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 Ingbars 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 Ingbars The Thyroid, 7th ed. 1996:1016.
 Physiological Effects of
Subclinical Hyperthyroidism

heart rate
bone density
risk of atrial fibrillation
serum osteocalcin
cardiac contractility2
urinary hydroxyproline
LV mass index
and pyrrolidine links
intraventricular septal and
posterior wall thickness

1. Ross DS. In: Werner and Ingbars 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 Ingbars 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
Low
Thyrotropin
Incidence 20
(TSH <0.1)
of Atrial
Fibrillation 15
High Slightly Low
(%) Thyrotropin Thyrotropin
10

5 Normal
Thyrotropin
0
0 1 2 3 4 5 6 7 8 9 10
Years
Sawin CT et al. New Engl J Med. 1994;331:1249.
 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 1.6 1.4
1.0

0
TSH mU/L < 0.1 0.1-0.4 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% 2.3%
0%
Controls Subclinical Overt
(n=22,300) Hyperthyroidism Hyperthyroidism
(n=725) (TSH<0.03) (n=613)
Auer et al. Am Heart J. 2001
 Thyroid Function Status and Isovolumetric
Contraction Time (ICT)
80
70

60

50
ICT ,
40 ,
(ms)
30

20
10
0
Overt Overt Subclin Normal Mild Overt Overt
hyper I hyper II hyper euthyroid thyroid hypo II hypo I
failure
P<.0005 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
>5.0
2.1-5.0
60 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 Exogenous
Because low TSH is Careful titration of
often transient, careful L-thyroxine to maintain
monitoring is needed normal TSH

Consider antithyroid Use smallest L-

drug treatment or thyroxine dose needed
radioiodine therapy to meet therapeutic
(depending on etiology) goals

Ross DS. In: Werner and Ingbars 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
Mild
Thyroid Overt
Euthyroid Failure Hypothyroidism

TSH

NORMAL
RANGE

T3
T4

Years

Adapted from Ayala AR, Wartofsky L. The Endocrinologist. 1997;7:44.

 Subclinical Hypothyroidism
Prevalence - Women

Whickham (n=2,779)
25%
Colorado (n=25,862)
20% 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 Ingbars 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

OBrien T et al. Mayo Clin Proc. 1993;68:860.

 LDL-C Levels Increase With
Increasing Hypothyroidism Grade
250 246
235 **
220
205 191
(mg/dL)
LDL-C

190 *
175 168
160
144 133 137
145
130
Hypothyroidism Grade C 1 2 3 4* 5
overt

Basal TSH (mU/L) 1.1 3.0 8.6 22.7 44.4 63.7

C=controls.
*P<.01 vs controls. P<.001 vs controls.
Staub JJ et al. Am J Med. 1992;92:631.
 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 (No subgroup
Reduction 5 with TSH < 12)
(mg/dl)
-7.9 mg/dl
10
-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) Group 3 (N=7)
TC*
400
TC*
350 TC* LDL-C* Before
300 LDL-C* After
250 LDL-C*
200
150
100
50
0
TSH before: 7.0 TSH before: 18.6 mU/LTSH before: 154.9
mU/L TSH after: 1.5 mU/LmU/L
TSH after: 1.9 TSH after: 1.8 mU/L
mU/L
*=mg/dL. 1Values are means SD.
Diekman T et al. Arch Intern Med. 1995;155:1490.
 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 Decreased
diastolic pressure, myocardial contractility,
peripheral vascular resistance myocardial oxygen demand,
cardiac output

Klein I, Ojamaa K. In: Werner and Ingbars 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 3 4
Odds Ratio

*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 Ingbars 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 Heart Disease2 Postmenopausal

Special
Pregnant/postpartum2 Patient Psychiatric Illness3
Populations

Use of Certain Drugs2 Chronic Illness

1. Singer PA et al. JAMA. 1995;273:808.

2. Brent GA, Larsen PR. In: Werner and Ingbars 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 Speaksthe
Heart Listens
MA Sussman
Circ. Res 2001