SUBCLINICAL THYRSUBCLINICAL THYR

Wilmar M.

Department of Endocr

A d i M di l CAcademic Medical Center

The NethThe Neth

ROID DYSFUNCTIONROID DYSFUNCTION

Wiersinga

rinology & Metabolism

U i i f A dr, University of Amsterdam

herlandsherlands

SUBCLINICAL THYR

1 Definitions and c1. Definitions and c- reference range- intra-individual- continuous risk

2 Subclinical hypot2. Subclinical hypot

3. Subclinical hyperyp

ROID DYSFUNCTION

conceptual problemsconceptual problemsesl variation

k

thyroidismthyroidism

rthyroidismy

SUBCLINICAL THYRDEFINI

Subclinical hypothyroidism= increased serum TSH but

Subclinical hyperthyroidismSubclinical hyperthyroidism= decreased serum TSH but

ROID DYSFUNCTIONITIONS

mt normal serum FT4

mmt normal serum FT4 and FT3

TRANSITIONS FROMHYPOTHYROIDISM OR

Serum TSH

Overt hyperthyroidism ↓

T3-toxicosis ↓

S b li i l h th idi ↓Subclinical hyperthyroidism ↓

Euthyroidism N

Subclinical hypothyroidism ↑

Mild hypothyroidism ↑Mild hypothyroidism ↑

Overt hypothyroidism ↑

N = norm

M EUTHYROIDISM TOR HYPERTHYROIDISM

Serum FT4 Serum FT3

↑ ↑

N ↑

N NN N

N N

N N

↓ N↓ N

↓ ↓

mal, ↓=decreased, ↑ = increased

WHAT IS NWHAT IS NTHAT WHAT IS N

80 100

intelligence

NORMAL?NORMAL?NOT ABNORMAL

120

quotient

NORMAL

“The normal range has a vgrole in laboratory medicinhorizon of our consciousnhorizon of our consciousnlike a Mount Fujijama, soits meanings yet gratefullits meanings, yet gratefullacknowledged. Far from bh lik h i d ilhowever, like a cherised ilon close examination it prcomplex and is indeed oneand difficult problems limof clinical laboratory data

Benson 1972

VALUES

vague but comfortingg gne. It looms on the ness, perfectly symmetricalness, perfectly symmetricalmewhat misty in ly revered andly revered and being pure and simple,ll i f hildh dllusion of childhood,roves to be maddeninglye of the most stubborn

miting the usefulness”

TSH REFERENCE RANGE DERIVSA S ( A S )USA SURVEY (NHANES III)

1 total population ≥ 12 yr1. total population ≥ 12 yr

excluded: people reporting p p p gthyroid disease, goiter, thyroid medication

2. disease-free population

excluded: pregnancy, lithium,excluded: pregnancy, lithium,sex steroids, thyroid antibodies,biochemical hyper/hypothyroidi

3. reference population

Hollowell et al., JCEM 2002

VED FROM A POPULATION-BASED

n TSH mU/ln TSH mU/lmedian P2.5-P97.5

17 353 1 49 0 33 5 8017.353 1.49 0.33-5.80

16.533 1.49 0.44-5.52

ism

13.344 1.39 0.45-4.12

TSH REFERENCE RANGE BYPOPULATION OF THE NHAN

AGE GROUPm

12-19 yr 1.20-29 yr 1.30-39 yr 1.40-49 yr 1.50-59 yr 1.60-69 yr 1.70-79 yr 1.≥80 yr 1.≥ y

Y AGE IN THE REFERENCE NES III SURVEY

TSH mU/lmedian P2.5-P97.5

.35 0.46-4.07

.26 0.40-3.56

.29 0.42-3.69

.40 0.50-3.82

.50 0.52-4.03

.67 0.49-4.33

.76 0.45-5.90

.90 0.33-7.50

POPULATION BASED TSPOPULATION-BASED TS

SKEWED AT THE UPPER END

TSH mU/L

SH REFERENCE VALUESSH REFERENCE VALUES

ND

• no normal distributionof serum TSHof serum TSH

• >95% had TSH <2.5 mU/lin reference populationof NHANES III

COMPONENTS OF VARIANCECOMPONENTS OF VARIANCE

ANALYTE COEFFICIE

ANALYTICAL INTR

T4 4.4

FT4 5.9

T3 8 7T3 8.7

FT3 7.6

TSH 7.5

B iBrowni

OF THYROID FUNCTION TESTSOF THYROID FUNCTION TESTS

ENT OF VARIATION (%)

RA-INDIVIDUAL INTER-INDIVIDUAL

5.1 10.2

9.5 12.1

10 4 20 410.4 20.4

7.9 22.5

16.2 31.7

i t l 1986ing et al. 1986

RELIABILITY OF RE

• Ratio of intra-individual to inter

• Ratio <0 6 population based r• Ratio <0.6 population-based rmeasure in majori

Ratio >1 4 population based rRatio >1.4 population-based r

• Ratio is <0.6 for all thyroid funcRatio for TSH is 0.36 (Nagayam0.50 (Browning 1986)

FERENCE RANGES

r-individual variation

reference range is insensitivereference range is insensitive ity of subjectsreference range works as intendedreference range works as intended

ction tests;ma 1993), 0.49 (Andersen 2002),

NARROW INTRA-INDIVISERUM TSH AND T4 IN 1

ti i t b

Andersen et al.

participant number

IDUAL VARIATIONS IN 16 NORMAL SUBJECTS

ti i t b

JCEM 2002

participant number

LOG-LINEAR RELATIONSHIP B

Spencer et a

BETWEEN SERUM TSH AND FT4

al., JCEM 1990

SUBCLINICAL HYP

PATIENT A

TSH 10 mU/lTSH 10 mU/lFT4 12 pmol/l

no complaints

POTHYROIDISM

PATIENT B

TSH 10 mU/lTSH 10 mU/lFT4 12 pmol/l

complaints,di i T4disappearing on T4 treatment

FT4 WITHIN THE REFEROF ATRIAL FIBRILLATIO

Gammage et al., Arc

RENCE RANGE AS A RISKON IN SUBJECTS >65 YR

ch Int Med 2007

TSH WITHIN THE REFEREOSTEOPOROSIS IN HEALTHY

TSH <0.5 0.5 11 1 1

Kim et al., Cli

1.1 1

ENCE RANGE AS A RISK OF Y POSTMENOPAUSAL WOMEN

1.2 1.6 2.0 2.81 5 1 9 2 7 5 0

n Endocrinol 2006

1.5 1.9 2.7 5.0

ADVERSE OUTCOMES OWITHIN THE REF

Taylor et al. JCEM

OF HIGHER TSH LEVELS FERENCE RANGE

M 2013; 98: 3562

SUBCLINICAL HYPO/

1 Subclinical hypo/hyperthyroid1. Subclinical hypo/hyperthyroid- clinical signs and symptoms- defined by biochemical crite

outside reference range

2 R f h l li2. Reference ranges have clear lim

3. Associated risks also observed

4. Utility of treatment at a particuh i k f (likother risk factors (like age, sex

diabetes)- indication for treatment by riindication for treatment by ri

/HYPERTHYROIDISM

dism is a misnomer:dism is a misnomer:may or may not be present

eria: TSH (but not FT4 or FT3)

it timitations

d for values within reference rangeg

ular TSH level may depend on ki bl d li idx, smoking, blood pressure, lipids,

isk charts?isk charts?

INDICATION FOR STATINABSOLUTE RISK (%) TOABSOLUTE RISK (%) TOHEART DISEASE IN THE

NoSmoking

No Smoking

Yes yesnono

yeson yno

yesyper

tens

i

yesno H

y

yesno

Total –cho

N TREATMENT BASED ONDEVELOP ISCHEMIC DEVELOP ISCHEMIC NEXT 10 YEARS

MALES

SmokingNo

SmokingYes

yr

yr

yr

yr

olesterol/HDL ratio

SUBCLINICAL THYR

1 Definitions and c1. Definitions and c

2. Subclinical hypot- prevalence and- associations

management- management

3. Subclinical hyperyp

ROID DYSFUNCTION

conceptual problemsconceptual problems

thyroidismd natural history

rthyroidismy

PREVALENCE ANDPREVALENCE AND OF SUBCLINICAL H

1. PREVALENCE- 5-10% in the general popu- higher in women than in m

2. NATURAL HISTORY- Cardiovascular Health StuCa d ovascu a ea S u- 35% spontaneous normali

TSH 4.5-6.9 mU/L 46% /TSH 7.0-9.9 mU/L 15%

TSH ≥ 10 mU/L 7%- 56% persistent subclinical56% persistent subclinical- 2% progression to overt

predominantly TSH ≥ 10

Somwaru et al. JCE

NATURAL HISTORYNATURAL HISTORYHYPOTHYROIDISM

ulationmen, increases with advancing age

udy of subjects ≥ 65 yr - after 2 yr:udy o subjec s ≥ 65 y a e y :ization of TSH TPO-Ab negative 48%

b i i TPO-Ab positive 15%

l hypothyroidisml hypothyroidismhypothyroidism

0 mU/L

EM 2012; 97: 1962

POTENTIAL CARDIOPOTENTIAL CARDIOLONG-TERM SUBCLINIC

Biondi et al. BPRC

OVASCULAR RISK OFOVASCULAR RISK OFCAL HYPOTHYROIDISM

CEM 2012; 26: 431

SUBCLINICAL HYPOSUBCLINICAL HYPORISK OF ADVERSE H

1. Adverse health outcomesdi l b t b- cardiovascular, bones, metabo

2. Cross-sectional association stud2. Cross sectional association studLongitudinal association studies

3. Large discrepancies in outcome- absent and present (positive or- many confounders too small s- many confounders, too small s

4. Association may not necessarily- but causal relationship often li

relationship with TSH and bio

5. Progress by pooling studies: m

OTHYROIDISM ANDOTHYROIDISM AND HEALTH OUTCOMES

li t l h ltholism, mental health

dies → prevalence of outcomesdies prevalence of outcomess → incidence of outcomes

es between individual studiesr negative) associations are describedsample sizesample size

y imply causationikely in view of dose-response ologic plausibility

eta-analyses

SUBCLINCAL HYPOTHYISCHEMIC HEART DISE

15 studies with 2531 subclinical hypo

Odds ratioSubclinical hySubclinical hy

Prevalence IHD 1.57 (1.19 – 2.P 0 001P<0.001

Incidence IHD 1.68 (1.27 – 2.P<0.001

Mortality IHD 1 37 (1 04 – 1Mortality IHD 1.37 (1.04 1.P=0.02

Razvi et al. JCEM

YROIDISM AND RISK OFEASE : EFFECT OF AGE

othyroid and 26491 euthroid subjexts

ypo <65 yrOdds ratio Subclinical hypo ≥65 yrypo <65 yr Subclinical hypo ≥65 yr

.06) 1.01 (0.87 – 1.18)NSNS

.23) 1.02 (0.85 – 1.22)NS

79) 0 85 (0 56 – 1 29).79) 0.85 (0.56 1.29)NS

M 2008; 93: 2998

SUBCLINICAL HYPOTHYCORONARY HEART DISEA

individual data analysisfrom 11 cohorts with 542494

Hazard ratioTSH 4.5-6.9 mU/L

Hazard ratTSH 7.0-9.9

CHDevents

1.00 (0.86 – 1.18) 1.17 (0.96 –

CHDmortality

1.09 (0.91 – 1.30) 1.42 (1.03 –

Hazard ratio’s adjusted for age and sex; HR

Rodondi et al. JAM

YROIDISM AND RISK OF ASE (CHD) – ROLE OF TSH

is of 55287 participants 94 person-years of follow-up

tio9 mU/L

Hazard ratioTSH 10-19.9 mU/L

P for trend

– 1.43) 1.89 (1.28 – 2.80) <0.001

– 1.95) 1.58 (1.10 – 2.27) 0.005

R 1.0 (reference) TSH 0.45-4.49 mU/L)

MA 2010; 304: 1365

SUBCLINICAL HYPOTHYCORONARY HEART DISE

individual data analysifrom 6 cohorts with 460333

Hazard ratio TPO-Ab positive

CHD events 1.16 (0.87 – 1.56)

CHD t lit 1 15 (0 87 1 53)CHD mortality 1.15 (0.87 – 1.53)

Ha ard ratio’s adj st for age and se ; HRHazard ratio’s adjust for age and sex; HR

Collet et al. JCEM

YROIDISM AND RISK OFEASE - ROLE OF TPO-Ab

is of 38274 participants 3 person-years of follow-up

Hazard ratio TPO-Ab negative

P-value

1.26 (1.02 – 1.56) NS

1 26 (1 01 1 58) NS1.26 (1.01 – 1.58) NS

R 1 0 (reference) TSH 0 45 4 49 mU/LR 1.0 (reference) TSH 0.45-4.49 mU/L

M 2014; 99: 3353

SUBCLINICAL HYPOTHYHEART FAILURE

individual data analysifrom 6 cohorts with 216248

Hazard ratioTSH 4 5 6 9 mU/l

Hazard ratTSH 7 0 9 9TSH 4.5-6.9 mU/l TSH 7.0-9.9

Heart 1.01 (0.81 – 1.26) 1.65 (0.84 –failure

( ) (

Hazard ratio’s adjusted for age and sex; H

Gencer et al. Circulati

YROIDISM AND RISK OF E – ROLE OF TSH

is of 25390 participants48 person-years of follow-up

tio9 mU/L

Hazard ratioTSH 10 19 9 mU/L

P for trend9 mU/L TSH 10-19.9 mU/L

– 3.23) 1.86 (1.27 – 2.72) <0.01) ( )

HR 1.0 (reference) TSH 0.45- 4.49 mU/L

ion 2012; 126: 1040

EXOGENOUS SUBCLINICEXOGENOUS SUBCLINICAND RISK OF ADVERSE

Population-based study of all patien

C tCategoryNormal TSH 0.4-4.0 mU/L

High TSH > 4.0 mU/L

Flynn et al. JCEM

CAL HYPOTHYROIDISMCAL HYPOTHYROIDISM E HEALTH OUTCOMES

nts taking L-T4 in Tayside, Scotland

P l H d ti (95% CI)Prevalence Hazard ratio (95% CI)61.7% Reference 1.0

11.2% 1.83 (1.41-2.37) fractures1.80 (1.33-2.44) dysrhythmias1.95 (1.73-2.21) cardiovascular

diseases

M 2010; 95: 186

BENEFIT OF T4 TREATMHYPOTHYROIDISM: AHYPOTHYROIDISM: A

● 12 randomized clinical trials com350 subjects, duration 6-14 mon

● no improvement of survival or cp● no improvement of quality-of-l● some improvement of lipids andsome improvement of lipids and

Cochrane Database S

MENT OF SUBCLINICAL A META-ANALYSISA META ANALYSIS

mparing T4 with placebo or nothingnths

cardiovascular morbidityyife or symptomsd left ventricular functiond left ventricular function

Syst Rev 2007

EFFECT OF L-T4 TREATMHYPOTHYROIDISM ON

HEART DISEASE (IHDS S (

GPSub

On

Incunt

young age 40-70 yr

InctreaHa(95

AAg age > 70 yr

MENT OF SUBCLINICAL N INCIDENT ISCHEMIC D) - EFFECT OF AGE) C O G

P reseach database UK 2001-2009bclinical hypo TSH 5-10 mU/L

Young age40-70 yr

Old age>70 yr

n L-T4 52.8% 49.9%

cident IHDtreated

6.6% 10.7%

cident IHDated

4.2% 12.7%

zard ratio 0.61 0.995% CI) (0.39 – 0.95) (0.59 – 1.33)

Ravzi et al Arch Int Med 2012; 172: 811Ravzi et al. Arch Int Med 2012; 172: 811

CUMULATIVE MORTALITY INCUMULATIVE MORTALITY IN

Gussekloo et al. JAMA

N THE LEIDEN 85 PLUS STUDYN THE LEIDEN 85-PLUS STUDY

A 2004; 292: 2591-2599

DIFFERENTIALDIFFERENTIALELEVATED TSH B

THYROID DISEASETHYROID DISEASE- chronic autoimmun

thyroidectomy 13- thyroidectomy, 13- inappropriate dosa

NO THYROID DISE- assay interference - euthyroid sick syn- impaired renal fun- adrenal insufficien

TSH RTH- TSHoma, RTH

DIAGNOSIS OF DIAGNOSIS OF BUT NORMAL FT4

EEne thyroiditis1I therapy1I therapy

age of antithyroid drugs

EASEby heterophilic antibodies

ndrome (recovery phase)nctionncy

TSH ↑TSH ↑

fi TSH ↑ FT4 N 3 6confirm TSH ↑ FT4 N at 3-6 motest also for TPO-Ab and lipids

TSH ≥10 mU/L TSH <10 m

Age ≥70 yr

no symptomsno total/LDL cno risk factorsno pregnancy

NO TREATMENTL-T4

honth

mU/L

Age <70 yr

↑symptoms

↑chol ↑s CVD(desire)

total/LDL chol ↑risk factors CVDpregnancy (desire)

CONSIDER L-T4

SUBCLINICAL THYR

1 Definitions and co1. Definitions and co

2. Subclinical hypoth

3. Subclinical hypertprevalence and- prevalence and

- associations- managementg

ROID DYSFUNCTION

onceptual problemsonceptual problems

hyroidism

thyroidismnatural historynatural history

PREVALENCE ANDPREVALENCE AND OF SUBCLINICAL H

1. PREVALENCE- 0.7 - 3.2% in the general pg p- higher in women than in m

2 NATURAL HISTORY2. NATURAL HISTORY- 24% spontaneous normaliz

TSH 0.1-0.4 mU/L 35% aTSH 0.1 0.4 mU/L 35% aTSH <0.1 mU/L rarely

- 73% persistence of subclin63% at 7 yr

- 3% progression to overt hyTSH 0 1-0 4 mU/L rarelyTSH 0.1 0.4 mU/L rarelyTSH <0.1 mU/L 26% at

multin

Rosario CE 2010; 72: 685; Schouten et al. CE

NATURAL HISTORYNATURAL HISTORYHYPERTHYROIDISM

populationp pmen, increases with advancing age

zation of TSH at 3.5 yrt 7 yrt 7 yr

nical hyperthyroidism at 3.5 yr

ypothyroidism at 3.5 yr0 5-0 7% at 7 yr0.5 0.7% at 7 yrt 5 yr (9% Graves’ disease, 21%

nodular goiter, 61% autonomous nodule)

2011; 74: 257; Vadiveloo JCEM 2011; 96: E1

POTENTIAL CARDIOPOTENTIAL CARDIOLONG-TERM SUBCLINIC

Biondi et al. BPRC

OVASCULAR RISK OFOVASCULAR RISK OFCAL HYPERTHYROIDISM

CEM 2012; 26: 431

SUBCLINICAL HYPSUBCLINICAL HYPAND RISK OF ATRIA

the US Cardiovascular Healt

Cappola et al. JAMA

PERTHYROIDISMPERTHYROIDISMAL FIBRILLATION

lth Study in the 65+ population

A 2006; 295: 1033

SUBCLINICAL HYPAND RISK O

11309 participants from 6 coh

Chaker et al. Eur J Ep

PERTHYROIDISMOF STROKE

hort studies with 665 stroke events

pidemiol 2014; 29: 791

SUBCLINICAL HYPERTHHEART FAILURE

individual data analysifrom 6 cohorts with 216248

Hazard ratioTSH <0 1 mU/lTSH <0.1 mU/l

Heart failure 1.94 (1.01 – 3.72)( )

Hazard ratio’s adjusted for age and sex; H

Gencer et al. Circulati

HYROIDISM AND RISK OF E – ROLE OF TSH

is of 25390 participants48 person-years of follow-up

Hazard ratioTSH 0 1 0 39 mU/L

P for trendTSH 0.1-0.39 mU/L

1.31 (0.88 – 1.95) 0.047( )

HR 1.0 (reference) TSH 0.45- 4.49 mU/L

ion 2012; 126: 1040

SUBCLINICAL HYSUBCLINICAL HYAND RISK OF

50245 participants from 7 cohorts with

Hazard ratio ll bj tall subjects

Hip fractures 1.26 (0.96 – 1.6

Non-spine fractures 1.16 (0.95 – 1.4

Wirth et al. Ann Intern

YPERTHYROIDISMYPERTHYROIDISMF FRACTURES

h 1966 hip and 3281 non-spine fractures

Hazard ratiol i bj t L T4exclusive subjects on L-T4

65) 2.16 (0.87 – 5.37)

42) 1.43 (0.73 – 2.78)

n Med 2014; 161: 189;

EXOGENOUS SUBCLINICAND RISK OF ADVERSE

Population-based study of all patien

Categoryg ySuppressed TSH ≤ 0.03 mU/L

Low TSH 0.04-0.4 mU/L

Normal TSH 0 4 4 0 mU/LNormal TSH 0.4-4.0 mU/L

Flynn et al. JCE

CAL HYPERTHYROIDISM E HEALTH OUTCOMES

nts taking L-T4 in Tayside, Scotland

Prevalence Hazard ratio (95% CI)( )6.1% 2.02 (1.55-2.62) fractures

1.60 (1.10-2.33) dysrhythmias1 37 (1 10-1 60) cardiovascular1.37 (1.10 1.60) cardiovascular

diseases21.1% 1.13 (0.92-1.39) fractures

1 13 (0 88-1 47) dysrhythmias1.13 (0.88-1.47) dysrhythmias1.10 (0.99-1.12) cardiovascular

diseases61 7% Reference 1 061.7% Reference 1.0

EM 2010; 95: 186

DIFFERENTIALDIFFERENTIALDECREASED TSH B

THYROID DISEASETHYROID DISEASE- Graves’ disease

multinodular goite- multinodular goite- autonomous thyroi- chronic lymphocytchronic lymphocyt- excessive dosage o

NO THYROID DISE- pituitary disease- dopaminergic drug

l i id (hi- glucocorticoids (hi

DIAGNOSIS OF DIAGNOSIS OF BUT NORMAL FT4

EE

ererid noduletic thyroiditistic thyroiditisof thyroxine

EASE

gsi h d )igh doses)

TSH < 0.4 FT4 normal

TSH < 0.4 FT4 normal

THYROID DISEASE ABSENT

TS

RISK FACTORS ABSENT

NO TREATMENT CONSIDE

confirm after 3-6 months

THYROID DISEASE PRESENT

TSH < 0.1 SH 0.1 – 0.39

RISK FACTORS PRESENT

RISK FACTORS- age >65 yr- postmenopause- osteoporosis- cardiovascular

risks

ER TREATMENT TREATMENT

SUBCLINICAL HYPO/SUBCLINICAL HYPO/HOW TO END THE

TO TREAT OR NTO TREAT OR N

● Thyroid Studies Collaboration: - individual participant data from

person-years of follow-up from - individual participant data analy

level of nonrandomized evidencelevel of nonrandomized evidence

● Randomized Clinical Trials- Thyoid hormone Replacement f

Subclinical hypothyroidism TriaEuropean Commission funded m- European Commission funded mcontrolled randomized trial amopersistent subclinical hypothyrop yp y

/HYPERTHYROIDISM/HYPERTHYROIDISME CONTROVERSY

NOT TO TREAT?NOT TO TREAT?

55287 participants with 54249411 international prospective cohorts

yses generally considered the highest ee

for Untreated older adults with al = TRUSTmulticenter double blind placebomulticenter, double-blind, placebo-ong 3000 adults age 65 and older withoidism