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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