Therapy of Hypothyroidism: New and Old Concepts of Columbia Chapter Scientific Meeting – 2015 November 6 – 7, 2015 Therapy of Hypothyroidism: New and Old Concepts Leonard Wartofsky,

District of Columbia Chapter Scientific Meeting – 2015

November 6 – 7, 2015

Therapy of Hypothyroidism:

New and Old Concepts

Leonard Wartofsky, M.D.

MedStar Washington Hospital Center

Georgetown University School of Medicine

Washington, DC

SUBCLINICAL THYROID DISEASE Case

• 51 y.o. WF with

high cholesterol; (-)

Hx; FHx: M --?

AITD

Bro: DM/gray

ROS:

menopause@44,

mild hypertension ;

? fatigue.

• Tchol = 245 mg%,

HDL 61, LDL 171,

hematocrit 35%,

P.E. : BP 145/93.

No palpable goiter

SUBCLINICAL THYROID DISEASE Case : Thyroid Function Tests

• Total T4 = 6.1 mcg/dl (NL 5-12)

• Free T4 = 0.99 ng/dl (NL 0.80-1.90)

• TSH = 4.978 mU/L (NL 0.4-5.5)

“SUBCLINICAL” THYROID DISEASE EARLY THYROID FAILURE

Objectives - 1

• What are the criteria for Dx ?

• What population is at risk ?

• How frequent is this entity in the population?

• If TSH is our most sensitive index of thyroid

function, how can there be thyroid failure if the

TSH is “normal” ?

“SUBCLINICAL” THYROID DISEASE EARLY THYROID FAILURE

Objectives -2

• What are the associated abnormalities?

• Should patients be followed or treated?

• What are the benefits of Rx ?

“SUBCLINICAL” HYPOTHYROIDISM

What is it ?

SUBCLINICAL HYPOTHYROIDISM DEFINITION

• Normal:

— TT4

— TT3

— FT4

— FT3

— RT3U

• TSH = 3 - 15 mIU/L

SUBCLINICAL HYPOTHYROIDISM

PATIENTS AT RISK

• Aging: Women > age 45

Men > age 60

• Hx of Rx for Graves’ disease

• Hypercholesterolemia

• +Family Hx of thyroid disease

• Infertility; menstrual irregularities

• Pregnancy; Post-partum period

Redefining the Normal Range

NHANES III (1988-1994) Median TSH in 13,344 with No Thyroid Disease.

No TPO ab, No HRT, No Thyroid RX T

SH

(u

U/m

L

AVERAGE: TSH 1.49 ± 0.04 uU/mL (mean ± SE)

0

0.5

1

1.5

2

2.5

12-1920-2930-3940-4950-5960-6970-7980+

AGE Hollowell et al. JCEM 87(2002)489

Individual TSH Normal Range

Participants

Mean +/- 2 SD = 1.27 (0.16 - 2.39)

Anderson S, et al. J Clin Endocrinol Metab. 2002;87:1068-1072.

Population normal TSH range may not equal

individual normal range

Person A

Normal Range

TSH = 0.9-1.5

TSH Normal Range

Person B

Normal Range

TSH = 1.2-3.0

Population vs Individual Variations in Serum TSH

Prevalence of Elevated Serum TSH by Decade of Age and Gender (n=798)

Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499.

NHANES III Study (n=17,353)

% P

artic

ipan

ts w

ith E

leva

ted

TS

H

0

5

10

15

20

13-19 20-29 30-39 40-49 50-59 6-69 70-79 >80

24

Males

3.0 2.0 2.5

4.1

2.0 3.0

11.0 10.8

Females

2.0 2.2 3.0

6.5

8.5

10.5

13.8

15.8

NHANES III: Prevalence of Positive Anti-TPO Antibodies

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

Pe

rce

nt

Age

Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499.

• Euthyroid Outliers - inherent TSH lability

• Measurement of bioinactive isoforms

• Occult thyroid dysfunction

TSH Population Reference Ranges

Reasons for the skew of the TSH

upper limit include:

~4.0 ~0.45 1-1.5 ~2.5 ~0.45 1-1.5 ~2.5 ~4.0

95% Limits

10

1,000

100

10

1

TSH mU/L

Sensitivity

Limit

0.01 0.1 1 10 100 1000

Normal Range

Demers LM, Spencer C. NACB: Laboratory Support for the Diagnosis and Monitoring of Thyroid

Disease, 2002.

ı TPOAb : Prevalence = 12.3%

“SUBCLINICAL” HYPOTHYROIDISM

What is the natural

history with follow-up ?

SUBCLINICAL HYPOTHYROIDISM

PROGRESSION TO OVERT DISEASE (Rosenthal et al., JAMA 1987;258:209)

• 258 healthy elderly followed x 4 yrs

• 13.2% had subclinical

hypothyroidism based on normal T4

and elevated TSH

• 4 yrs later:

• 33% overtly hypothyroid

• 80% of those with (+) Ab’s

SUBCLINICAL HYPOTHYROIDISM PROGRESSION IN THE ELDERLY

0

10

20

30

40

50

60

70

80

TgAb(+) TgAb(-)

Rosenthal et al., JAMA 1987;258:209

% Overtly Hypothyroid after 4 years

Developing Autoimmune Thyroid Dysfunction

TPO-Ab

Elevation

Subclinical

Hypothyroidism

Overt

Hypothyroidism

(FT4 Decrease)

Years

5%/Year

Activation of

Autoimmune

Process

Environmental

Factor(s)

Genetic

Predisposition

Spencer

Progression of Mild Thyroid Failure

Years

NORMAL RANGE

Overt Hypothyroidism

Mild Thyroid Failure Euthyroid

T3 T4

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

TSH

MILD THYROID FAILURE REPORTED ABNORMALITIES

• Symptoms

• Cognition; memory; psychometrics

• Neurologic function

• Muscle function; CPK

• TChol, LDL, apo(a), apo(b), TG

• PVR/systolic function; Diastolic function

• STI’s;Atherogenesis; plaque progression

• Pregnancy outcomes

Lipid Profiles in Mild Thyroid Failure

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

Even mild Hypothyroidism is associated with increased

total Chol and LDL-Chol, both markers of CV disease

Cholesterol LDL-C HDL-C

Colorado Thyroid Disease Prevalence Study (N=25,862)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

%

The Heart in Mild Thyroid Failure

MILD THYROID FAILURE AND RISK OF ISCHEMIC HEART DISEASE

(Imaizumi et al. JCEM 2004; 89:3365-70)

• 257 pts with TSH > 5 and NL FT4

240/257 had TSH = 5 - 10

vs. 2293 controls (TSH 0.6-5.0)

• X-sectional analysis; MTF associated with

ischemic HD (OR 2.7) independent of age,

BP, BMI, TChol, smoking, or DM

• 10 yr F/U: Increased all cause mortality

(HR 1.9-2.1) for men

MILD THYROID FAILURE AND

RISK OF ISCHEMIC

HEART DISEASE

• Risk of Ischemic

Heart disease (O.R.)

– Overall = 2.7

– Women = 1.7

– Men = 4.5

(Imaizumi et al. JCEM 2004; 89:3365-70)

Mild Thyroid Failure as a Risk Factor for Myocardial Infarction

• The Rotterdam Study

– Population study of 7983 Subjects

– Baseline Study: 1990-1993

– 1149 Women Evaluated for:

• Lipids and BMI

• TSH (Free T4 if TSH abnormal)

• Aortic Calcifications

• EKG and History of MI

– Followed-up Chart Review in 1996

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

Association of MTF with risk of MI & atherosclerosis

Subclinical hypothyroid*

2.3

1.7

Od

ds

Ra

tio‡

0

0.5

1

1.5

2

2.5

3

3.5

Myocardial Infarction

Subclinical hypothyroid*

and antibodies†

3.1

1.9

Euthyroid

1.0 1.0

Aortic Atherosclerosis

* Normal T4 & TSH > 4.0 mU/L; †To thyroid peroxidase; ‡Adjusted for patient age.

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

Rotterdam Study (N=1149 elderly women)

Age-adjusted RR for M.I. attributed to MTF compared to other classic

CV risk factors.

Rotterdam Study (N=1149 elderly women)

2.4

Rela

tive R

isk

0

0.5

1

1.5

2

2.5

3

3.5

Subclinical

Hypothyroidism

2.0*

2.4

1.6

2.5

1.2†

Hypercholes

-terolemia

Hyper-

tension

Smoking

(Current)

Smoking

(Past)

Diabetes

Mellitus

*Current compared with never smoked; †Past compared with never smoked.

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

INCREASED RISK FOR ALL CAUSE & CV

MORTALITY Tseng et al., J Am Coll Cardiol

2012; 60:730-7

•115,746 subjects without thyroid

disease; SCH = TSH >5

•10 yr F/U

All cause

CV

SUBCLINICAL HYPOTHYROIDISM & ALL CAUSE MORTALITY

McQuade et al, Thyroid 2011; 21:837-43

Amer J Med 2006; 119:541-51

Overall O.R. = 1.81-2.38 Subgroup Analysis: O.R. = 1.42-1.72

SUBCLINICAL HYPOTHYROIDISM

BENEFICIAL EFFECT OF L-T4 Rx ON CV RISK FACTORS & QOL (Razvi et al JCEM 2007; 92:1715)

• 100 pts in a RCT, double blind, crossover of 100 mcg LT-4 vs. placebo

• Measured TC, LDL, endothelial function, & pt. reported outcomes

• Significant improvement seen in TC, LDL-C, waist/hip ratio, flow-mediated dilatation, complaints of fatigue

• Sustained changes would yield a 10% reduction in 10 yr CV mortality

Stratified Analysis of Effect of Subclinical Hypothyroidism

on Risk of CHD

Ochs N et al, Ann Intern Med 2008;148:832-45

– <65 years RR 1.51 (1.09-2.09)

– ≥65 years RR 1.05 (0.90-1.22)

Razvi S et al, JCE&M 2008;93:2998-3007

– <65 years RR 1.68 (1.27-2.23)

– ≥65 years RR 1.02 (0.85-1.22)

SUBCLINICAL HYPOTHYROIDISM, AGE, & ISCHEMIC HEART DISEASE

Mariotti S., JCEM 2008; 93:2969-

71

MILD THYROID FAILURE REPORTED BENEFITS OF L-T4 THERAPY

• Prevent progression to overt disease

• Relieve symptoms

• Cognition; memory; psychometrics

• Neurologic function

• Muscle function; CPK

• TChol, LDL, apo(a), apo(b), TG

• PVR/systolic function; Diastolic function

• STI’s;Atherogenesis; plaque progression

• Pregnancy outcomes

SO, THE TSH IS >3 mU/L START L-T4 OR WHAT ?

• Repeat TSH in 6-8 weeks

• Measure anti-TPO antibodies

• Rx’tic trial if symptomatic or TSH => 10

• Or, first determine if Hx supports the Dx:

• ? Goiter, diastolic dysfunction, dyslipidemia

• ? Pregnancy, infertility

• ? (+) Family Hx

• ? Lithium Rx, Amiodarone, etc.

• and then treat.

T4/T3 Combination Therapy

Case Discussion • 41-year-old woman with Grave’s disease

undergoes RAI ablative therapy rendering her hypothyroid

• She is seen in follow-up 2 years later with the following thyroid function test results on levothyroxine therapy:

– TT4 10.2 (NL 5 – 12) – TT3 98 (NL 80 – 180) – TSH 0.988 (NL 0.3 – 3.5)

Case Discussion (cont.)

• Complains of fatigue, weakness and lethargy she claims have been a problem only since the RAI therapy

• Recently visited internet web sites and wants to know why you are not treating her with T3

T4/T3 COMBINATION THERAPY QUESTIONS

• Can hypothyroid patients be optimally replaced by thyroxine therapy alone?

• Are there convincing data that combined T4/T3 results in: – more physiologic tissue T4/T3 and serum TSH levels?

– improved clinical status?

• Are there new data that may provide a rationale for T4/T3 therapy?

ARGUMENTS FOR T3

SUPPLEMENTATION

1. The thyroid produces both T3 and T4

2. L-T4 therapy has no T3

3. Patients on T4 alone have higher than NL T4/T3 ratios

4. Peripheral conversion of T4 to T3 is inadequate

5. Tissues have deficient T3 levels

6. T4 monotherapy = “Tissue hypothyroidism”

Studies in rodents indicated that combined T4/T3 therapy simultaneously normalizes plasma and all tissue T4 and T3 concentrations.

T4/T3 COMBINATION THERAPY

Tissue T4 and T3 Content

Escobar-Morreale et al. J Clin Invest. 1995;96:2828.

T4/T3/rT3

T4

T3 rT3

T4 T3 rT3

30 ug/d

100 ug/d

30 ug/d

15%

85%

SOURCES OF T4 AND T3

T4/T3 = 10/1-14/1

Type 1 5’

Deiodinase

T4/T3 COMBINATION THERAPY THE “PERFECT” PILL

For the 1.78 m2 patient:

• T4 content = 112 µg

• Bioavailable T4 = 100 µg

• T3 Content = 5 µg (delayed release)

• Bioavailable T3 = 5 µg +25 µg(from T4)

T3 + T4 COMBINATION THERAPY

CONCERNS WITH PRIOR STUDIES

• Focus on QOL and psychological endpoints

• Limited data on thyroid hormone action

• Usually fixed dose/d of T3; variable T4/T3 ratio

• Studies not targeted to TSH level

• Lack of statistical power to account for genetic

polymorphisms

• Small sample size; lack of homogeneity of

patient population

• Brief duration of study period

T4/T3 Combination Therapy

The ‘Ultimate Solution’?

1. T4/T3 Tablets with correct 14:1 molar ratio 2. True slow or constant release formulation x 24 hrs 3. RCT’s showing optimal TSH levels and clinical benefit 4. Greater understanding of genetic influences on thyroid function 5. Maintenance of normal FT3/FT4 ratio

T4 Rx ALONE DOES NOT GUARANTEE EUTHYROIDISM

Gullo et al., PLoS one 6 (8):e22552; August 2011

• Measured FT4, FT3 in 1811 athyreotic pts on

LT4 with NL TSH vs. 3875 euthyroid controls

• Patients had higher FT4/lower FT3 (p = <0.001)

• Found ~ 20% of patients do not maintain FT4

and FT3 in reference range in spite of NL TSH

• Reflects inadequate peripheral T4 → T3

deiodination to compensate for missing T3

secretion

• ? Longterm effects /clinical consequences

Athyreotic patients on LT4

with normal

TSH

Gullo et al., PLoS one 6 (8):e22552; August 2011

% with higher than

Normal range FT4

% with lower

than normal

range FT3

% with lower than normal

range FT3/FT4 ratio

[2.5% of euthyroid controls]

Gullo et al., PLoS one 6 (8):e22552; August 2011

% pts with abnormally low FT3/FT4 ratio increases with higher

dose of LT4 (?due to inhibition of deiodinase by high T4)

• Could variants in DIO2 gene influence well

being on T4 Rx irrespective of TSH levels?

• Analyzed common variants of 3 DIO2 genes

vs. response to T4/T3 in 552 subjects on T4

• CC genotype

• Present in 16% of population

• Had worse baseline GHQ scores on LT4

• Improved scores on T4/T3

• No change in T4, T3, TSH levels

DIO2 POLYMORPHISM AND RESPONSE TO T4/T3 Rx Panicker et al., JCEM 94:1623-29, 2009.

• With CC variant in only 16% of population,

prior studies may have been underpowered

to detect difference

• May explain why some patients on T4 do not

feel ‘back to normal’

• ? Influence of DIO2 activity in the brain and

psychological well being

• Perhaps variations in other candidate genes,

e.g., thyroid hormone transporters, might

also influence well being

DIO2 POLYMORPHISM AND RESPONSE TO T4/T3 Rx Panicker et al., JCEM 94:1623-29, 2009.

GENETIC INFLUENCES ON TSH Panicker et al., Am J Hum Gen 87:430-5, 2010

• Genome wide association study of 2.1

million single nucleotide polymorphisms

(SNP’s) in 2014 female twins

• Found significant association between TSH

and rs10917469 that was replicated in a

community based sample of 1154 people

• 29% carry the variant with TSH difference

between wild type and variant = 0.5 mIU/L

• Likely to be clinically relevant

WHICH IS BETTER - T4 or T3? Celi et al., JCEM 2011; 96:3466-74

• 14 hypothyroid pts Rx’d with either T3 or T4

• Randomized, double blind, crossover

• Rx: T4 or T3 TID to achieve target TSH

• Lipids, glucose metab assessed 6 wks after

stable at target TSH level

• NSD in heart rate, TSH, BP, HDL, exercise

tolerance, or insulin sensitivity

WHICH IS BETTER - T4 or T3? Celi et al., JCEM 2011; 96:3466-74

• While taking T3, patients had a significantly greater decrease in:

– weight loss

– total cholesterol

– LDL cholesterol

– apolipoprotein B

• Conclusion: T3, at T4 equivalent dose based

on TSH level, had greater effects on weight &

lipid metabolism without differences in CV

function or insulin sensitivity

T3 vs. T4 for Hypothyroidism: Celi et al. JCEM 2011

T3 vs. T4 for Hypothyroidism: Celi et al. JCEM 2011

TREATMENT OF HYPOTHYROIDISM

AACE/ATA PRACTICE GUIDELINES 2012 Garber et al., Thyroid 22:1200-1235

• “not known whether genotyping will identify patients who will benefit from T4/T3”

• “Treatment is best accomplished using synthetic LT4”

T4/T3 COMBINATION THERAPY QUESTIONS

• Can hypothyroid patients be optimally replaced by thyroxine therapy alone?

• Are there convincing data that combined T4/T3 results in: – more physiologic tissue T4/T3 and serum TSH levels?

– improved clinical status?

• Are there new data that may provide a rationale for T4/T3 therapy?

T4/T3 COMBINATION THERAPY CONCLUSIONS

• Optimal Rx with T4 + T3 difficult due to lack of sustained release product

• No evidence of clear benefit of T3 + T4 in all patients, but patients with genetic polymorphisms may benefit

• Safest to follow ATA/AACE Guidelines

• But, in selected patients, may consider adding T3 to restore low FT3/FT4 ratio to NL while maintaining NL TSH

Back to our Case Discussion:

• 41-year-old woman who had RAI for Graves’ disease and is hypothyroid -

• Complains of fatigue and lethargy and is unhappy with her L-T4 treatment

SHOULD T3 BE ADDED TO T4 THERAPY FOR HYPOTHYROIDISM ?

SHOULD T3 BE ADDED TO T4 THERAPY FOR HYPOTHYROIDISM ?

District of Columbia Chapter Scientific Meeting – 2015

November 6 – 7, 2015

Therapy of Hypothyroidism:

New and Old Concepts

Leonard Wartofsky, M.D.

MedStar Washington Hospital Center

Georgetown University School of Medicine

Washington, DC

Review of Images Tools to assess attenuation

• Tomographic Images Location

Pattern

Does the pattern fit vascular territory

Look at individual frames

Cold defect on transaxial slices anterolateral to heart DePuey pp235 #6.