Cardiovascular Disease Risk and Mild Thyroid Failure

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.


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


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.


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


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.


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*


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


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

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58

60

62

64

66

68

70

72

74

Oxi

dize

d LD

L-C

Lev

el,

mU

/L


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.


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


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


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


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


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

Cardiovascular Disease Risk and Mild Thyroid Failure

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