Impact of “Mild-Subclinical” Thyroid
Disease on
Cardiovascular Health
Harry L. Uy, MD
UP College of Medicine Class 1986
Private Practice, Endocrinology
Clinical Associate Professor UTHSC-San Antonio
Should mild thyroid
dysfunction be treated? Is there
any clinical consequence if this
is left untreated?
Subclinical Hyperthyroidism
Definition
• Normal T4, FT4, TT3, FT3
• TSH = Low
– Not necessarily below the limit of detection
• Some patients have symptoms of
“mild hyperthyroidism” – more often than
not, this remains unrecognized
Subclinical Hyperthyroidism
Small Increase in Free T4 = Large Decrease in TSH
Free T4
TSH
Normal Range Change
Normal Range Change
1.8 ng/dl
4.5 mU/L
0.8 ng/dl
0.45 mU/L
Subclinical Hyperthyroidism:
Definition and Prevalence
• Usually asymptomatic1
• Low or undetectable serum TSH1
• Normal or borderline serum FT4 and FT31
• Variable prevalence (0.7% to 6.0%)2
• More common in women3
• More common in older people than overt
hyperthyroidism4
• Most common cause is overtreatment with
L-thyroxine
1. Ross DS. Mayo Clin Proc. 1988;63:1223. 2. Ross DS. In: Werner and Ingbar’s The Thyroid, 7th ed.
1996:1016.
3. Sawin CT. Adv Intern Med. 1991;37:223. 4. Sawin CT et al. N Engl J Med. 1994;331:1249.
Common Causes of Subclinical
Hyperthyroidism
Exogenous
• Excessive thyroid hormone
replacement
• Thyroid hormone suppressive therapy
Endogenous
• Thyroid gland autonomy: thyroid
adenoma or multinodular goiter
• Graves’ disease
Ross DS. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:1016.
Physiological Effects of
Subclinical Hyperthyroidism
bone density
serum osteocalcin
urinary hydroxyproline
and pyrrolidine links
heart rate
risk of atrial fibrillation
cardiac contractility2
LV mass index
intraventricular septal and
posterior wall thickness
1. Ross DS. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:1016.
2. Biondi B et al. J Clin Endocrinol. 1993;77:334.
Other Biological Effects of
Subclinical Hyperthyroidism
Total and LDL cholesterol
Liver enzymes
Creatine kinase
Sex hormone binding globulin
Time asleep at night
Mood (using multidimensional
scale for state of well-being)
Ross DS. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:1016
Hyperthyroidism
Risk of Atrial Fibrillation or Flutter
A Population-Based Study
Frost, L. et al. Arch Intern Med 2004;164:1675-1678
.
Hyperthyroidism
Risk of Atrial Fibrillation or Flutter
A Population-Based Study
Frost, L. et al. Arch Intern Med 2004;164:1675-1678
.
Subclinical Hyperthyroidism
Atrial Fibrillation
30
Serum Thyrotropin Values at Baseline
25
Incidence
of Atrial
Fibrillation
(%)
Low
Thyrotropin
(TSH <0.1)
20
15
High
Thyrotropin
10
Slightly Low
Thyrotropin
Normal
Thyrotropin
5
0
0
1
2
3
4
5
Years
Sawin CT et al. New Engl J Med. 1994;331:1249.
6
7
8
9
10
Subclinical Hyperthyroidism
Risk of Atrial Fibrillation
2007 subjects > 60 yo (1193 women, 814 men)
TSH measured; 10 year follow-up
4
3.1*
Relative
Risk
2
0
TSH mU/L < 0.1
1.6
0.1-0.4
1.0
1.4
0.4-5.0
> 5.0
Sawin CT, NEJM 331: 1249, 1994
Subclinical Hyperthyroidism
Atrial Fibrillation
Mean age (66-68), prevalence of underlying CV disease (57-65%)
similar in all 3 groups
*P<0.01
16%
14%
*
12%
13.8%
10%
*
12.7%
8%
6%
4%
2%
0%
2.3%
Controls
(n=22,300)
Subclinical
Hyperthyroidism
(n=725) (TSH<0.03)
Overt
Hyperthyroidism
(n=613)
Auer et al. Am Heart J. 2001
Thyroid Function Status and Isovolumetric
Contraction Time (ICT)
80
70
‡
60
ICT
(ms)
40
30
0
P<.0005
§
50
20
10
º
,†
†,‡

Overt
Overt Subclin Normal Mild
Overt
hyper I hyper II hyper euthyroid thyroid hypo II
failure
Overt
hypo I
vs normal euthyroid; †P<.0005 vs overt hyper I; ‡P<.05 vs euthyroid
controls;
§P<.05 vs overt hypo I; •
P<.005 vs normal euthyroid.
Tseng KH et al. J Clin Endocrinol Metab. 1989;69:633.
Survival vs Thyroid Function
•
•
•
•
•
1191 subjects in Birmingham, UK
Enrollment 1988-89, Analyzed 1999
> 60 y/o, Mean age 70 y/o
509 died during the 10 yrs
Exclusions: Thyroid Hormone or ATD
Parle J et al Lancet 358:861,2001
Survival vs Serum TSH
Age > 60 yrs
100
80
TSH
60
>5.0
2.1-5.0
1.3-2.0
0.5-1.2
<0.5
45
Cardiovascular events were responsible for the excess mortality
No difference between TSH < 0.1 and TSH 0.1-0.5 mU/L
Parle J et al Lancet 358:861,2001
Subclinical Hyperthyroidism
Concerns
n
Osteoporosis
n
Atrial fibrillation
n
Cardiac dysfunction
n
Progression to overt disease
Prevention and Treatment of
Subclinical Hyperthyroidism
Endogenous
• Because low TSH is
often transient, careful
monitoring is needed
Exogenous
• Careful titration of
L-thyroxine to maintain
normal TSH
• Consider antithyroid
drug treatment or
radioiodine therapy
(depending on etiology)
• Use smallest Lthyroxine dose needed
to meet therapeutic
goals
Ross DS. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:1016.
Subclinical Hypothyroidism
Definition
• Elevated TSH (80-85% < 10 mU/L)
• Normal Free T4
• + Anti-TPO antibodies in 60-80%
• “Mild hypothyroidism”
• “Mild thyroid failure”
Subclinical Hypothyroidism
Small Decrease in Free T4 = Large Increase in TSH
Free T4
TSH
Normal Range Change
Normal Range Change
1.8 ng/dl
4.5 mU/L
0.8 ng/dl
0.45 mU/L
Progression of Mild Thyroid Failure
Euthyroid
Mild
Thyroid
Failure
Overt
Hypothyroidism
TSH
NORMAL
RANGE
T3
T4
Years
Adapted from Ayala AR, Wartofsky L. The Endocrinologist. 1997;7:44.
Subclinical Hypothyroidism
Prevalence - Women
25%
20%
Whickham (n=2,779)
Colorado (n=25,862)
NHANES (n=17,353)
15%
10%
5%
0%
Age
~ 30 yr.
~ 50 yr.
~ 80 yr.
Tunbridge W, Clin Endo 7:481, 1977
Canaris G, Arch Intern Med 160:526, 2000
Hollowell J, J Clin Endo Metab 87: 489, 2002
Diagnosing Mild Thyroid Failure:
The Challenge
• Insidious onset
• Patients often have few specific clinical
symptoms or signs
• Symptoms are ordinary and nonspecific
• Specific age- and gender-related presentations
Ladenson PW. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:878.
Subclinical Hypothyroidism
Issues
n
Lipid elevation
n
CAD risk factor
n
Cardiac function
n
Progression to overt disease
Why Treat Patients With
Mild Thyroid Failure With L-Thyroxine?
• Prevent progression to overt hypothyroidism1
• Alleviate symptoms1,2
• Normalize serum lipids1,3
• Normalize cardiac function2,4
• May help depression5
1. Ayala AR, Wartofsky L. The Endocrinologist. 1997;7:44.
2. Cooper DS et al. Ann Intern Med. 1984;101:18.
3. Kinlaw WB. Thyroid Today. 1991;14:1.
4. Nystrom E et al. Clin Endocrinol. 1988;29:63.
5. Hennessey JU, Jackson IMD. The Endocrinologist. 1996;18:214.
Types of Lipid Abnormalities in
Patients With Hypothyroidism
8.6%
56.3%
Hypercholesterolemia
(>200 mg/dL)
Hypertriglyceridemia
(>150 mg/dL)
33.6%
Hypercholesterolemia and
mild hypertriglyceridemia
Normal Lipids
1.5%
N = 268
O’Brien T et al. Mayo Clin Proc. 1993;68:860.
LDL-C Levels Increase With
Increasing Hypothyroidism Grade
246
LDL-C
(mg/dL)
250
235
220
205
190
175
160
145
130
Hypothyroidism Grade
**
191
*
168
144
133
137
C
1
2
3
4*
5†
overt
Basal TSH (mU/L)
1.1
3.0
C=controls.
*P<.01 vs controls. †P<.001 vs controls.
Staub JJ et al. Am J Med. 1992;92:631.
8.6
22.7
44.4
63.7
Subclinical Hypothyroidism
Lipid Changes with LT4 Therapy
Meta-analysis: 13 Studies 247 patients
Mean TSH 4.8-19.0 mU/L
Total
LDL
Cholesterol Cholesterol
0
Cholesterol
Reduction 5
(mg/dl)
10
(No subgroup
with TSH < 12)
-7.9 mg/dl
-10.3 mg/dl
Danese M, J Clin Endo Metab 85:2993, 2000
Effect of L-Thyroxine Treatment on
Lipid Levels in Dyslipidemia1
450
Group 1 (N=6)
Group 2 (N=6)
400
350
TC*
TC*
LDL-C*
TC*
300
250
Group 3 (N=7)
LDL-C*
LDL-C*
200
150
100
50
0
TSH before: 7.0
mU/L
TSH after: 1.9
mU/L
TSH before: 18.6 mU/LTSH before: 154.9
TSH after:
1.5 mU/LmU/L
TSH after: 1.8 mU/L
*=mg/dL. 1Values are means ±SD.
Diekman T et al. Arch Intern Med. 1995;155:1490.
Before
After
Effect of L-Thyroxine Therapy on
Hypercholesterolemia in Patients With Mild
Thyroid Failure
“The decrease in total cholesterol achieved
with L-thyroxine replacement] substitution
therapy in patients with subclinical
hypothyroidism [mild thyroid failure] may be
considered as an important decrease in
cardiovascular risk favoring treatment.”
Tanis BC et al. Clin Endocrinol. 1996;44:643.
Cardiovascular Changes Often
Associated With Hypothyroidism
Apparent
cardiomegaly
ECG changes
Hypothyroidism
Increased
diastolic pressure,
peripheral vascular resistance
Decreased
myocardial contractility,
myocardial oxygen demand,
cardiac output
Klein I, Ojamaa K. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:799.
Subclinical Hypothyroidism
Issues
n
Lipid elevation
n
CAD risk factor
n
Cardiac function
n
Progression to overt disease
Subclinical Hypothyroidism and Atherosclerosis
The Rotterdam Study
Random Sample: 1149 Females (age: 69 +/- 7.5 yr)
TSH Elevated: 10.8% (> 4 mU/L)
End Points: Aortic Atherosclerosis (Aortic Calcification)
Myocardial Infarction ( EKG)
Methods: Cross-sectional
Hak AE,l Ann Int Med 132:270, 2000
Subclinical Hypothyroidism and Atherosclerosis
The Rotterdam Study
Myocardial
Infarction
High TSH + TAB
High TSH
Euthyroid
Aortic
Calcification
0
1
2
Odds Ratio
3
4
*Adjusted for age, BP, BMI, smoking, lipids
Hak AE,l Ann Int Med 132:270, 2000
When to Suspect Mild Thyroid Failure
• Hypercholesterolemia1,2
• Refractory depression2
• Previous episode of postpartum thyroiditis2
• Goiter1
• Family or personal history of thyroid disease1
• Over 40 with nonspecific complaints2
• Insidious weight change
• Unexplained infertility2
• Overweight
1. Ayala AR, Wartofsky L. The Endocrinologist. 1997;44:401.
2. Weetman, AP. British Journal Med. 1997;314:1175.
Hypothyroidism:
Many Causes, One Treatment
• Goal: normalize TSH level regardless of cause
of hypothyroidism1
• Treatment: once daily dosing with L-thyroxine
(1.6  g/kg/day)2
• Monitor TSH levels at 6 to 8 weeks, after
initiation of therapy or dosage change3
• If lipids are elevated, recheck when euthyroid
1. Brent GA, Larsen PR. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:883.
2. AACE. Endocrine Pract. 1995;1:56.
3. Singer PA et al. JAMA. 1995;273:808.
Management of Hypothyroidism: Special
Patient Populations
Age >50 years1
Pregnant/postpartum2
Heart Disease2
Special
Patient
Populations
Use of Certain Drugs2
Postmenopausal
Psychiatric Illness3
Chronic Illness
1. Singer PA et al. JAMA. 1995;273:808.
2. Brent GA, Larsen PR. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:883.
3. Whybrow PC. AMA. 1994;21:47.
Over- and Under-Replacement Risks
Over-Replacement Risks
• Reduced bone density/osteoporosis1
• Tachycardia, arrhythmia,2 atrial fibrillation
• In elderly or patients with heart disease, angina,
arrhythmia, or myocardial infarction2
Under-Replacement Risks
• Continued hypothyroid state
• Long-term end-organ effects of hypothyroidism
• Increased risk of hyperlipidemia
1. Stall GM et al. Ann Intern Med. 1990;113:265.
2. Ridgway EC. Family Practice Recertification. 1992;14:127.
Consensus Statement
Subclinical Hypothyroidism
• Treatment reasonable for patients with TSH levels >10
mU/liter
• Treatment should be considered with TSH levels of 4.5-10
mU/liter with key determinant being the clinical
judgment of the provider
Subclinical Hyperthyroidism
• Treatment recommended with TSH <0.1 mU/liter even if
asymptomatic and with room to observe and monitor in
patients with partial TSH suppression (0.1-0.4 mU/liter)
Consensus Statement: Subclinical Thyroid Dysfunction: - A Joint Statement – AACE, ATA,
Endocrine Society. Gharib H. et al. JCEM 90:581-585.
Subclinical Thyroid Disease
and the Heart
“When the Thyroid Speaks…the
Heart Listens”
MA Sussman
Circ. Res 2001