis during lifetime onset of sub. hypothyroidism

• Positive TPO antibodies• Iodine sufficiency

SCH Clinical Symptoms and Signs

• Similar to overt hypothyroidism• less severe and less specific• fatigue & weight gain very common (and very non-specific)

• Elderly• Symptoms and signs less common• Controversial if reference range

changes with age

Bremne et al. J Clin Endocrinol Metab. May 2012, 97(5):155-1562

Symptoms • Colorado Thyroid Disease Prevalence Study

• 2,336 (13.7%) subjects with mild thyroid failure reported the following more than euthyroid subjects:• dry skin (28%; P < 0.001)• poor memory (24%; P < 0.001)• slow thinking (22%; P < 0.001)• muscle weakness (22%; P < 0.001)• fatigue (18%; P < 0.01)• muscle cramps (17%; P < 0.01)• cold intolerance (15%; P < 0.01)• puffy eyes (12%; P < 0.05)• constipation (8%; P < 0.05)• hoarseness (7%; P < 0.05)

Colorado Thyroid Disease Prevalence Study

McDermott M T , and Ridgway E C JCEM 2001;86:4585-4590

©2001 by Endocrine Society

n = 22,84212.1%

n = 2,33613.7%

N= 11416.6%

Clinical Implications of Untreated SCH• Progression to overt hypothyroidism• Adverse cardiac endpoints• Dyslipidemia• Neuropsychiatric symptoms

• Fatigue, poor memory, quality of life• Adverse pregnancy outcomes

Progression to Overt Hypothyroidism• Progression varies with initial TSH and TPO-Ab

positivity• Estimates of progression range from 2 – 18% per year

• Whickham 1995: women with both high TSH & + TPO-Ab developed hypothyroidism at a rate of 4.3%/ year (cumulative incidence 55%)

• Huber et al:154 female patients over a 10-yr period • 57% continued to have mild thyroid failure• 34% progressed to overt hypothyroidism• 9% of patients reverted to a normal TSH level

• TSH normalizes in 5- 10% after 1 year

Vanderpump et al. Clin Endocrinol (Oxf). 1995;43(1):55Huber G, 71st Annual Meeting of the American Thyroid Association, Portland, 1998; Abstract 109

Predictors of Progression • Higher risk of progression:

• Female• Age >60-65 • TSH >10• Positive thyroid antibodies

• 4.3% per year with + TPO-Ab• 2.6% per year without elevated TPO-Ab titers

• History of radioiodine ablation for Graves• History of radiation for nonthyroidal malignancies• Chronic lithium treatment

Parle JV et al. 1991 Jan;34(1):77-83. Ann Intern Med. 15 February 2000;132(4):270-278

Canaris GJ et al. Ach Intern Med. 2000;160(4):526-534

Possible Cardiovascular Effects• Cardiac function

• Associated with impaired left ventricular diastolic function• Slowed myocardial relaxation and impaired ventricular filling• Impaired diastolic and systolic cardiac performance with effort

• Vascular System• Increased systemic vascular resistance• Increased arterial stiffness• Disruption of endothelial function

• Attributed to reduce NO

• Increased carotid intima-media thickness

Subclinical Hypothyroidism and CV Risk

• Large epidemiological studies with varying results: • Whickham: cohort with 20-year f/u

• No association found• Rotterdam study: cross sectional study

• Increased aortic atherosclerosis & MI

• Rodondi: Meta-analysis of 11 prospective cohort studies • no overall association of subclinical hypothyroidism with coronary heart disease

events, cardiac mortality or total mortality.• significant associations when degree of elevation of serum TSH stratified for CAD

events:

• HR 1.0 for TSH 4.5-6.9• HR 1.17 for TSH 7-9.9• HR 1.89 for TSH 10-19.9

• Cardiovascular Health Study: US population study. Various spin-offs• No association with cardiovascular or cerebrovascular diseases• No association with all-cause mortality

• UK GP Research Database: • SCH pts <70yrs on LT4 had lower rates of heart disease over 8 years of follow-up

Vanderpump, M.P et al. (1995) Clinical endocrinology (Oxford), 43, 55–68Hak, A.E. et al. (2000) Annals of Internal Medicine, 132, 270–278.

Rodondi et al.. JAMA.2010;304:1365–1374.

Hyland KA et al. J Clin Endocrinol Metab. 2013;98:533–540. Cappola, A.R et al. (2006) JAMA, 295, 1033–1041. Razvi et al. Arch Intern Med 2012: 172:811-818

Vascular Changes• Clear indications in overt hypothyroidism • Less data to clearly support significant changes in

subclinical hypothyroidism• Large epidemiological study (2007) found no significant

evidence of LV dysfunction in subclinical hypo• Several non-randomized interventional studies

demonstrated that surrogate markers for vascular disease (e.g. carotid artery intima-media thickness) improve with LT4 therapy.

Iqbal. J Clin Endocrinol Metab. 2007;92(9):3504.Monzani et al. J Clin Endocinol Metab 2004;89:2099-2106

Lipid Profile • Historically conflicting data, mainly in population studies:

• NHANES III: elevated total cholesterol• Rotterdam Study: lower cholesterol • Colorado: elevated total cholesterol for Euthyroid vs Shypo

• 5.6 versus 5.8 mmol/L• Not adjusted for age• Unclear clinical significance

• Several small studies & meta-analyses since 2000 indicate that SCH does affect lipid profiles:• EPIC-Norfolk & Tognini et al: increased total cholesterol, LDL &

triglyceride in SCH women only• Meier et al & Caraccio et al: Treatment with LT4 improves total

cholesterol, LDL & triglyceridesBoekholdt et al. Clin Endocrinol (Oxf) 201072:404-410

Tognini et al. Thyroid 2012;22:1096-1103.Meier et al. J Clin Endocrinol Metab 2001;86:4860-4866

Caraccio et al. J Clin Endocrinol Metab 2002;87;1533-1538

Neuropsychiatric Symptoms• Conflicting, heterogeneous data that is difficult to compare

• Small studies suggest association with fatigue, memory impairment and cognitive dysfunction

• Large study of primary care patients in England failed to demonstrate an association of subclinical hypothyroidism with depression, anxiety, or cognitive dysfunction

Pregnancy Outcomes• Risk factor for miscarriage, preterm labour & low birth weight

TPOAb(+) & LT4 / TPOAb(+ )/ TPOAb (-)

PretermDelivery

Miscarriage

Negro et al. JCEM 91(7):2587–2591, 2006

Evaluation of Subclinical Hypothyroidism• High TSH: repeat with free T4

• In next 2 weeks if very high• In 2-3 months if mildly high

• Evaluate for signs and symptoms of hypothyroidism, previous tx for hyperthyroidism, thyroid gland enlargement, family hx thyroid disease

• Review lipid profile • ATA & ETA recommend checking TPO-Ab

• NHANES III: 10% had TPO+ antibodies • Potential indicator of autoimmune thyroid failure• TPO-Ab may be associated with CV risks• Risk of miscarriage higher

• Special consideration if pregnant woman/plans for conception

SCH Treatment Recommendations• 2004 USPSTF:

• Subclinical hypo is risk for progression to overt disease but insufficient evidence to estimate effect of early treatment on clinical outcomes

• 2015 USPSTF re-evaluation (Annals of Int. Med):• insufficient evidence to change previous recommendations

• Despite above, thyroid replacement therapy in USA dramatically increased• 1989: 8.1% of population• 2005: 20.0% of population• 2006: 49.8 million prescriptions• 2010: 70.5 million prescriptions

ATA SCH Guidelines: Who to Treat• Treat if TSH > 10 mIU/L• Based on individual factors when TSH between the upper

limit of reference range and 10 mIU/L • Should be considered:

• Symptoms suggestive of hypothyroidism• Positive TPOAb• Evidence of atherosclerotic cardiovascular disease, heart

failure, or associated risk factors for these diseases• No data to support treating patients with subclinical

hypothyroidism with TSH 2.5 - 4.5 mIU/L. • Exception for pregnancy: treat to appropriate trimester

ranges

Biondi et al. Endocrine Reviews. 2008; 29:76-131

ATA SCH Guidelines: How to Treat• Initial L-thyroxine dosing is generally lower than

requirements in treatment of overt hypothyroidism • Daily dose of 25–75 mcg, depending degree of TSH

elevation:• Upper limit of Normal - 8.00mlU/L: 25mcg • TSH 8.01 to 12.00mlU/L: 50mcg• TSH >12.01mlU/L: 75 mcg

• Further adjustments should be guided by clinical response and follow-up laboratory determinations including TSH values.

ETA SCH Guidelines: Age Classification• Younger < 65• Moderately Older 60-70• Older 70-80• Oldest Old/Elderly > 80-85• Centenarians >100

• Ultimately, for SCH treatment, separate into:• Young < 65-70• No longer young > 70

ETA Guidelines: Who to treat

ETA Guidelines: Who to treat

ETA SCH Guidelines: How to treat• Without cardiac disease, dose LT4 at 1.5mg/kg/day

• Target TSH in lower half of reference range (0.4-2.5mU/L)• With cardiac disease or age >70, start with 25-50mcg/day

• Titrate by 25mcg/day every 2-3wks• Target TSH 1-5mU/L

• Avoid treatment if age >80-85 and TSH <10• Age specific reference ranges should be considered

• If starting symptomatic pt with TSH <10 on LT4, review response 3-4m after TSH at target• If symptoms not resolved, discontinue therapy• No evidence that LT4 will favourably affect obesity• Lipid goal is reduction in total chol & LDL. Normalization is not expected

Effects of Treatment• Early LT4 does not alter natural course of disease but

may prevent findings of overt disease if patients progress• Cardiac:

• Improved diastolic function• Decreased MI & cardiovascular mortality if <70 (no benefit >70)

• Decreased LDL. Limited effect on HDL & Triglycerides• Cochrane meta-analysis disagrees

• No significant differences between LT4 and placebo groups for symptoms, signs, QOL and psychometric testing• Cochrane meta-analysis • Small trial shows improved memory

Villar et al. Cochrane Database of Systematic Reviews. 2007.

Levothyroxine vs no treatment Observational over mean of 7.6 years

UK Retrospective data40 - 70 yearsOutcome Rate LT4 No treatment Hazard Ratio 95% Confidence IntervalsIschemic heart disease events 4.20% 6.60% 0.61 0.38 - 0.95All-cause mortality 3.40% 6.40% 0.36 0.19 - 0.66Death due to circulatory disease 1.40% 2.40% 0.54 0.37 - 0.92Cancer mortality 1.20% 2.20% 0.59 0.21 - 0.88

over 70 yearsOutcome Rate LT4 No treatment Hazard Ratio 95% Confidence IntervalsIschemic heart disease events 12.70% 10.70% 0.99 0.59 - 1.33All-cause mortality 35.20% 40.50% 0.71 0.56 - 1.08Death due to circulatory disease 17.10% 18.30% 0.91 0.56 - 1.46Cancer mortality 4.60% 6.50% 0.51 0.24 - 1.09

Subclinical hypothyroidism outcomes

2015 USPSTF: Outcomes on LT4 therapy

• Benefits:• Quality of Life:

• Improved if recent Graves• Otherwise no effect

• Cognative Function• Small improvement in memory if

age >55• Lipids

• Total choll: -0.3 to -0.7mmol/L• LDL: -0.2 to -0.6 mmol/L• HDL & Triglycerides: no

significant difference• BMI & BP

• no significant difference

• Harms• Some patients with SCH

after treatment of Graves felt slightly worse on LT4 (4/17) vs placebo (6/15)

• 1 case of angina• 1 case of Afib• 1 case of decreased vitality

score on SF36v2 questionnaire

Rugge et al. Annals of Internal Medicine, 162; 1: 35-46

Summary• Subclinical Hypothyroidism

• Insufficient quality data to make firm recommendations• Symptoms often not present or non-specific• Treatment consistently associated with reduced LDL• Expert consensus recommends treatment for:

• TSH >10 given high rate of progression to overt disease and improved lipid profile

• Pregnant women• Consider trial of treatment when TSH < 10 if:

• Cardiovascular risk factors• Symptoms in keeping with hypothyroidism• No clear end point

• Watch for SubClinical Hypothyroidism Treatment Response Evaluation by N-of-1 Design (SCH-TREND)