Cardiovascular Disease Risk and Mild Thyroid Failure
Sponsored by
ACCESS Medical Group
Department of Continuing Medical Education
Funded by an unrestricted educational grant from Abbott Laboratories.
Introduction to Mild Thyroid Failure
Definition of Mild Thyroid Failure
• Elevated thyroid stimulating hormone ([TSH]; >4.0 IU/mL)
• Normal total or free serum T4 and T3 levels
• Few or no signs or symptoms of hypothyroidism
McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590.
Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
Causes of Mild Thyroid FailureExogenous and Endogenous Factors
• Exogenous factors– Levothyroxine underreplacement– Medications containing lithium, cytokines, or iodine– Antithyroid medications– Iodine131 therapy or thyroidectomy
• Endogenous factors– Hashimoto thyroiditis– Previous subacute or silent thyroiditis
Biondi B, et al. Ann Intern Med. 2002;137:904-914.
Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins.
Causes of Mild Thyroid FailureHashimoto Thyroiditis
• Hashimoto thyroiditis– Causes an autoimmune reaction that destroys
thyroid proteins– Results in hypothyroidism– Symptoms include tiredness, forgetfulness, or
depression
Surks MI. The Thyroid Book: What Goes Wrong and How to Treat It. Yonkers, NY: Consumer Reports Books; 1993.
Prevalence and Incidence of Mild Thyroid Failure
• Prevalence– 4% to 10% in large population screening surveys– 7% to 26% in studies of the elderly– Higher in women than men
• Incidence– 2.1% to 3.8% per year in thyroid antibody–positive
patients– 0.3% per year in thyroid antibody–negative patients
McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590. Caraccio N, et al. J Clin Endocrinol Metab. 2002;87:1533-1538.
Biondi B, et al. Ann Intern Med. 2002;137:904-914.
NHANES IIIPatient Populations and Mean TSH Levels
01234567
Pat
ient
s, %
All White African American
MexicanAmerican
Patient Populations
Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499.
Serum TSH Levels >4.5 mIU/L Serum TSH Levels <0.4 mIU/L
Male FemaleMale Female
0
1
2
3
4
5
6
Pat
ient
s, %
Patient Populations
All WhiteAfrican
AmericanMexicanAmerican
Populations at Risk for Mild Thyroid Failure
• Women• Elderly• Family history of
– Thyroid disease– Pernicious anemia– Type 1 diabetes mellitus– Rheumatoid arthritis– Lupus
Caraccio N, et al. J Clin Endocrinol Metab. 2002;87:1533-1538.
Carmel R, et al. Arch Intern Med. 1982;142:1465-1469.
Perros P, et al. Diabetes Med. 1995;12:622-627.
University of California Davis Health System Web site. Available at: http://www.ucdmc.ucdavis.edu/ucdhs/health/a-z/38Hypothyroidism/doc38risks.html.
Accessed April 17, 2003.
Role of Thyroid Hormone in Normal Cardiovascular Effects
• Cardiac effects– Directly affects the heart and peripheral vascular
system– Increases myocardial inotropy and heart rate
– Changes in cardiac function are mediated by T3 regulation of cardiac-specific genes
• Coronary effects– Dilate peripheral arteries to increase cardiac
output
Gomberg-Maitland M, et al. Am Heart J. 1998;135:187-196.
Mild Thyroid Failure and Cardiovascular Disease
• Cardiac manifestations– Left ventricular mass– Left ventricular systolic and diastolic function– Cardiac function– Myocardial infarction (MI)
• Coronary artery disease– Elevated total cholesterol levels, low-density lipoprotein
cholesterol (LDL-C) levels, and triglyceride levels– Aortic atherosclerosis– Elevated lipoprotein(a) levels– Hyperhomocysteinemia
Biondi B, et al. Ann Intern Med. 2002;137:904-914.
Gomberg-Maitland M, et al. Am Heart J. 1998;135:187-196.
Cardiac Manifestations of Mild Thyroid Failure
Increased Left Ventricular Mass With Mild Thyroid Failure
0102030405060708090
100
Left
Ven
tric
ular
Mas
s In
dex,
g/m
2
Patients With Mild ThyroidFailure
Control Group
Di Bello V, et al. J Am Soc Echocardiogr. 2000;13:832-840.
P<.01
Slowed Left Ventricular Relaxation in Mild Thyroid Failure
Biondi B, et al. Thyroid. 2002;12:505-510.
Mild Thyroid Failure
Heart Vascular Smooth Muscle
Slowed LV Relaxation at Rest
Impaired LV Diastolic Filling on Exercise
Increased Vascular Tone at Rest
Impaired Peripheral Vasodilation on Exercise
LV Systolic Dysfunction on Effort
Cardiovascular Abnormalities Leading to LV Dysfunction on Effort in Mild Thyroid Failure
Mild Thyroid Failure Impacts Heart Function
Kahaly GJ. Thyroid. 2000;10:665-679.
Perk M, et al. Can J Cardiol. 1997;13:273-276.
Mild Thyroid Failure
Euthyroidism Control Group*
91
94
97
100
Vita
l Cap
acity
, %
P=.001
*The control group was comprised of gender- and age-matched healthy individuals
• During exercise, vital capacity was statistically significantly (P<.001) reduced in patients with mild thyroid failure compared with euthyroid patients and control patients
• The author concluded that mild thyroid failure impacts heart function and patients with mild thyroid failure should receive appropriate and efficacious treatment to prevent any cardiac manifestations
• Perk et al also found that mild thyroid failure can lead to angiographic CAD progression
Mild Thyroid Failure Increases Risk of Myocardial Infarction
• Population-based cross-sectional study• Data collected from August 1990 through July
1993• Random sample of 1149 women
55 years of age– 1055 women had mild thyroid failure or were
euthyroid– 975 women included in aortic atherosclerosis
analysis– 1036 women included in analysis of MI incident
Hak AE, et al. Ann Intern Med. 2000;132:270-278.
Mild Thyroid Failure Increases Risk of Myocardial Infarction (cont.)
• Mild thyroid failure contributed to 60% of MI cases in patients with diagnosed mild thyroid failure
• Mild thyroid failure contributed to 14% of all MI instances in the study population
• Mild thyroid failure is independently associated with MI
Hak AE, et al. Ann Intern Med. 2000;132:270-278.
Mild Thyroid Failure and Coronary Artery Disease
Mild Thyroid Failure and Coronary Artery Disease
Luboshitzky R, et al. Thyroid. 2002;12:421-425.
Wartofsky L. Diabetes Endocrinol. 2001;3.
Mild Thyroid Failure
Elevated Lipid Levels
Abnormal Vascular Reactivity
Hyperhomo-cysteinemia
Elevated Lipoprotein(a)
Levels
Aortic Atherosclerosis
Risk
Mild Thyroid Failure Associated With Aortic Atherosclerosis
0
1
2
3
4
Odd
s R
atio
sPresence of Aortic Atherosclerosis*
Hak AE, et al. Ann Intern Med. 2000;132:270-278.
Women With Mild Thyroid
Failure
Euthyroid
Women
Women With Mild Thyroid
Failure and Antibodies to Thyroid
Peroxidase
Euthyroid Women Without
Antibodies to Thyroid
Peroxidase*Numbers in parentheses are 95% confidence intervals.
†Reference risk.
(1.2-3.1)
†
(1.1-4.3)
†
Mild Thyroid Failure Associated With Aortic Atherosclerosis (cont.)
• Mild thyroid failure is associated with a greater prevalence of aortic atherosclerosis
• Thyroid autoimmunity is not associated with aortic atherosclerosis
• More research should be conducted to further confirm this association
Hak AE, et al. Ann Intern Med. 2000;132:270-278.
Mild Thyroid Syndrome Elevates Serum Lipid Levels
0
50
100
150
200
250
300
Lip
id L
evel
s, m
g/d
L
Total-C* LDL-C* HDL-C* Triglycerides
Hypothyroid
Mild ThyroidFailure
Euthyroid
SubclinicalHyperthyroid
Hyperthyroid
Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.*Total-C indicates total cholesterol; LDL-C, LDL cholesterol; HDL-C, HDL cholesterol.
Cholesterol Levels Elevate With Increasing TSH Levels
Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.
209216
223 226229
238 239
270 267
200
210
220
230
240
250
260
270
280
Mea
n T
otal
Cho
lest
erol
Le
vel,
mg/
dL
<0.3 0.3-5.1
>5.1-10
>10-15
>15-20
>20-40
>40-60
>60-80
>80
TSH, mIU/mL
Abnormal
Euthyroid
Mild Thyroid Failure Elevates Serum Lipid Levels
• Modest elevations of TSH corresponded to changes in lipid levels that may affect cardiovascular health
Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.
Mild Thyroid Failure Decreases LDL Receptor Expression
56
58
60
62
64
66
68
70
72
74
Oxi
dize
d LD
L-C
Lev
el,
mU
/L
Mild Thyroid Failure
Control Group*
*Control group consists of euthyroid patients
• Patients with mild thyroid failure have statistically significant (P<.001) increased levels of oxidized LDL compared with patients in the control group
• Changes in LDL-C levels in patients with mild thyroid failure are associated with decreases in LDL receptor expression, leading to an increased risk of elevated LDL-C and CAD development
P<.001
Duntas LH, et al. Thyroid. 2002;12:1003-1007.
Diekman MJM, et al. J Clin Endocrinol Metab. 2000;85:1857-1862.
Hyperhomocysteinemia Increases Coronary Artery Disease Risk
00.5
11.5
22.5
33.5
4
4.55
Mor
talit
y R
atio
9-14.9 15-19.9 20
Boushey CJ, et al. JAMA. 1995;274:1049-1057.
Catargi B, et al. Thyroid. 1999;9:1163-1166.Nygård O, et al. N Engl J Med. 1997;337:230-236.
Hussein WI, et al. Ann Intern Med. 1999;131:348-351.
Homocysteine Level, mol/L
• Hyperhomocysteinemia increases CAD risk
• Patients with hyperhomocysteinemia and CAD have an almost 4 times higher mortality rate than patients with lower homocysteine levels
• Hyperhomocysteinemia is present in patients with mild thyroid failure, increasing their CAD risk
Elevated Lipoprotein(a) Levels Increase CAD Risk
0
50
100
150
200
250
300
Lipo
prot
ein(
a) L
evel
s,
U/L
Patients With Mild Thyroid
Failure
Control Group*
PROCAM. Lipoprotein(a) and cardiovascular risk.
Available at: http://www.chd-taskforce.de/pdf/sk_procam_03.pdf.
Accessed April 17, 2003.
Kung AW, et al. Clin Endocrinol. 1995;43:445-449.
• Elevated lipoprotein(a) levels are associated with an increased risk of CAD development and MI occurrence
• Patients with mild thyroid failure have higher lipoprotein(a) levels, which increases their risk of CAD
P<.005
*Control group consisted of age- and gender-matched healthy patients.
Endothelial Function in Patients With Mild Thyroid Failure and CAD Risk
Lekakis J, et al. Thyroid. 1997;7:411-414.
Flow-mediated vasodilatation is impaired in patients with mild thyroid failure, which
could contribute to the development of CAD.
0
2
4
6
8
10
12
14
<2 >10
TSH Levels, mIU/ML
Flo
w-M
edi
ate
d E
ndo
the
lium
-D
epe
nde
nt V
aso
dila
tatio
n, %
2-4 >4-10
Mild Thyroid Failure Testing and Treatment
Thyroid Function Testing
• Biochemical testing or cytopathologic evaluation can detect thyroid disease in patients with subtle symptoms
• Most accurate way to detect abnormal thyroid levels is by testing TSH levels
• Serum-based testing is available– TT4 and TT3
– Free T4 and free T3
• Thyroid hormone-binding plasma proteins, thyroxine-binding globulin, transthyretin/prealbumin, and albumin testing are also available
Baloch Z, et al. Thyroid. 2003;13:3-126.
Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
Hyperthyroid
Free T4
0.01
0.1
1.0
10
100
1000
TS
H L
eve
l , m
IU/L
Hypothyroid Euthyroid
Undetectable
Spencer CA, et al. J Clin Endocrinol Metab. 1990;70:453-460.
Relationship Between TSH Levels and Free T4
Normal
NCEP Adult Treatment Panel III Guidelines for Thyroid Function Testing
• Patients with mild thyroid failure can have elevated LDL-C
• “Any person with elevated LDL-C or other form of hyperlipidemia should undergo evaluation before initiating drug therapy to rule out causes of secondary dyslipidemia, including hypothyroidism.”
National Institute of Health. Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Washington, DC:
National Institutes of Health; 2002.
Additional Testing Guidelines for Patients Who May Be at Risk for Mild Thyroid Failure
• American College of Cardiology/American Heart Association– Thyroid function should be measured because of CAD
risk
• American Diabetes Association– All patients with type 1 diabetes– Patients with type 2 diabetes as clinically indicated
• American Association of Clinical Endocrinologists– Every patients with diagnosed depression should be
tested
Abbott Laboratories. Data on file.
Serum Thyroid HormonesTypical Reference Ranges
Hormone Normal Reference Range
TSH 0.4-4.0 mIU/mL
Free T3 0.2-0.5 ng/dL
Free T4* 0.7-1.8 ng/dL
Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
Abbott Laboratories. Data on file.
*For measurement methods that employ physical separation, the upper limit of normal free T4 may extend beyond 2.5 ng/dL
Thyroid Function Testing Frequency in Specific Patient Populations
Population Testing Frequency
MenEvery 5 years beginning at 35 years of age
WomenEvery 5 years beginning at 35 years of age
Pregnant womenAs soon as possible after conception; up to 3 months after giving birth
Patients >60 years of age Once a year
The Endocrine Society Web site. Available at: http://www.endo-society.org/pubrelations/pressReleases/archives/1999/hypothyroid.cfm. Accessed April
17, 2003.
Loyola University New Orleans Web site. Available at: http://www.loyno.edu/~msthomas/hypo.html. Accessed April 17, 2003.
Treatment Goals for Mild Thyroid Failure
• Prevent progression to overt hypothyroidism• Reduce cardiovascular disease risk
– Maintain TSH levels in the normal range– Lower LDL-C, total cholesterol, and triglycerides
Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000.
Levothyroxine Treatment Reduces Lipoprotein(a) Levels in Patients With Mild Thyroid Failure
• Lipoprotein(a) levels in patients with mild thyroid failure had a statistically significant (P<.001) mean decrease after treatment with levothyroxine
• Levothyroxine therapy is effective in lowering lipoprotein(a) levels and had beneficial effects on lipid profiles
100
110
120
130
140
150
160
170
Lipo
prot
ein(
a) L
evel
s, m
g/L
Before Levothyroxine
Treatment
After Levothyroxine
Treatment
Yildirimkaya M, et al. Endocrin J. 1996;43:731-736.
Levothyroxine Treatment Reduces Serum Lipid Levels
• Levothyroxine adequately reduced TSH levels
• Levothyroxine therapy prevented progression to overt hypothyroidism
• Levothyroxine therapy lowers mean lipid levels, thereby reducing cardiovascular disease risk
Danese MD, et al. J Clin Endocrinol Metab. 2000;85:2993-3001.
Levothyroxine Reduces Cholesterol Levels
-0.4-0.35-0.3
-0.25-0.2
-0.15-0.1-.05
0
Dec
reas
e in
Lip
id
Leve
ls,
mm
ol/L
Total-C* LDL-C*
Patients Treated With Levothyroxine
Patients With Elevated TSH Levels Treated With Levothyroxine
Meier C, et al. J Clin Endocrinol Metab. 2001;86:4860-4866.
*Total-C indicates total cholesterol; LDL-C, low-density lipoprotein cholesterol.
P<.015
P<.03P<.004
Levothyroxine Reduces Cardiovascular Mortality
• Mild thyroid failure has negative clinical and metabolic effects
• Levothyroxine treatment– Improves LDL-C levels and total cholesterol levels– Improves clinical signs and symptoms of mild
thyroid failure– Reduces morbidity and mortality in patients with
mild thyroid failure
Meier C, et al. J Clin Endocrinol Metab. 2001;86:4860-4866.
0
1
2
3
4
5
6
Pat
ient
s, n
Progression No Progression
P=.02 P=.01
Levothyroxine Treatment Prevents Coronary Artery Disease Progression
Perk M, et al. Can J Cardiol. 1997;13:273-276.
Inadequate Levothyroxine Replacement
Adequate Levothyroxine Replacement
Fixed/Decremental Dose of
Levothyroxine Therapy
Fixed/Incremental Dose of
Levothyroxine Therapy
Levothyroxine Cautions
• Using levothyroxine in the presence of ischemic heart disease – Possible MI, aggravation of angina, or cardiac
arrhythmias
• Using levothyroxine in the elderly or in patients with CAD– Initiated at lower doses (25 to 50 g/d) and
gradually titrated up at 6- to 8-week intervals
Perk M, et al. Can J Cardiol. 1997;13:273-276.
Kohno A, et al. Endocr J. 2001;48:565-572.
Physician’s Desk Reference. 57th ed. Montvale, NJ: Medical Economics Company; 2002.
Conclusions
• Mild thyroid failure is a serious illness that warrants clinical attention– Affects heart rate, LV function, cardiac output, and
systemic vascular resistance– Increases total cholesterol levels, LDL-C levels,
and triglyceride levels and decreases HDL-C levels in patients
• Factors contributing to CAD
Conclusions (cont.)
• Levothyroxine treatment is effective in treating patients with mild thyroid failure– Stabilizes TSH concentrations– Reduces total cholesterol levels, LDL-C levels,
and triglyceride levels– Prevents progression of CAD– May reduce cardiovascular morbidity and mortality
in patients