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Subclinical thyroid disorders: still a matter of controversy. Simon HS Pearce. • Background • Subclinical hypothyroidism -Vascular risk • Subclinical hyperthyroidism -Understand the pathophysiology -Approach to Management. Plan. What is normal?. - PowerPoint PPT Presentation
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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
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