Post on 13-Dec-2015
What’s New in Subclinical Thyroid Disease
Mary H. Samuels, M.D.
Oregon Health & Sciences University
“Subclinical” Thyroid Disease
Subclinical Hypothyroidism:
• Elevated TSH
• Normal fT4, fT3
• 4% of population
• Increases to 20% of older population
• More common in women
Subclinical Hyperthyroidism:
• Low to suppressed TSH
• Normal fT4, fT3
• 0.7% of population
• Does not increase with aging
• More common in women
Hypo-Thyroid
Hyperthyroidid
Relationship Between TSH and Free T4 Levels
1,000
TSH ReferenceRange
Spencer ‘90
Undetectable TSH
100x
0.7 1.8
FT4 Reference
Range
~2x
10
100
4.0
0.1
0.4
0.01
TS
H (
mL
U/L
)
Elevated TSH
fT4 (ng/dL)
Mild(Subclinical)
Overt(Clinical)
DevelopingHypothyroidism
DevelopingHyperthyroidism
TSH
FT4FT3
NormalizedReference
Ranges
Mild(Subclinical)
Overt(Clinical)
TSH
FT4 FT3
Months / Years
Mild(Subclinical)
Overt(Clinical)
DevelopingHypothyroidism
DevelopingHyperthyroidism
TSH
FT4FT3
NormalizedReference
Ranges
Mild(Subclinical)
Overt(Clinical)
TSH
FT4 FT3
Months / Years
The Spectrum of Subclinical Thyroid Disease
Subclinical Hypothyroidism
“Euthyroid” Subjects
Subclinical Hyperthyroidism
The Spectrum of Subclinical Thyroid Disease
Subclinical Hypothyroidism
“Euthyroid” Subjects
Subclinical Hyperthyroidism
Subclinical Hypothyroidism - Prevalence -
0
5
10
15
20
25
20 30 40 50 60 70 80+
Age
% e
leva
ted
TSH Wickham - F
Wickham - MColorado - FColorado - MNHANES III
Mostly due to autoimmune thyroid disease
Case Report
HPI: A 45 year old woman complains of fatigue, poor memory.
PE: Unremarkable
Labs: TSH = 8.2 mU/Lfree T4 = 1.1 ng/dL
Is her subclinical hypothyroidism related to her complaints?
Possible Effects of Subclinical Hypothyroidism
• Progression to overt hypothyroidism• Effects on symptoms and quality of life• Effects on lipid levels• Effects on the cardiovascular system• Effects on mood and cognition• Effects on metabolism
Possible Effects of Subclinical Hypothyroidism
• Progression to overt hypothyroidism• Effects on symptoms and quality of life• Effects on lipid levels• Effects on the cardiovascular system• Effects on mood and cognition• Effects on metabolism
Incidence of Overt HypothyroidismThe 20-year Wickham Survey Follow-up
3
17 17
55
44
83
0
20
40
60
80
100
% h
ypo
thyr
oid
TSH = 2 TSH = 5 TSH = 10
Ab neg Ab pos
Vanderpump ‘03
Courtesy of M. McDermott
Spontaneous subclinical hypothyroidism in patients older than 55 years
0
10
20
30
40
50
60
TSH 5-9.9
TSH 10-14.9
TSH 15-19.9
Rate of TSH normalizationas a function of baseline TSH
%
Diez ‘04
Possible Effects of Subclinical Hypothyroidism
• Progression to overt hypothyroidism• Effects on symptoms and quality of life• Effects on lipid levels• Effects on the cardiovascular system• Effects on mood and cognition• Effects on metabolism
Symptoms and Quality of Life in Subclinical Hypothyroidism
• Cross sectional studies are inconsistent, including two large, community-based studies (Bell ’07, Razvi ’05)
• Six placebo-controlled L-T4 treatment studies tended to be negative– Outcomes included validated symptom
scores and generic QoL measures
Possible Effects of Subclinical Hypothyroidism
• Progression to overt hypothyroidism• Effects on symptoms and quality of life• Effects on lipid levels• Effects on the cardiovascular system• Effects on mood and cognition• Effects on metabolism
Lipid Levels in Subjects with Subclinical Hypothyroidism
• Cross-sectional and treatment studies are inconsistent
• Meta-analysis of 13 treatment studies to 2000 (Danese ’00)
• Since 2000, 8 placebo-controlled randomized L-T4 treatment studies: 4 showed effect, 4 showed no effect
Danese ‘00
Correlation between initial cholesterol and change in cholesterol with treatment of SCHypo (Danese ‘00)
Treatment of subclinical hypothyroidism more likely to reduce cholesterol levels if initial cholesterol is high
Possible Effects of Subclinical Hypothyroidism
• Progression to overt hypothyroidism• Effects on symptoms and quality of life• Effects on lipid levels• Effects on the cardiovascular system• Effects on mood and cognition• Effects on metabolism
Effects of Subclinical Hypothyroidism on the Cardiovascular System
• Consistent decrements in LV systolic and diastolic function, even at minimal TSH elevations
• Impaired cardiac performance with exercise• Increased SVR, impaired endothelium-dependent
vasodilation• One study showed increased risk of CHF (Rodondi
‘05)
• LV function improved in all studies (only 4 were double-blind, placebo-controlled)
Cross-sectional studies:
L-T4 treatment studies:
Subclinical Hypothyroidism and Cardiovascular Disease
Prevalent CVD Incident CVD Mortality
Overall RR Razvi ’08 Ochs ‘08
1.23* 1.271.20
1.091.18
• Two recent large meta-analyses of 8-10 studies of the relationship between subclinical hypothyroidism and cardiovascular disease
• Effects not large, confidence intervals overlap 1.0
Subclinical Hypothyroidism and Coronary Heart Disease
Prevalent CVD Incident CVD Mortality
Overall Razvi ’08 Ochs ‘08
1.23* 1.271.20
1.091.18
< age 65 Razvi ‘08 Ochs ‘08
1.57* 1.68*1.51*
1.37*1.50*
< age 65 Razvi ’08 Ochs ‘08
1.01 1.021.20
0.851.12
Does Subclinical Hypothyroidism Protect the “Oldest Old?”
Low TSH
Normal TSH
SCHypo
Overt Hypo
558 subjects, aged 85 years at entry, followed for 4 years
Gussekloo ‘04
Hypothesis:
CV risk of subclinical hypothyroidism depends on age (Biondi and Cooper ’08):
Possible Effects of Subclinical Hypothyroidism
• Progression to overt hypothyroidism• Effects on symptoms and quality of life• Effects on lipid levels• Effects on the cardiovascular system• Effects on mood and cognition• Effects on metabolism
Mood and Cognition in Subclinical Hypothyroidism
• Some cross-sectional studies suggest decrements in mood (depression, anxiety), while others do not
• 2 randomized, placebo-controlled, blinded L-T4 treatment studies showed no improvement in depression or psychological distress scores (Kong ’02, Jorde ’06)
Mood: Cognition:
• Numerous cross-sectional and L-T4 treatment studies of cognition in SCHypo, but methods limited and results variable– Memory most
commonly affected– Executive function
poorly studied
fMRI of Working Memory in Subclinical Hypothyroidism
• 11 SCHypo subjects vs. 12 euthyroid controls– TSH = 14.7 vs. 1.7 mU/L
• N-Back test (working memory/executive function)
• fMRI with BOLD• 6 SCHypo subjects
restudied 6 mo after L-T4– TSH = 1.4
Zhu ‘06
fMRI of Working Memory in Subclinical Hypothyroidism
Zhu ‘06
• N-Back activated frontoparietal network in all subjects
• SCHypo subjects had fewer frontoparietal areas of BOLD response (executive function areas)
• Normalized after 6 mo of L-T4
Subclinical Hypothyroidism and Dementia
Baseline TSH levels vs. risk of developing Alzheimer’s Disease during mean follow-up of 13 years (Framingham study, Tan ’08)
Women Men
TSH 0-1.0
TSH 2-50
Possible Effects of Subclinical Hypothyroidism
• Progression to overt hypothyroidism• Effects on symptoms and quality of life• Effects on lipid levels• Effects on the cardiovascular system• Effects on mood and cognition• Effects on metabolism
Metabolic Effects of Subclinical Hypothyroidism
• In healthy humans, thyroid function plays a major role in energy homeostasis– Thyroid hormone levels directly correlate with resting
energy expenditure (REE)
– T3 levels account for 20-25% of variation in REE
• Small changes in thyroid hormone levels lead to large changes in energy metabolism (Al-Adsani ‘97)– REE decreases 17% when TSH increases from 0.1 to
10 mU/L
Case Report – Subclinical Hypothyroid Patient
•Progression: 50% chance of overt hypothyroidism over 20 years, but recheck TSH first
•Symptoms: Fatigue may improve with L-T4
•Lipids: Chol/LDL may improve with L-T4, especially if elevated at baseline
•Heart: Mildly impaired, will improve with L-T4, but ? clinical significance
•Mood/cognition: May improve, ? clinical significance
•Metabolism: May improve, ? clinical significance
The Spectrum of Subclinical Thyroid Disease
Subclinical Hypothyroidism
“Euthyroid” Subjects
Subclinical Hyperthyroidism
Case Report
The 45 year old woman with a TSH of 8.2 mU/L starts taking L-T4. Three months later her memory is slightly better, but she still complains of fatigue.
Her TSH is now 3.9 mU/L.
Now do her symptoms have anything to do with her thyroid?
0
20
40
60
80
100
TypicalTSH Reference Range
Subclinical Hypothyroidism
TSH mIU/L
0.1 0.4 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5 10 >20
SubclinicalHyperthyroid
NHANES III - Population with no Pre-diagnosed Thyroid Disease
% TPOAb(±TgAb)
85.296.5
32.5
*
5.7 5.5 5.8 8.313.5 14.4
18.1
30.6
** * *
*28.0
30.9
54.6
Courtesy of C. Spencer
The True “Normal” TSH Range• The “normal” TSH range is skewed at the upper range, possibly
by subjects with early autoimmune thyroid disease• In reference subjects ages 20-29 years, the normal TSH range is
0.40 – 3.56 mU/L (NHANES III, Hollowell ’02)• If TSH levels are normalized to a Gaussian distribution, the
normal range is 0.40 – 2.5 mU/L• If this normal TSH range is adapted, 17% of the U.S. population
(51 million people) will have “low-normal” thyroid function
# of Subjects
0.28 2.5 3.5 5.0
TSH (mU/L)
Theoretical (Gaussian) upper normal curve
Actual upper normal curve
Anti-TPO positive subjects removed
The True “Normal” TSH Range
• Hypothesis: The upper normal TSH range is skewed because it includes subjects with occult thyroid disease, even without anti-thyroid antibodies (Spencer ’07)
• Alternative hypothesis: Upper normal TSH range is skewed because normal TSH levels increase with healthy aging (Surks ’07)
• Clinical correlations are sparse for these TSH levels
Disease free
Reference
NHANES III data
Possible Effects of Variations in Thyroid Function within the “Normal” TSH Range
• Progression to overt hypothyroidism– Increases as TSH increases within normal range
• Effects on symptoms and quality of life– No consistent effects
• Effects on lipid levels– Direct correlations between TH levels and lipids, improvements when lower TSH within the normal range
• Effects on the cardiovascular system– Studies inconsistent (? High-normal TSH protective in “oldest-old”)
• Effects on bone– Inverse correlations between TH levels and BMD
• Effects on mood and cognition– No consistent effects
• Effects on metabolism– Strong correlation between TH and REE within normal range
The Spectrum of Subclinical Thyroid Disease
Subclinical Hypothyroidism
“Euthyroid” Subjects
Subclinical Hyperthyroidism
Prevalence of Subclinical Hyperthyroidism
Weighted sample of U.S. population 12 years or older
“Total” pop = 17,353
“Disease free” = Excluding subjects with thyroid disease
“Reference” = Disease free excluding pregnant, on certain meds, with overt thyroid disease, or with anti-thyroid antibodies
NHANES III Hollowell ‘02
Case Report
The 45 year old woman with a TSH of 3.9 mU/L has her L-T4 dose increased. She returns to clinic three months later. She states that she feels “great.” Her TSH is now 0.2 mU/L.
Do her improved symptoms have anything to do with her thyroid now?
Possible Effects of Subclinical Hyperthyroidism
• Progression to overt hyperthyroidism• Effects on symptoms and quality of life• Effects on the cardiovascular system• Effects on bone• Effects on mood and cognition• Effects on metabolism
Possible Effects of Subclinical Hyperthyroidism
• Progression to overt hyperthyroidism• Effects on symptoms and quality of life• Effects on the cardiovascular system• Effects on bone• Effects on mood and cognition• Effects on metabolism
Progression of Subclinical Hyperthyroidism
• Progression rates to overt hyperthyroidism 1-5% per year
• Depend on cause of hyperthyroidism, initial TSH (more common with undetectable vs. low TSH levels)
• Also high normalization rates
Possible Effects of Subclinical Hyperthyroidism
• Progression to overt hyperthyroidism• Effects on symptoms and quality of life• Effects on the cardiovascular system• Effects on bone• Effects on mood and cognition• Effects on metabolism
Symptoms and Quality of Life in Subclinical Hyperthyroidism
• A number of studies suggest increased hyperthyroid symptoms, decreased QoL in subclinical hyperthyroidism
• A few studies suggest that lowering the L-T4 dose (in exogenous subclinical hyperthyroidism) or ATD (in endogenous subclinical hyperthyroidism) may improve QoL– Extremely small sample sizes
Possible Effects of Subclinical Hyperthyroidism
• Progression to overt hyperthyroidism• Effects on symptoms and quality of life• Effects on the cardiovascular system• Effects on bone• Effects on mood and cognition• Effects on metabolism
Effects of Subclinical Hyperthyroidism on the Cardiovascular System
• Consistent deleterious effects on heart rate, exercise capacity, LV mass, bp, diastolic function, risk of atrial fibrillation– Unclear what TSH cut-off increases risk
• Lowering L-T4 dose or adding beta blockers in exogenous subclinical hyperthyroidism probably reverses effects
• Only 2 extremely small studies of treating endogenous subclinical hyperthyroidism: both reported improved HR and cardiac function
Cross-sectional studies:
L-T4 treatment studies:
Subclinical Hyperthyroidism and Coronary Heart Disease
• Recent meta-analysis of 5 large population-based studies showed no increased risk of CVD or mortality with subclinical hyperthyroidism (Ochs ‘08), no differential effect of age
Possible Effects of Subclinical Hyperthyroidism
• Progression to overt hyperthyroidism• Effects on symptoms and quality of life• Effects on the cardiovascular system• Effects on bone• Effects on mood and cognition• Effects on metabolism
Effects of Subclinical Hyperthyroidism on Bone
• TSH suppression from L-T4 therapy probably does not affect men or pre-menopausal women, may affect post-menopausal women
• Similar effects of endogenous subclinical hyperthyroidism, but few studies
Effects of Subclinical Hyperthyroidism on Bone-The SOF Study-
• Case-control study of Caucasian women > 65 years old followed for up to 6 years for fractures
• Increased risk of hip fracture if baseline TSH undetectable; increased risk of vertebral fracture if TSH low or undetectable Bauer ‘01
**
*
Possible Effects of Subclinical Hyperthyroidism
• Progression to overt hyperthyroidism• Effects on symptoms and quality of life• Effects on the cardiovascular system• Effects on bone• Effects on mood and cognition• Effects on metabolism
Neurocognition in Subclinical Hyperthyroidism
• Mood: increased rates of depression, anxiety, hostility, irritability in some cross-sectional studies, but variable
• However, patients on L-T4 may report increased well-being when their TSH levels are suppressed (Carr ’88)
• Cognition: Very few studies
• Positive findings in attention/concentration, memory, executive function
Subclinical Hyperthyroidism and Dementia
Baseline TSH levels vs. risk of developing Alzheimer’s Disease during mean follow-up of 13 years (Framingham study, Tan ’08)
Women Men
TSH 0-1.0
TSH 2-50
Possible Effects of Subclinical Hyperthyroidism
• Progression to overt hyperthyroidism• Effects on symptoms and quality of life• Effects on the cardiovascular system• Effects on bone• Effects on mood and cognition• Effects on metabolism
– REE increases 17% when TSH lowered from 10 to 0.1 mU/L (Al-Adsani ’97)
Case Report – Subclinical Hyperthyroid Patient
•Progression: Not relevant
•Symptoms: Suggestion of adverse effects
•Heart: Probably not a good idea
•Bone: Probably not a good idea
•Mood/cognition: ?
•Metabolism: ?
Subclinical Thyroid Disease- Some Practical Recommendations -
• Treat patients who have TSH levels greater than 10 mU/L with low doses of L-T4.– Data for symptoms, QoL, lipid levels, cardiovascular
disease, (mood, cognition)– May not apply to elderly patients (? normal TSH range)
• Aim for a mid-normal TSH level (0.5 – 2.5 mU/L).– (Emerging data on effects of variation in normal thyroid
function)• Don’t give in to the temptation to increase L-T4
doses if the TSH is already mid-normal.– Data for adverse effects on heart, bone