Thyroid Disease on Cardiovascular Health
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Transcript Thyroid Disease on Cardiovascular Health
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