Impact of “Mild-Subclinical” Thyroid Disease on

Cardiovascular Health

Harry L. Uy, MD UP College of Medicine Class 1986

Private Practice, EndocrinologyClinical Associate Professor UTHSC-San Antonio

Should mild thyroid dysfunction be treated? Is

there any clinical consequence if this is left untreated?

Subclinical HyperthyroidismDefinition

• 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 HyperthyroidismSmall Increase in Free T4 = Large Decrease in TSH

0.8 ng/dl

1.8 ng/dl 4.5 mU/L

0.45 mU/L

Free T4 TSHNormal RangeChange Normal RangeChange

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 withL-thyroxine

1. Ross DS. 1. Ross DS. Mayo Clin Mayo Clin Proc. 1988;63:1223. 2. Ross DS. In: Proc. 1988;63:1223. 2. Ross DS. In: Werner and Ingbar’s The Thyroid, Werner and Ingbar’s The Thyroid, 7th ed7th ed.. 1996:1016. 1996:1016.3. Sawin CT. 3. Sawin CT. Adv Intern Med.Adv Intern Med. 1991;37:223. 4. Sawin CT et al. 1991;37:223. 4. Sawin CT et al. N Engl J Med.N Engl J Med. 1994;331:1249. 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’ diseaseRoss DS. In: Ross DS. In: Werner and Ingbar’s The Thyroid, Werner and Ingbar’s The Thyroid, 7th ed7th ed.. 1996:1016. 1996:1016.

Physiological Effects of Subclinical Hyperthyroidism

↓↓bone densitybone density↑↑serum osteocalcinserum osteocalcin

↑↑urinary hydroxyprolineurinary hydroxyproline

and pyrrolidine linksand pyrrolidine links

↑↑heart rate heart rate ↑↑risk of atrial fibrillationrisk of atrial fibrillation↑↑cardiac contractilitycardiac contractility22

↑↑LV mass indexLV mass index↑↑intraventricular septal andintraventricular septal and

posterior wall thicknessposterior wall thickness

1. Ross DS. In: 1. Ross DS. In: Werner and Ingbar’s The Thyroid, Werner and Ingbar’s The Thyroid, 7th ed7th ed.. 1996:1016. 1996:1016.2. Biondi B et al. 2. Biondi B et al. J Clin Endocrinol.J Clin Endocrinol. 1993;77:334. 1993;77:334.

Total and LDL cholesterol

Liver enzymes

Creatine kinase

Sex hormone binding globulin

Time asleep at night

Mood (using multidimensionalscale for state of well-being)

Ross DS. In: Ross DS. In: Werner and Ingbar’s The ThyroidWerner and Ingbar’s The Thyroid, 7th ed. 1996:1016, 7th ed. 1996:1016

Other Biological Effects of Subclinical Hyperthyroidism

Frost, L. et al. Arch Intern Med 2004;164:1675-1678.

Hyperthyroidism Risk of Atrial Fibrillation or Flutter

A Population-Based Study

Hyperthyroidism Risk of Atrial Fibrillation or Flutter

A Population-Based Study

Frost, L. et al. Arch Intern Med 2004;164:1675-1678.

IncidenceIncidenceof Atrialof Atrial

Fibrillation Fibrillation (%)(%)

3030

2525

2020

1515

1010

55

00

Low Thyrotropin (TSH <0.1)

YearsYears

00 11 22 33 44 55 66 77 88 99 1010

HighThyrotropin

NormalThyrotropin

Slightly LowThyrotropin

Serum Thyrotropin Values at Baseline

Sawin CT et al. Sawin CT et al. New Engl J Med.New Engl J Med. 1994;331:1249. 1994;331:1249.

Subclinical Hyperthyroidism Atrial Fibrillation

2007 subjects > 60 yo (1193 women, 814 men) TSH measured; 10 year follow-up

Relative Risk

4

2

0

3.1*

< 0.1

Subclinical Hyperthyroidism Risk of Atrial Fibrillation

Sawin CT, NEJM 331: 1249, 1994

0.1-0.4TSH mU/L 0.4-5.0 > 5.0

1.61.0 1.4

Subclinical Hyperthyroidism Atrial Fibrillation

Mean age (66-68), prevalence of underlying CV disease (57-65%)similar in all 3 groups

Auer et al. Am Heart J. 2001

2.3%

12.7%13.8%

0%

2%

4%

6%

8%

10%

12%

14%

16%

Controls(n=22,300)

Subclinical Hyperthyroidism

(n=725) (TSH<0.03)

Overt Hyperthyroidism

(n=613)

*P<0.01

* *

Thyroid Function Status and Isovolumetric Contraction Time (ICT)

ICTICT(ms)(ms)

8080

7070

6060

5050

4040

3030

2020

1010

00OvertOvert

hyper Ihyper IOvertOvert

hyper IIhyper IISubclinSubclinhyperhyper

NormalNormaleuthyroideuthyroid

MildMildthyroidthyroidfailurefailure

OvertOverthypo IIhypo II

OvertOverthypo Ihypo I

∗

∗,,††,,‡

§

‡º

Tseng KH et al. Tseng KH et al. J Clin Endocrinol Metab. J Clin Endocrinol Metab. 1989;69:633.1989;69:633.

∗∗PP<.0005 vs normal euthyroid; <.0005 vs normal euthyroid; ††PP<.0005 vs overt hyper I; <.0005 vs overt hyper I; ‡‡PP<.05 vs <.05 vs euthyroid controls;euthyroid controls;§§PP<.05 vs overt hypo I; <.05 vs overt hypo I; ��PP<.005 vs normal euthyroid.<.005 vs normal euthyroid.

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 TSHAge > 60 yrs

Parle J et al Lancet 358:861,2001

100

80

60

45

Sur

viva

l (%

)

TSH

<0.5

>5.02.1-5.01.3-2.00.5-1.2

Cardiovascular events were responsible for the excess mortalityNo difference between TSH < 0.1 and TSH 0.1-0.5 mU/L

Subclinical HyperthyroidismConcerns

n OsteoporosisOsteoporosis

n Atrial fibrillationAtrial fibrillation

n Cardiac dysfunctionCardiac dysfunction

n Progression to overt Progression to overt

diseasedisease

Ross DS. In: Ross DS. In: Werner and Ingbar’s The Thyroid, Werner and Ingbar’s The Thyroid, 7th ed7th ed.. 1996:1016. 1996:1016.

Prevention and Treatment ofSubclinical Hyperthyroidism

Endogenous

• Because low TSH is often transient, careful monitoring is needed

• Consider antithyroid drug treatment or

radioiodine therapy (depending on etiology)

Exogenous • Careful titration of L-thyroxine to maintain

normal TSH

• Use smallest L-thyroxine dose needed

to meet therapeutic goals

Subclinical HypothyroidismDefinition

• Elevated TSH (80-85% < 10 mU/L)

• Normal Free T4

• + Anti-TPO antibodies in 60-80%

• “Mild hypothyroidism”

• “Mild thyroid failure”

Subclinical HypothyroidismSmall Decrease in Free T4 = Large Increase

in TSH

0.8 ng/dl

1.8 ng/dl

Free T4Normal RangeChange

4.5 mU/L

0.45 mU/L

TSHNormal RangeChange

Progression of Mild Thyroid Failure

YearsYears

NORMAL NORMAL RANGERANGE

TSHTSH

Overt Overt HypothyroidismHypothyroidism

MildMildThyroidThyroidFailureFailureEuthyroidEuthyroid

TT33

TT44

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

Subclinical Hypothyroidism Prevalence - Women

25%

20%

15%

10%

5%

0%

Whickham (n=2,779)Colorado (n=25,862)

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

NHANES (n=17,353)

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: Ladenson PW. In: Werner and Ingbar’s The Thyroid, Werner and Ingbar’s The Thyroid, 7th ed7th ed. . 1996:878.1996:878.

Subclinical HypothyroidismIssues

n Lipid elevationLipid elevation

n CAD risk factorCAD risk factor

n Cardiac functionCardiac function

n Progression to overt diseaseProgression to overt disease

Why Treat Patients WithMild 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.1. Ayala AR, Wartofsky L. The Endocrinologist. The Endocrinologist. 1997;7:44. 1997;7:44.2. Cooper DS et al. 2. Cooper DS et al. Ann Intern Med.Ann Intern Med. 1984;101:18. 1984;101:18. 3. Kinlaw WB. 3. Kinlaw WB. Thyroid TodayThyroid Today. 1991;14:1.. 1991;14:1.4. Nystrom E et al. 4. Nystrom E et al. Clin Endocrinol.Clin Endocrinol. 1988;29:63. 1988;29:63.5. Hennessey JU, Jackson IMD. 5. Hennessey JU, Jackson IMD. The Endocrinologist.The Endocrinologist. 1996;18:214. 1996;18:214.

Types of Lipid Abnormalities in Patients With Hypothyroidism

33.6%33.6%

1.5%1.5%

8.6%8.6%

56.3%56.3% HypercholesterolemiaHypercholesterolemia

((200 mg/dL)200 mg/dL)

HypertriglyceridemiaHypertriglyceridemia((150 mg/dL)150 mg/dL)

Hypercholesterolemia Hypercholesterolemia and mild and mild hypertriglyceridemia hypertriglyceridemia

Normal LipidsNormal Lipids

N = 268N = 268

O’Brien T et al. O’Brien T et al. Mayo Clin Proc.Mayo Clin Proc. 1993;68:860. 1993;68:860.

LDL-C Levels Increase With Increasing Hypothyroidism Grade

C=controls.C=controls.**PP<.01 vs controls. <.01 vs controls. †PP<.001 vs controls.<.001 vs controls.

LDL-

CLD

L-C

(mg/d

L(m

g/d

L ))****

Hypothyroidism GradeHypothyroidism Grade

**

CC 11 22 33 4*4* 55†

1.11.1 3.03.0 8.68.6 22.722.7 44.444.4 63.763.7Basal TSH (mU/L)Basal TSH (mU/L)

144144 133133 137137

168168

191191

246246250250

235235

220220

205205

190190

175175

160160

145145

130130

overtovert

Staub JJ et al. Staub JJ et al. Am J MedAm J Med. 1992;92:631.. 1992;92:631.

Subclinical Hypothyroidism Lipid Changes with LT4 Therapy

0

5

10

Total Cholesterol

LDLCholesterol

Meta-analysis: 13 Studies 247 patients Mean TSH 4.8-19.0 mU/L

Danese M, J Clin Endo Metab 85:2993, 2000

CholesterolReduction(mg/dl)

-7.9 mg/dl

-10.3 mg/dl

(No subgroupwith TSH < 12)

Group 1 (N=6)Group 1 (N=6) Group 2 (N=6)Group 2 (N=6) Group 3 (N=7)Group 3 (N=7)

BeforeBefore

AfterAfter

450450

400400

350350

300300

250250

200200

150150

100100

5050

00

TC*TC*

LDL-C*LDL-C*

TC*TC*

LDL-C*LDL-C*

TC*TC*

LDL-C*LDL-C*

TSH before: 7.0 TSH before: 7.0 mU/LmU/LTSH after: 1.9 TSH after: 1.9 mU/LmU/L

TSH before: 18.6 TSH before: 18.6 mU/LmU/LTSH after: 1.5 TSH after: 1.5 mU/LmU/L

TSH before: 154.9 TSH before: 154.9 mU/LmU/LTSH after: 1.8 mU/LTSH after: 1.8 mU/L

*=mg/dL. *=mg/dL. 11Values are means ±SD.Values are means ±SD.Diekman T et al. Diekman T et al. Arch Intern MedArch Intern Med. 1995;155:1490.. 1995;155:1490.

Effect of L-Thyroxine Treatment on Lipid Levels in Dyslipidemia1

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. Tanis BC et al. Clin Endocrinol.Clin Endocrinol. 1996;44:643. 1996;44:643.

Cardiovascular Changes Often Associated With Hypothyroidism

HypothyroidismHypothyroidism

ECG changesECG changesApparentApparent

cardiomegalycardiomegaly

DecreasedDecreasedmyocardial contractility,myocardial contractility,

myocardial oxygen demand, myocardial oxygen demand, cardiac outputcardiac output

Increased Increased diastolic pressure, diastolic pressure,

peripheral vascular resistanceperipheral vascular resistance

Klein I, Ojamaa K. In: Klein I, Ojamaa K. In: Werner and Ingbar’s The Thyroid, Werner and Ingbar’s The Thyroid, 7th ed7th ed.. 1996:799. 1996:799.

Subclinical HypothyroidismIssues

n Lipid elevationLipid elevation

n CAD risk factorCAD risk factor

n Cardiac functionCardiac function

n Progression to overt diseaseProgression to overt disease

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

Subclinical Hypothyroidism and Atherosclerosis

The Rotterdam Study

Hak AE,l Ann Int Med 132:270, 2000

0 1 2 3 4

AorticCalcification

MyocardialInfarction

High TSH + TABHigh TSHEuthyroid

Odds Ratio

Subclinical Hypothyroidism and Atherosclerosis

The Rotterdam Study

Hak AE,l Ann Int Med 132:270, 2000

*Adjusted for age, BP, BMI, smoking, lipids

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. 1. Ayala AR, Wartofsky L. The EndocrinologistThe Endocrinologist. 1997;44:401.. 1997;44:401.2. Weetman, AP. 2. Weetman, AP. British Journal MedBritish Journal Med. 1997;314:1175.. 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 μg/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: 1. Brent GA, Larsen PR. In: Werner and Ingbar’s The Thyroid, Werner and Ingbar’s The Thyroid, 7th ed7th ed.. 1996:883. 1996:883.2. AACE. 2. AACE. Endocrine Pract.Endocrine Pract. 1995;1:56. 1995;1:56.3. Singer PA et al. 3. Singer PA et al. JAMA.JAMA. 1995;273:808. 1995;273:808.

Management of Hypothyroidism: Special Patient Populations

SpecialSpecialPatientPatient

PopulationsPopulations

Heart DiseaseHeart Disease22 PostmenopausalPostmenopausalAge >50 yearsAge >50 years11

Psychiatric IllnessPsychiatric Illness33

Use of Certain DrugsUse of Certain Drugs22 Chronic IllnessChronic Illness

Pregnant/postpartumPregnant/postpartum22

1. Singer PA et al. 1. Singer PA et al. JAMA.JAMA. 1995;273:808. 1995;273:808.2. Brent GA, Larsen PR. In: 2. Brent GA, Larsen PR. In: Werner and Ingbar’s The Thyroid, Werner and Ingbar’s The Thyroid, 7th ed7th ed.. 1996:883. 1996:883.3. Whybrow PC. 3. Whybrow PC. AMA.AMA. 1994;21:47. 1994;21:47.

1. Stall GM et al. 1. Stall GM et al. Ann Intern Med.Ann Intern Med. 1990;113:265. 1990;113:265.2. Ridgway EC. 2. Ridgway EC. Family Practice Recertification.Family Practice Recertification. 1992;14:127. 1992;14:127.

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

Over- and Under-Replacement Risks

Consensus Statement: Subclinical Thyroid Dysfunction: - A Joint Statement – AACE, ATA, Consensus Statement: Subclinical Thyroid Dysfunction: - A Joint Statement – AACE, ATA, Endocrine Society. Gharib H. et al. JCEM 90:581-585.Endocrine Society. Gharib H. et al. JCEM 90:581-585.

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 Disease and the Heart

“When the Thyroid Speaks…the Heart Listens”

MA Sussman

Circ. Res 2001