Subclinical thyroid disorders:

still a matter of controversy

Simon HS Pearce

Plan• Background

• Subclinical hypothyroidism-Vascular risk

• Subclinical hyperthyroidism-Understand the pathophysiology-Approach to Management

What is normal?

Andersen et al. JCEM 2002

• 16 healthy individuals, having monthly TFTs for 1 year• People stick to their own “reference” interval• Extrapolating to Free T4 values -setpoint +/- ~2.5 pmol/l • “My normal range is different from yours”

TSH in centenarians and offspring

Atzmon et al. JCEM 2009

Δ 232 Ashkenazim, age

97

o 366 of offspring, age 69

177 age-matched

controls

Lancet 1971; I: 203

Possible mechanisms

• Dyslipidaemia

• Cardiac systolic & diastolic dysfunction

• Hypertension

• Endothelial dysfunction

• Hypercoagulability

Hard outcomes

• Rotterdam Heart Study– Community-based cross sectional survey– 1149 women (mean age 69 +/-7 yrs)– 10.8% had “subclinical hypothyroidism” (TSH>4.0, N FT4)

– Odds ratio for MI= 2.3 (CI; 1.3-4.0)– OR for aortic atherosclerosis 1.7 (1.1-2.6)– Population attributable risk of TSH to MI estimated

to be 14% • N.B. Diabetes 14%, Smoking 15%

Hak et al. Ann Intern Med 2000;132: 270

Meta-summary of meta-analyses

Author Number Cardiovascular events

Cardiovascular mortality

All cause mortality

Singh 2008 13,267 1.53 (1.31–1.79) 1.28 (1.02–1.60) 1.12 (0.99-1.26)

Ochs 2008 14,449 1.20 (0.97-1.49) 1.18 (0.98-1.42) 1.12 (0.99-1.26)

Haentjens 2008 14,619 NI NI 1.22 (0.95-1.57)

Razvi 2008 29,022 1.23 (1.02– 1.48) 1.09 (0.84 –1.41) NI

Rodondi 2010 55,287 1.18 (0.99- 1.42) 1.14 (0.99- 1.32) 1.09 (0.96-1.24)

Thvilum 2012 35,740 NI NI 1.17 (1.00-1.37)

• Relative risks (5-95% confidence intervals)

Meta-summary of meta-analyses

Author Number Cardiovascular events

Cardiovascular mortality

All cause mortality

Singh 2008 13,267 1.53 (1.31–1.79) 1.28 (1.02–1.60) 1.12 (0.99-1.26)

Ochs 2008 14,449 1.20 (0.97-1.49) 1.18 (0.98-1.42) 1.12 (0.99-1.26)

Haentjens 2008 14,619 NI NI 1.22 (0.95-1.57)

Razvi 2008 29,022 1.23 (1.02– 1.48) 1.09 (0.84 –1.41) NI

Rodondi 2010 55,287 1.18 (0.99- 1.42) 1.14 (0.99- 1.32) 1.09 (0.96-1.24)

Thvilum 2012 35,740 NI NI 1.17 (1.00-1.37)

• Relative risks (5-95% confidence intervals)

M Thvilum, F Brandt, TH Brix & L Hegedus. Nat Rev Endocrinol 2012

All cause mortality in SCH

Janus response: Age

•Thanks to Stefano Mariotti & David Cooper

Meta-analysis

• Performed by Salman Razvi/ Abdul Shakoor

• Longitudinal or cross sectional studies of

independent community-based subjects

• 14 studies fitted stringent criteria

• 2,531 SCH participants

• 26,491 euthyroid individuals

• Divided studies according to age of inclusion• <65 yr vs 65 and above: median 60 & 74 yr

IHD prevalence in cross-sectional studies of SCH & euthyroid controls

Younger

Older

IHD incidence in longitudinal studies of SCH & euthyroid controls

Younger

Older

Cardiovascular mortality in longitudinal studies of SCH & euthyroid controls

Younger

Older

Summary

• Prevalent and incident IHD, and IHD mortality is increased in SCH compared to euthyroid population

• Evidence of increased IHD confined to studies that have included people aged less than 65 years

Razvi et al. JCEM 2008

Patient-level analysis

• 55,287 participants; 3,450 with SCH (6.2%)

• Information derived from 11 studies

• 9664 deaths; 2168 from CHD

• SCH defined as TSH 4.5-19.99 mU/l (N FT4)

Rodondi et al. JAMA 2010

Patient-level analysis: TSH

Patient-level analysis: TSH

Patient-level analysis: Age

Interim Summary

• Meta-analysis with many thousands of patient events shows vascular death is associated with SCH

• Effect is greater at higher TSH levels, reaching significance at TSH of 7.0 mU and above

• Effect is attenuated at older ages

UK General Practice Research Database

• Primary care resource linking ~10 million patient records, labs, prescriptions & death certificates

• During 2001 there were 322,291 TSH measurements

• Identified 4,735 people >40 yrs with TSH 5.0- 10.0 mU/l, normal FT4

• Excluded individuals on L-T4, ATDs, previous thyroid disease, previous IHD, stroke, other vascular disease

Razvi S et al. Arch Intern Med 2012

UK General Practice Research Database

• Participants followed until March 2008 (median 7.6 yrs)

• People aged 40- 70 yrs (n=3093) and >70 yrs (n=1642)

• 52.9% and 49.9% were treated with L-thyroxine during follow up (Primary Care decision)

• Analysed outcomes for incident IHD, vascular and all cause mortality over follow up period (Cox regression MVA)

L-Thyroxine treated group

• 94% of people continued to take L-T4• Median dose 75μg (12.5-175 μg) daily

Untreated group

• 1.3% developed overt hypothyroidism -(TSH >10, or FT4)

• 58% remained with elevated TSH

• 38% reverted to euthyroidism

• 2.5% developed low TSH

Baseline characteristics40-70 yrs >70 yrs

Untreated L-T4 Rx Untreated L-T4 Rx

Number 1459 1634 823 819

Age 55.9 ± 8.3 55.9 ± 8.4 79.9 ± 6.5 79.4 ± 6.2

Females 82.5% 87.4% 75.6% 84.6%

Serum TSH (mU/l) 6.3 ± 1.3 6.7 ± 1.4 6.3 ± 1.2 6.8 ± 1.4

Serum FT4 (pM) 13.4 ± 4.4 12.9 ± 3.0 14.6 ± 4.4 13.9 ± 3.4

BMI (Kg/m2) 27.8 ± 5.9 28.1 ± 6.2 25.4 ± 4.6 26.3 ± 5.1

Systolic BP (mmHg) 136.5 ± 20.0 135.2 ± 19.3 149.4 ± 23.5 149.4 ± 22.0

T Cholesterol (mM) 5.86 ± 1.34 5.82 ± 1.21 5.93 ± 1.36 5.95 ± 1.25

Diabetes 18.0% 18.1% 26.9% 26.6%

Smokers (current) 18.3% 17.9% 10.9% 10.1%

Deprivation index 17.5 16.75 15.86 16.58

GP contacts/yr 1.2 1.3 2.3 2.4

Fatal & non-fatal vascular events 40-70 yrs

HR 0.61 (0.39- 0.95); p=0.02

All cause mortality40-70 yrs

HR= 0.36 (0.19 – 0.66) ; p<0.001

Fatal & non-fatal IHD events >70 yrs

HR 0.99 (0.59- 1.33); p=0.56

All cause mortality>70 yrs

HR= 0.71 (0.56 – 1.08) ; p=0.11

Event rate stratified by age

• LT4 vs untreated; Fatal + non fatal CV events

Degree of serum TSH elevation

Hazard Ratio for vascular events P value for trend

TSH 6.6 or less TSH > 6.6

40-70 yrs 0.62 (0.39-0.96) 0.41(0.26-0.81) 0.007

>70 yrs 1.02 (0.66-1.82) 1.19 (0.74-1.80) NS

• Median serum TSH 6.6 mU/l• Reference group (HR=1) is untreated patients

Razvi et al. Arch Intern Med; 2012

Atrial fibrillation

Hazard Ratio for AF/ month L-T4 exposure

5-95% CI

40-70 yrs 0.998 0.995- 1.001

>70 yrs 1.000 0.999- 1.001

Summary

• L-T4 treatment of SCH was associated with a lower CV mortality and CV event rate in patients <70 yrs

• Importantly, L-T4 treatment was not associated with AF

• Not an RCT study, but represents outcome of real-life practice

Razvi et al. Arch Intern Med 2012

Who should we treat?

• Pregnant patients, or planning pregnancy

• Patients with serum TSH > 10.0 mU/l

Who should we consider treating?

• Symptoms or signs of hypothyroidism

• Age less than 70 yrs• TSH >7.0 mU/l• Goitre• High vascular risk including

– Ischaemic heart disease– Diabetes– Dyslipidaemia

• 380 attendees at ITC 2010• Electronic voting system • Female, serum TSH 6.8

Pearce, Wemeau, Vaisman. Eur Thyroid J 2012

Subclinical hyperthyroidism

What is normal in extreme old age?

Mariotti et al. JCEM 1993

• Age-related decline in median TSH levels (ill people excluded)

What is normal in extreme old age?

Mariotti et al. JCEM 1993

• Age related decline in T3 levels (ill people excluded)• FT4 (and TT4) levels remain constant

Magri et al. 2002

Change to function of HPT axis

• Reduced hepatic thyroid hormone clearance-glucuronidation, sulfation

• Reduced T4 to T3 conversion

• Reduced type 1 deiodinase activity

• Blunted diurnal TSH secretion

• Flattened TSH response to TRH

Subclinical Hyperthyroidism

Degrees of hyperthyroidism

Degrees of hyperthyroidism

87% remained <0.176% returned to normal

12 months follow up

Parle JV et al. 1991 Clin Endo

NHANES III

Prevalence

Both grades

• 1-3% of elderly subjects in NHANESIII

• 2.1 % in Colorado HealthFair study

Suppressed TSH

• ~0.7% of TFTs from people not on T4 at RVI

Should we be concerned about subclinical hyperthyroidism?

Evidence

Small risk of progressionto overt disease

• Parle et al. 1991 TSH <0.1 2%/ year

• Wiersinga et al. 1995 5%/ year

• Pirich et al. 2000TSH <0.1 7%/ year

• Schouten et al. 2011 5-8%/ year

• Rosario et al. 2010 TSH 0.1-0.4 1% /year

Sawin et al. NEJM; 1994

AF in Framingham survey

<0.1

0.1- 0.4>5.0

0.4- 5.0

TSH(mU/l)

Cardiovascular Health Study

• 3233 US community dwelling individuals over 65, mean age 73• AF rate 2.0 (CI 1.3-3.0) in Sub Hyper

Cappola et al. JAMA 2006

Overall survival “Circulatory” survival

Parle et al. Lancet 2001

• Community-living >60 year olds; overt thyroid disease excluded

Gussekloo et al. JAMA 2004; 292:2591

TSH>4.8mU/l

Normal TSH

TSH <0.3mU/l

• n=558 • Birth cohort design • All 85 yrs at baseline • Leiden, NL

• Hazard Ratio per 2.71 mU/l increase in TSH is 0.77 (0.63-0.94)

• 20 yr follow up of population survey, Western Australia; n=2108• Mean age 51 (17-89); subclin hypER 1.8%• No effect of subclinical hyperthyroidism

Busselton Health Study; Arch Intern Med 2005

CH

D (

fata

l &

non

-fata

l)

Meta-analysis of 10 cohort studies

• 52,000 participants (2188 with SH)Collet et al. Arch Intern Med 2012

Summary of observational studies

• Increased incidence of AF in SH

• Increased vascular mortality in SH groups in most, but not all studies

• SH sounds like bad news for your heart

Functional cardiac effects of subclinical hyperthyroidism

• Resting tachycardia

• LV hypertrophy

• Increase LV mass index

• Increase cardiac workload

• Diastolic dysfunction (impaired relaxation)

• Increased systolic function at rest

• Impaired systolic response to excercise

Biondi, Kahaly, Klein and others

Non-vascular effects of SH

Effect Reference

Bone mineral density Decreased Mudde 1994, Faber 1998, Tauchmanovà et al. 2004

Fracture Increased x3 & 4.5; hip & vertebral

Bauer et al. 2001

Muscle strength Knee extension Decreased by 30%

Brennan et al. 2006

Dementia Increased x 3.5 Kalmijn et al. 2000

OK:

• Subclinical hyperthyroidism is bad news

•Let’s treat everybody and make them better

No evidence that treatment is effective

Problem?

RCTs of radioiodine in SH

• Dutch trial: poor recruitment rate, other factors: Trial terminated 2005

• UK Trial: poor recruitment rate (< 10% of SH patients agreed to randomisation). Trial terminated 2009

• French trial: Prof. B Goichot,- ongoing- AF as primary endpoint (target 300 patients)

No evidence that treatment is effective

Problem?

Problems with study designs

• Participant cohort defined by a single TSH measurement

• AF and mortality followed subsequently

• Many subjects (>50%) will have subsequently normalised TSH levels during follow up

• How to interpret adverse outcome of low TSH/ Subclinical hyperthyroidism group?

Formulation 1

• Low TSH represents true endogenous hyperthyroidism

• Adverse cardiac events & AF are an expected consequence of excess thyroid hormones

• Need to treat for hyperthyroidism

Formulation 2• Low TSH represents an effect of ageing and reduced

turnover of pituitary-thyroid axis (biomarker for age)

• Decreased hepatic thyroid hormone clearance, ‘blunted’ diurnal TSH secretion & flattened TSH response to TRH with ageing

• Adverse cardiac events & AF (+ OP & dementia) simply are consequences of “biological age”

• No need to treat for hyperthyroidism

Formulation 1.5

• Both the previous suggestions are true

• Adverse cardiac effects are due to excess thyroid hormones in some

• In others, low TSH is a biomarker for aging & hence associated with poor outcome

• Need to distinguish between these two groups to treat some for hyperthyroidism

Cardiovascular Health Study

• AF rate little different between

grade I and grade II SH

TSH

mU/l

N AF rate/1000 pt yrs

Hazard ratio (5-95% CI)

Euthyroid 2502 31 1.00 (ref)

<0.44 47 67 1.98 (1.29-3.03)

0.1-0.44 40 59 1.85 (1.14-3.00)

Cappola et al. 2006

Vadiveloo et al. JCEM 2011

• 2004 patients with SH vs 10,111 controls• 2 TSH measurements 4/12 apart• Median follow up 5.6 yrs

TEARS study

What to do?

• Observe 3 to 6 months• Look out for drug/ contrast effects

-Thyroxine-Opiates-Glucocorticoid-Metformin-L-DOPA-Amiodarone-CT contrast (Iopaque)

What to do?

• TSH <0.1 mU/l

• Age <75

• Symptoms, goitre

• Above median FT3, FT4

• +ve Antibodies, nuclide scan

• Complications, AF

Intrinsic thyroid disease Ageing process

TSH 0.1-0.4 mU/l •

Age >75 •

No symptoms •

Below median FT3, FT4 •

-ve Antibodies, scan •

No complications •

Algorithm

Mitchell & Pearce. Clin Endo 2010

* Rare causes• Pituitary disease• Tumour hCG

† Repeat testing• May need investigations• Maybe yearly re-testing• Maybe never re-test

“There is no reason to treat a patient with subclinical hyperthyroidism for thyrotoxicosis, provided they are in sinus rhythm”

Vaidya B et al. Clin Endo 2008

27% agree

55% disagree

Peer opinion: BTA Survey

Summary

• Low serum TSH is common in advanced age

• In many, it is transient & in others may be a

feature of ageing

• The minority will require treatment

• Large evidence vacuum remains

Dr. Salman RazviPerformed much of the hard work

Acknowledgements

TRISH Investigators and Steering committee

• Amit Allahabadia & Alison Mortimer

• Diana Elbourne, Jayne Franklyn, Malcolm Prentice, Graham

Williams, Janis Hickey, Murray Stewart, Wilmar Wiersinga

Newcastle Co-investigators

• Salman Razvi, Anna Mitchell, Joanna Collerton, Andrew

Kingston & 85+ Core study team

• BTA survey: Bijay Vaidya

& Newcastle Healthcare Charity

The End