Thyroid Dysfunction: Clinical Overview

T4

T3

Hypothalamic-Pituitary-Thyroid Axis

Physiology

Pituitary

Thyroid Gland

Hypothalamus TRH

T4 T3 Liver

T4 T3

Heart

Liver

Bone

CNS

TR

Target Tissues

–

–

TSH

Adapted from Merck Manual of Medical Information. ed. R Berkow. 704:1997.

Hypothalamus

Pituitary

Thyroid Gland

T4 T3 Liver

T4

TRH

T4

T3

TSH

• TSH reflects tissue thyroid hormone actions

• TSH as an index of therapeutic success and potential toxicity

T3

–

–

Hypothalamic-Pituitary-Thyroid Axis

Clinical Utility of TSH

Adapted from Merck Manual of Medical Information. ed. R Berkow. 704:1997.

Mild Hypothyroidism & Mild ThyrotoxicosisDefinitions

TSHTSH

FTFT44

Euthyroidism

Overt

Hypothyroidism

Mild Overt

Thyrotoxicosis

Mild

Distribution of TSH Valuesby Race/Ethnicity (NHANES III)

Lab reference range defined from values in “normal” population:

0.4 – 5.5 mU/L

Data from the National Health and Nutrition Examination Survey (NHANES) III.Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499.

Hypothyroidism & ThyrotoxicosisPrevalences

Data from the National Health and Nutrition Examination Survey (NHANES) III.Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499.

0.3

4.3

0.50.7

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

MildOvert Mild Overt

Pre

vale

nc

e, %

Hypothyroidism Thyrotoxicosis

Individuals with TSH >2.5 mU/L are at risk for overt hypothyroidism during a

20-year follow-up Vanderpump et al. Clinical Endocrin. 1995;43(1):55-68.

Thyroid disease is more prevalent than which of the following:

A. Asthma

B. Heart disease

C. Diabetes

D. All of the above

www.accessdata.fda.gov/scripts/cder/ob/docs/temptn.cfm

?

Thyroid Disease: Relative to Other

Diseases in the United States

1. Canaris GJ, et al. Arch Intern Med. 2000;160:526-534. 2. National Center for Health Statistics. Fast stats A-Z. Available at: http://www.cdc.gov/nchs/ fastats/default.htm. Accessed February 16, 2006. 3. U.S. Census Bureau Web site. 1997 Population Profile of the United States, p23-194. Available at: http:// www.census.gov/prod/3/98pubs/p23-194.pdf. Accessed February 16, 2006. 4. AACE Thyroid Task Force. Guidelines. Endocr Pract. 2002;8:458-469.

Arthritis 33.0

Asthma 17.6

Diabetes 10.0

COPD 9.6

Thyroid Disease Hypothyroidism Nodules 21.3

Heart Disease 15.0

0 5 10 15 20 Cases (millions)1,2,3,4

25 3530

Mild Hypothyroidism & Mild ThyrotoxicosisCommon Causes

Mild Hypothyroidism• Autoimmune

thyroiditis• Previous thyroid

surgery and/or 131I therapy for thyrotoxicosis

Mild Thyrotoxicosis• Graves’ disease• Nodular goiter

Mild Hypothyroidism & Mild ThyrotoxicosisCommon Causes

Mild Hypothyroidism• Autoimmune

thyroiditis• Previous thyroid

surgery and/or 131I therapy for thyrotoxicosis

• Inadequate thyroxine therapy

Mild Thyrotoxicosis• Graves’ disease• Nodular goiter• Excessive thyroxine

therapy

Diagnosis and Treatment

Cost-Effectiveness of TSH Screening q. 5 yrs vs Other Preventive Medical Practices

0Most cost-effective

2020 4040 6060 8080 100Least cost-

effectiveDollars

(1994 $ thousands)

Cholesterol screening of asymptomatic population

Breast cancer screening: women aged 65 to 74 yBreast cancer screening: women aged 65 to 74 y

Hypertension screening: women aged 40 yHypertension screening: women aged 40 y

Hypertension screening: men aged 40 yHypertension screening: men aged 40 y

Hypothyroidism: men aged 35 yHypothyroidism: men aged 35 y

Exercise for CHD preventionExercise for CHD prevention

Smoking cessationSmoking cessation

Hypothyroidism: women aged 35 yHypothyroidism: women aged 35 y

Flu vaccine: adults aged 45 to 65 yFlu vaccine: adults aged 45 to 65 y

Breast cancer screening: women aged 40 to 74 yBreast cancer screening: women aged 40 to 74 y

Adapted from Danese MD et al. JAMA. 1996;276:285.

Screening: Recommendations• Various societies and authors disagree about population-based

screening

• The AAFP recommends screening high-risk populations:

– women with a family hx of thyroid disease

– women >35 yo

– pregnant women

– abnormal physical exam

– diabetic patients

– Hx of autoimmune disorder

• The American Thyroid Association indicates that screening is justifiable in men > 35 yo as well (q 5 years)

Surks. JAMA. 2004 Jan 14;291(2):228-38.American Academy of Family Physicians. Subclinical Thyroid Disease. Available at: http://www.aafp.org/afp/20051015/1517.pdf Accessed February 16, 2006. The American Thyroid Association Web site. American Thyroid Association Guidelines for Detection of Thyroid Dysfunction. Available at: http://thyroid.org/professionals/publications/documents/GuidelinesdetectionThyDysfunc_2000.pdf. Accessed February 16, 2006.

Diagnostic Algorithm

1. Adapted from: Singer PA, Cooper DS, et al. Treatment guidelines for patients with hyperthyroidism and hypothyroidism. ATA. JAMA. 1995;273:808-12. 2. Nat’l. Academy of Clinical Biochemistry. Laboratory Med. Practice Guidelines. Lab. support for the diagnosis and monitoring of thyroid disease. 2002.

TSH0.3 to 3.5U/mL

Euthyroid

TSH<0.3

U/mL

Hyperthyroid?

TSH 3.5-9.0 U/mL, NL free

T4

TSH >9.0 g/mL, LOW free T4

SuspectHypothyroid?

Test TSH,free T4

Overt Hypothyroidism

Mild Thyroid Failure

REPEAT TSH and Treat

Diagnosis: TPO Antibodies

Sieiro Netto L, et al. Am J Reprod Immunol. 2004;52:312-316. Lazarus JH. Minerva Endocrinol. 2005 Jun;30(2):71-87. Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499. Hak AE, et al. Ann Intern Med. 2000;132:270-278.

• ~10% of NHANES population had TPO+ antibodies

• Potential indicator of autoimmune thyroid failure

• Risk of miscarriage higher in women with TPO+ antibodies

• Screening for TPO+ab warranted pre-conception

• TPO+ab may be associated with CV risks

0

5

10

15

20

25

30

35

13-19 20-29 30-39 40-49 50-59 60-69 70-79 >80

Male

Female

Prevalence of antibodies

Levothyroxine Therapy

• LT4 is the synthetic version of the naturally-occurring hormone thyroxine (T4)

• Physicians use TSH to individualize the optimal LT4 dose

• Small changes in LT4 dose can cause significant changes in TSH levels

• LT4 is provided in 12 dosage strengths that differ by as little as 9%

Food and Drub Administration Web site. Active Ingredients. Available at: http://www.accessdata.fda.gov/scripts/cder/ob/docs/tempai.cfm. Accessed February 16, 2006.

Starting Therapy• Otherwise healthy, < 60 yrs, no cardiac Hx:

• ~1.7 g/kg/day• 8 week F/U TSH, 25 g dose increments

• Older patients, > 60: require 20-30% less• 50 g/day• 6 week F/U TSH, 12-25 g dose increments

• Congenital hypothyroidism • Initiate therapy with 10-15 g/kg/day • Usually 50 g/d X 1 week, then 37 g/d

• Pediatric hypothyroidism• Initial dose: 25-50 g/day X 2-4 weeks• Titration: 25 g increments Q 4- 8 weeks

American Thyroid Association Web site. Treatment Guidelines for Patients with Hyperthyroidism and Hypothyroidism. Available at: http://thyroid.org/professionals/publications/documents/GuidelinesHyperHypo_1995.pdf. Accessed February 16, 2006. Hennessey J. Endocrinologist. 13(6):479-487, Nov/Dec 2003. Sperling. Pediatric Endocrinology, Second Edition. Saunders, Philadelphia: 175-177. Foley. Congenital Hypothyroidism, Acquired Hypothyroidism in Infants, Children, and Adolescents. The Thyroid, 8th Edition. Braverman & Utiger eds. pp.977-988.

Maintenance

• Periodic monitoring essential to ensure appropriate dosing and consistent effect

• Once TSH normalized:– Visit frequency decreased to Q 6-12

months

• TSH should be measured at least annually• Re-measure TSH (in 8-12 weeks)

following:– Dosage, type or brand of thyroxine change

Singer et al. JAMA. 1995;273:808-812.

Combined T4/T3 TherapySummary of Studies

SameSame

LowerHigher

HigherSame

SHBGCholesterol

SameSameSame

SameSame

SameSame

ImprovedImproved

CognitiveMood

2.0 vs 2.11.8 vs 1.73.1 vs 1.5

0.7 vs 0.8

0.5 vs 0.8

TSHT4/T3 vs T4

16 wks15

15 wks25

10 Wks10

5 wks12.5

5 wks12.5

DurationT3 Dose

4467%

40100%

11085%

11100%

3348%

N Thyroiditis

ClydeJAMA

SawkaJCEM

WalshJCEM

BuneviciusJIN

BuneviciusNEJM

Bunevicius. N Engl J Med. 1999 Feb 11;340(6):424-9. Bunevicius. Int J Neuropsychopharmacol. 2000 Jun;3(2):167-174. Walsh et al. J Clin Endocrinol Metab. 2003 Oct;88(10):4543-50. Sawka et al. J Clin Endocrinol Metab. 2003 Oct;88(10):4551-5. Clyde. JAMA. 2003 Dec 10;290(22):2952-8.

T3 and T4 / T3 Therapy

RxList Web site. Liothyronine Sodium Indications. Available at: http://www.rxlist.com/cgi/generic3/liothyronine_ids.htm. Accessed February 16, 2006.

The American Thyroid Association Web site. Thyroid Hormone Treatment FAQ. Available at: http://thyroid.org/patients/brochures/HormoneTreatmentFAQ.pdf. Accessed February 16, 2006.

• T3 has a very short half-life

• Liothyronine– Synthetic

– T3 is more biologically active that LT4

– No indication for the use of T3 alone

• Thyroid extract– Porcine-derived

– T4 and T3

Suboptimal Thyroxine TherapyWhat Causes It?

Mild Hypothyroidism• Low Rx dose• Poor compliance• Drug interaction• Dietary interference

with absorption• Pregnancy• ↓ Residual gland

function• Formulation switch

Mild Hypothyroidism• Low Rx dose• Poor compliance• Drug interaction• Dietary interference

with absorption• Pregnancy• ↓ Residual gland

function• Formulation switch

Mild Thyrotoxicosis• High Rx dose• Factitious ingestion• Aging with ↓

requirement for LT4

• Nonsuppressed endogenous gland function

• Stopping estrogen therapy

• Formulation switch

Suboptimal Thyroxine TherapyWhat Causes It?

According to current guidelines, what TSH range should I treat my

hypothyroid patients to:

A. 1 – 5.5 mU/L

B. 0.5 – 4.5 mU/L

C. 0.5 – 2.0 mU/L

D. 1 mU/L

www.accessdata.fda.gov/scripts/cder/ob/docs/temptn.cfm

?

Treatment Target

The TSH target for hypothyroid patients is generally considered to be .5 – 2.0 mu/L

ThyroidToday Web site. Hypothyroidism Treatment Failure: Differential Diagnosis. Available at: http://www.thyroidtoday.com/ExpertOpinions/S320%20Hypothyroidism%20Differential%20Diagnosis.pdf. Accessed February 16, 2006.

How Common Is Suboptimal Thyroxine Therapy?

a. 1%

b. 10%

c. 20%

d. 40%

?

Excessive Thyroxine Therapy

Inadequate Thyroxine Therapy

30%

20%

10%

Ross, 1990 Parle,

1993

Canaris, 2000

Hollowell, 2002

27%

21%

14%

18% 18%

22%

15%

18%

10%

20%

30%

Ross DS, et al. JCEM.1990;71:764-769. Parle JV, et al. Br J Gen Pract. 1993;43:107-109. Canaris GJ, et al. Arch Intern Med. 2000;160:526-534. Hollowell J, et al. JCEM. 2002;87:489-499.

How Common Is Suboptimal Thyroxine Therapy?

Potential Reasons to Increase LT4 DoseDecreased L-T4 AbsorptionA. Malabsorption Syndromes

1. Jejunoileal Bypass Surgery2. Short Bowel Syndrome3. Cirrhosis

Drugs or Diet1. Cholestyramine2. Aluminum Hydroxide3. Sucralfate4. Ferrous Sulfate5. Calcium Carbonate6. Cation-Exchange Resin7. High Fiber Diet8. Infants Fed Soybean Formula9. ? Excess Soybean in Adults10. Achlorhydria11. ? Proton Pump Inhibitors12. ? H-2 Blockers

Increased Biliary ExcretionA. Phenytoin sodium B. RifampinC. PhenobarbitalD. Carbamazepine

Decreased Deiodination of T4 to T3

A. AmiodaroneIncreased TBGA. PregnancyB. BCPC. EstrogensD. HepatitisE. HereditaryUnknownA. Sertraline

ThyroidToday Web site. Hypothyroidism Treatment Failure: Differential Diagnosis. Available at: http://www.thyroidtoday.com/ExpertOpinions/S320%20Hypothyroidism%20Differential%20Diagnosis.pdf. Accessed February 16, 2006.

Carr D, et al. Clin Endocrinol. 1988;28:325-333.

Suboptimal Thyroxine Therapy Impact of Small Thyroxine Dose Changes

10

8

6

4

2

0.2.1

-50 -25 +25 +50

TSHmU/L

T4 (g/day) Dose

• 21 hypothyroid adults with normal TSH on thyroxine

• Dose changed by 25 µg q. 6 weeks

+75Optimum

10

8

6

4

2

0.2.1

-50 -25 +25 +50

TSHmU/L

T4 (g/day) Dose+75

Normal TSH range

Above-normal TSH

Below-normal TSH

Optimum

Carr D, et al. Clin Endocrinol. 1988;28:325-333.

Suboptimal Thyroxine Therapy Impact of Small Thyroxine Dose Changes

Clinical Consequences of Elevated and Decreased TSH

Mild Hypothyroidism & Mild Thyrotoxicosis

Consequences

Mild Hypothyroidism• ↑ Cholesterol• ↑ Atherosclerotic

cardiovascular disease and MI risk

• ↑ Miscarriage risk• Impaired fetal

development• Inadequate TSH

suppression in thyroid cancer patients

Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.

7.2

7.0

6.8

6.6

6.4

6.2

6.0

5.8

5.6

5.4

5.2

Mea

n T

ota

l Ch

ole

ster

ol L

evel

, mm

ol/L

280

270

260

250

240

230

220

210

200

(mg

/dL

)

>10-

15<0

.3

0.3-

5.1

>5.1

-10

>15-

20

>20-

40

>40-

60

>60-

80 >80

TSH, mlU/L

Abnormal TSH LevelEuthyroid

5.41(209)

5.59(216)

5.78(223)

5.85(226)

5.93(229)

6.16(238)

6.19(239)

6.99(270) 6.92

(267)

Consequences of Hypothyroidism

↑ Cholesterol When Mild & Overt

*P<0.003 compared with euthyroid

*

* *

**

*

* *

1.41.251.13

0.95

0

0.5

1

1.5

2

2.5

3

SubclinicalHypothyroid

Euthyroid

Triglycerides (mmol/L)

CRP mg/L

Kvetny J et al. Clin Endocrinology. 2004;61:232-238.

Consequences of Hypothyroidism

CRP and LipidsN=1212 Danish subjects mean age 42 years963 euthyroid TSH 0.6-2.8mU/L249 with subclinical hypothyroid TSH 2.81- 10mU/L

P=0.01

P<0.01

Consequences of Hypothyroidism

Abnormal Lipid Profile

T4 Therapy

Hypothyroid State

Total cholesterol

LDL-cholesterol

HDL-cholesterol

Triglycerides

Modified from Frankyn JA. In: Braverman LE, Utiger RD, eds. Werner & Ingbar's The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2000:833-836.

Effect of LTEffect of LT44 Rx on Total Cholesterol Rx on Total Cholesterol

in Subclinical Hypothyroidismin Subclinical Hypothyroidism

• LT4 tx may lower LDL but does not appear to affect HDL or TG

Danese M et al. JCEM. 2000;85(9):2993-3001.

Jaeschke (n=31)Caron (n=29)Miura (n=15)

Nilsson (n=29)(n=18)

Nystrom (n=17)Paoli (n=15)

Cooper (n=33)Franklyn (n=11)

Arem (95) (n=14)Arem (90) (n=13)

Powell (n=15)Bogner (n=7)

Bell

Overall (n=238)0.50.0-0.5-1.0-1.5-2.0

Change in Total Cholesterol, mmol/L

-0.20(7.9mg)

0

50

100

150

200

250

TC HDL LDL TG

Baseline

LT-4 Rx

Placebo

*

*

* p<0.05

Monzani F, et al. J Clin Endocrinol Metab. 2004;89:2099-2106.

Levothyroxine Effect on Cholesterol

TC 10%LDL 13%

Od

ds

Rat

io (

95%

CI)

†

0

0.5

1

1.5

2

2.5

3

3.5

Aortic Atherosclerosis Myocardial Infarction

Euthyroid

1.0* 1.0*

Mild Hypothyroidism (TSH >4.0)

1.7 (1.1-2.6)

2.3 (1.3-4.0)

Hak AE, et al. Ann Intern Med. 2000;132:270-278.

Consequences of Mild Hypothyroidism Atherosclerosis

*Reference risk†Adjusted for age

N=1149 women

Imaizumi M. JCEM. 2004;89(7):3365-3370.

Consequences of Mild Hypothyroidism Ischemic Heart Disease

• 2293 controls (no Hx of thyroid disease)

• 257 pts with mild hypothyroidism (TSH>5.0 mU/L; nl FT4)

• Mild hypothyroidism was associated with the prevalence of MI after adjustment for age and sex (odds ratio 2.6; 95% CI [1.2-5.6])

• Significantly more deaths from nonneoplastic disease in men with subclinical hypothyroidism at 6 years.

Controls (men)

controls

A

B

Ove

rall

surv

ival

Ove

rall

surv

ival

1.00

.95

.90

.85

.80

.75

.70

1.00

.95

.90

.85

.80

.75

.70

0 1 2 3 4 5 6 7 8 9 10

0 1 2 3 4 5 6 7 8 9 10

Years of follow-up

Years of follow-up

Men with subclinical hypothyroidism

Controls (men)

Women with subclinical hypothyroidism

controls

Parameter Biondi, 1999 Monzani, 2001

Number 10 hypo, 30 control 20 hypo, 20 control

Systolic Function — Echo PEP/LVET

Hypo (vs Control) — ↓

T4 Therapy Effect — Normalization

Diastolic Function IVRT, A wave, MVQ IVRT, MVQ

Hypo (vs Control) ↓ ↓

T4 Therapy Effect Normalization Normalization

IVRT = isovolumic relaxation time; MVQ = mitral valve flow velocity; PEP = preejection period; LVET = left ventricular ejection time.

Biondi B, et al. J Clin Endocrinol Metab. 1999;84:2064-2067. Monzani F, et al. J Clin Endocrinol Metab. 2001;86:1110-1115.

Consequences of Mild Hypothyroidism Cardiac Function

Mild Hypothyroidism during Pregnancy

Subclinical Hypothyroidism and Pregnancy Outcomes

• 17,298 tested women• 404 with subclinical hypothyroidism (2.3%)

– TSH < 10 mU/L 88%

– TSH > 10mU/L 12%

• Increased risk of placental abruption and pre-term delivery

• Increased incidence of respiratory distress syndrome

Casey et al. Obstet Gynecol. 2005; 105:239.

Consequences of Mild Hypothyroidism Fetal Death

0.9%

3.8%

0 1 2 3 4 5

Maternal TSH 6 mU/L

Maternal TSH <6 mU/L

• TSH >6 mU/L in 2.2% of mothers with singleton pregnancies (n = 9403)

• Fetal death rate 4x greater with high TSH • Other pregnancy complications were equivalent

Rate of Fetal Death and Thyroid Deficiency

(P<0.001)

Allan WC, et al. J Med Screen. 2000;7:127-130.

5%

19%

0 5 10 15 20 25

Consequences of Mild Hypothyroidism Fetal Brain Development

• Children of women with untreated hypothyroidism during pregnancy:– Averaged 7 points lower on IQ testing*– Had a significant percentage (19%) of IQ 85

IQ Scores of 85

Control

Children

Children of Mothers withUntreated Hypothyroidism

(P<0.005)

*Full-scale Wechsler Intelligence Scale for Children.

Haddow JE, et al. N Engl J Med. 1999;341:549-555.

• TSH testing recommended in 1st trimester

• To maintain euthyroid state, LT4 dose may need to be increased during pregnancy1

• Maternal hypothyroidism during gestation may result in a variety of fetal complications1,2

Mild Hypothyroidism and Pregnancy

1Idris I et al. Clin Endocrinol. 2005;63:560-565. 2Pop. Clin Endocrinol (Oxf). 2003 Sep;59(3):280-1.

N N (%)pregnancies w/ TSH

Kaplan (1992) 42 27 (64%)Girling (1992) 33 7 (21%)McDougal (1995) 20 20 (100%)Caixas (1999) 41 19 (46%)Abalovich (2002) 95 66 (70%)Chopra (2003) 13 6 (46%)Alexander (2004) 19 17 (89%)

L-T4 Dosage Adjustment in Pregnancy

OVERALL 263 162 (61%)

Kaplan. Postgrad Med.1993 Jan;93(1):249-52, 255-6, 260-2. Girling JC, deSwiet M. Br. J Obstet Gynaecol. 1992 May;99(5):368-70. Caixas. J Clin Endocrinol Metab. 1999 Nov;84(11):4000-5. Abalovich. Thyroid. 2002 Jan;12(1):63-8. Chopra. Metabolism. 2003 Jan;52(1):122-8. Alexander EK. N Engl J Med. 2004 Jul 15;351(3):241-9.

• Cardiac arrhythmias,especially atrial fibrillation

•↑ CV mortality

Mild Thyrotoxicosis

Consequences

TSH 0.1 mU/L

TSH>0.1 – 0.4 mU/L

Consequences of Mild Thyrotoxicosis

Atrial Fibrillation

Adapted from: Sawin CT, et al. N Engl J Med. 1994;331:1249-1252.

30

25

20

15

10

5

00 1 2 3 4 5 6 7 8 9 10

Inci

den

ce o

f A

tria

l Fib

rilla

tio

n (

%)

Years

Normal TSH(>0.4 – 5.0 mU/L)

N=2007 pts > 60

• 1191 UK persons 60 years • No thyroid meds

• Assessments• Serum TSH in 1988-89• 10-year mortality

• Results• Low TSH in 6% • TSH correlated with

CV mortality • Hazard ratio for TSH

<0.5 at 2 years:• All-cause death: 2.1• CV death: 3.3

Parle JV, et al. Lancet. 2001;358:861-865.

Consequences of Mild Thyrotoxicosis

Cardiovascular Mortality

<0.5 <0.5

2.1–5.01.3–2.00.5–1.2

100

95

90

85

80

75

70

65

01 2 3 4 5 6 7 8 9 100

Years of Follow-up

Su

rviv

al f

rom

Cir

cula

tory

Dis

ease

TSH (mU/L)

2.1–5.0

1.3–2.0

0.5–1.2