# Presentation: 396659

## TSH as a Pharmacodynamic MarkerWhy do We Need It?

- E. Chester Ridgway, M.D.
- University of Colorado Health Sciences Center
- Past President, American Thyroid Association
- Past President, The Endocrine Society
- Joint Public Meeting onEquivalence of Levothyroxine Sodium Products Monday, May 23, 2005Washington, DC
- Co-Sponsored by the Food and Drug Administration and
- the American Thyroid Association, The Endocrine Society,
- and the American Association of Clinical Endocrinologists

## TSH as a Pharmacodynamic MarkerWhy do We Need It?

**TSH is the most sensitive measure of Thyroid Hormone Action**
- Normal Thyroid Hormone Levels are _not_ accurate measures of  Normal Thyroid Hormone Action
- Past BE studies, using TT4, have made mistakes which TSH levels Predicted.  Blood T4 levels are not the ‘active ingredient’ at the ‘site of action’.
- The Toxicities of Excessive or Deficient Thyroid Hormone Levels are now defined by TSH Levels, _not_ by Thyroid Hormone Levels

## TSH

**Pituitary Glycoprotein Hormone**
**Controls Thyroid Gland Growth and Function**
**TSH Production and Secretion Very Sensitive to Circulating Thyroid Hormones**
**TSH Secretion is Pulsatile and Circadian**
- Mean Pulse Frequency = 7-13 Pulses/24 hrs
- Mean Pulse Amplitude = 2.5 mU/L
- Mean Daytime = 1.5-2.0 mU/L
- Mean Nightime = 3.0-4.0 mU/L

## 24-hour TSH Levels in a Healthy Subject

**TSH (mU/L)**

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**24-hour TSH Levels in a Healthy Subject**

## 24-hour TSH Levels in a LT-4

**TSH (mU/L)**

**24-hour TSH Levels in a LT-4**
**Treated Hypothyroidism**

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## Monthly Individual TSH Levels

**Monthly Individual TSH Levels**
**15 Euthyroid Volunteers**

**Andersen JCEM 87:1068, 2002**

**4**

**3**

**2**

**1**

**0**

**TSH**

**mIU/L**

## TSH Reference Range

**0.3**

**~5.0**

**2.5**

**Notes:**
Biochemical tests for most diseases are typically reported by the laboratory alongside a reference range that represents the values from individuals without the disease in question. 

When a large enough cohort of disease-free individuals is tested, their values can typicallybe  expressed as a Gaussian distribution. The laboratory typically uses the 2-standard deviation or 95% confidence limits to represent the “normal range” of the test.

It is important to note that reference ranges established in this way do not include all normal subjects. 5% of normal individuals will have values outside the 2 sd range, 2.5% will be below the lower limit and 2.5 above the upper limit. These concepts hold for most biochemical tests reported by the laboratory.

## TSH vs Free T4

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- Adapted from Spencer , C A

**TSH vs Free T4**
**Ambulatory Subjects**

**Notes:**
The slide illustrates the inverse log/linear relationship seen between serum TSH and T4 levels both at steady state and after L-thyroxine treatment. 
Doubling the serum free T4 level was associated with an approximately 100-fold reduction in serum TSH. 
The sensitivity of the pituitary to minor changes in the level of circulating T4 is “exquisite.”
Moreover, the fact that the log/linear relationship between serum TSH and T4 levels is maintained throughout a broad range of TSH values highlights the usefulness of measuring TSH to establish the severity of thyroid dysfunction. 

## TSH as a Pharmacodynamic MarkerWhy do We Need It?

- TSH is the most sensitive measure of Thyroid Hormone Action
**Normal Thyroid Hormone Levels are **_**not**_** accurate measures of  Normal Thyroid Hormone Action**
- Past BE studies, using TT4, have made mistakes which TSH levels Predicted.  Blood T4 levels are not the ‘active ingredient’ at the ‘site of action’.
- The Toxicities of Excessive or Deficient Thyroid Hormone Levels are now defined by TSH Levels, _not_ by Thyroid Hormone Levels

## Thyroid Failure 

**NORMAL RANGE**

**Overt Hypothyroidism**

**Mild****Thyroid****Failure**

**Euthyroid**

- Adapted from Ayala AR, Wartofsky L. *The Endocrinologist.* 1997;7:44-50.

**Notes:**
This diagram shows the progression of mild thyroid failure, which may be associated with no symptoms or very mild symptoms, to overt thyroid failure. Over time, TSH increases, and T4 and T3 decline to below-normal ranges.
Note that, for a period of months or years, levels of TSH are elevated while T4 and T3 may be normal or near-normal.

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

## THE COLORADO STUDY

**	****Total = 9.5%**
**	****Normal TT4 = 95%**

**THE COLORADO STUDY**

**25,862 SUBJECTS**

**Canaris et al Archives Int Med 160:526, 2000**

_**TSH < 0.3 uU/ml**_
**	****Total = 2.2%**
**	****Normal TT4 = 94%**

## TSH as a Pharmacodynamic MarkerWhy do We Need It?

- TSH is the most sensitive measure of Thyroid Hormone Action
- Normal Thyroid Hormone Levels are _not_ accurate measures of  Normal Thyroid Hormone Action
**Past BE studies, using TT4, have made mistakes which TSH levels Predicted.  Blood T4 levels are not the ‘active ingredient’ at the ‘site of action’.**
- The Toxicities of Excessive or Deficient Thyroid Hormone Levels are defined by TSH Levels, _not_ by Thyroid Hormone Levels

## The Dong Study:  LT4 Bioequivalence

**Mayor GH, et al.  *****AJT. *****1995;2:417-432.**

**Parameter**

**Regimens**

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**1.0**

**1.2**

**.8**

**1.2**

**Range of Bioequivalence**

**Uncorrected**

**Uncorrected**

**Uncorrected**

**Uncorrected**

**Uncorrected**

**Uncorrected**

**The Dong Study:  LT4 Bioequivalence**

**TT4**

**Compared 4 LT4 Drugs**
**	****2 Branded**
**	****2 Generics**

## The Dong Study:  LT4 Bioequivalence

**Mayor GH, et al.  *****AJT. *****1995;2:417-432.**

**Parameter**

**Regimens**

**.8**

**1.0**

**1.2**

**.8**

**1.2**

**Range of Bioequivalence**

**The Dong Study:  LT4 Bioequivalence**

**TSH**

**Compared 4 LT4 Drugs**
**	****2 Branded**
**	****2 Generics**

## LT4 Bioequivalence vs Therapeutic Equivalence24 hr Levels

**LT4 Bioequivalence vs Therapeutic Equivalence****24 hr Levels**

**TSH Levels**

**Mayor GH, et al.  *****AJT. *****1995;2:417-432.**

## LT4 Bioequivalence vs Therapeutic Equivalence24 hr Levels

**LT4 Bioequivalence vs Therapeutic Equivalence****24 hr Levels**

**Mayor GH, et al.  *****AJT. *****1995;2:417-432.**

## LT4 Bioequivalence vs Therapeutic Equivalence24 hr Levels

**LT4 Bioequivalence vs Therapeutic Equivalence****24 hr Levels**

**Mayor GH, et al.  *****AJT. *****1995;2:417-432.**

## LT4 Bioequivalence vs Therapeutic Equivalence

**Mean TSH ****	****1.4****	****3.1****	****2.4****	****1.5****	****4.3**
**  ****(0.5-4.8) **
**No. (%) hypo*****	****0****	****4 (19%)****	****3 (14%)****	****3 (14%)****	****3 (14%)**
**No. (%) hyper****	****0****	****4 (19%)****	****6 (29%)****	****8 (38%)****	****8 (38%)**
**No. (%) with ****	****0****	****8 ****(38%)****	****9 ****(43%)****	****11 ****(52%)****	****11 ****(52%)**
**  ****abnormal TSH**

***3 subjects with low baseline TSH values excluded from data.**
**Hypo = hypothyroid; hyper = hyperthyroid. **

**Mayor GH, et al. *****Am J Ther*****. 1995;2:417-432.**

**LT4 Bioequivalence vs Therapeutic Equivalence**

## T4 Activation and Metabolism

- Bianco et al Endo Rev 23:38, 2002

**T4 Activation and Metabolism**

## THYROID HORMONE ACTION

**THYROID HORMONE ACTION**

**BIOLOGICAL EFFECTS**

**BIOLOGICAL EFFECTS**

**D1**

**D2**

## TSH as a Pharmacodynamic MarkerWhy do We Need It?

- TSH is the most sensitive measure of Thyroid Hormone Action
- Normal Thyroid Hormone Levels are _not_ accurate measures of  Normal Thyroid Hormone Action
- Past BE studies, using TT4, have made mistakes which TSH levels Predicted.  Blood T4 levels are not the ‘active ingredient’ at the ‘site of action’.
**The Toxicities of Excessive or Deficient Thyroid Hormone Levels are now defined by TSH Levels, **_**not**_** by Thyroid Hormone Levels**

## In the Past, Thyroxine Toxicity 

**In the Past, Thyroxine Toxicity **
**Defined By Clinical Presentation**
**T4 and TSH Levels**

**Normal**

**Normal**

**Notes:**
This schematic is intended to illustrate the relationship between TSH and T4 levels in euthyroidism, mild and overt hypothyroidism, and mild and overt thyrotoxicosis. 
When both TSH and T4 are in the normal range, the patient is euthyroid.
Mild hypothyroidism consists of a normal T4 with a elevated TSH.
In overt hypothyroidism both TSH and T4 are out of the normal range.
Mild thyrotoxicosis consists of a normal T4 with a below-normal TSH.
In overt thyrotoxicosis both TSH and T4 are out of the normal range.

Note: Schematic is not drawn to scale.

## Currently, Thyroxine Toxicity Defined

**Currently, Thyroxine Toxicity Defined**
**Only By TSH Level**

**Bone Loss**
**Fractures**
**Myocardial Dysfunction**
**Cardiac Arrhythmias**
**Death**

**Decreased Fetal IQ**
**Increased Lipids**
**Abnormal Vascular Function**
**Atherosclerosis, MI**
**?Death**
**Thyroid Cancer **
**Recurrence and Death**

**Notes:**
This schematic is intended to illustrate the relationship between TSH and T4 levels in euthyroidism, mild and overt hypothyroidism, and mild and overt thyrotoxicosis. 
When both TSH and T4 are in the normal range, the patient is euthyroid.
Mild hypothyroidism consists of a normal T4 with a elevated TSH.
In overt hypothyroidism both TSH and T4 are out of the normal range.
Mild thyrotoxicosis consists of a normal T4 with a below-normal TSH.
In overt thyrotoxicosis both TSH and T4 are out of the normal range.

Note: Schematic is not drawn to scale.

## Subclinical Hyperthyroidism and Fractures

**The Study of Osteoporotic Fractures**

## Subclinical Hyperthyroidism and Fractures

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**Fracture**

**Spine**

**Fracture**

**TSH 0.5-5.5**

**Subclinical Hyperthyroidism and Fractures**
**The Study of Osteoporotic Fractures**

**Bauer DC et al AIM 134:561-568, 2001**

**Relative Risk**

## Framingham database: 2007 patients  60 y.o.
No A-fib at onset of 10 yr follow-up
Patients grouped according to initial TSH
Low (< 0.1 mU/L)
Slightly low (0.1 - 0.4 mU/L)
Normal (> 0.4 but < 5.0 mU/L)

**No A-fib at onset of 10 yr follow-up**
**Patients grouped according to initial TSH**
- Low (< 0.1 mU/L)
- Slightly low (0.1 - 0.4 mU/L)
- Normal (> 0.4 but < 5.0 mU/L)

**Epidemiologic Study:  Low TSH vs. A-fib**

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

**Subclinical Hyperthyroidism ****Atrial Fibrillation**

**Notes:**
But the study that I think has really changed our approach to patients with mild hyperthyroidism is this study by Dr Sawin.
This study looked at over 2000 patients in the Framingham cohort and greater than 60 years of age at the onset of a 10 year period of follow-up.
They grouped these patients according to their initial TSH value into those with a low TSH (less than 0.1), slightly low TSH, normal TSH values , and those with high TSH values.

## SUBCLINICAL HYPERTHYROIDISM

**0.9**

**1.4**

**1.9**

**2.4**

**2.9**

**3.4**

**TSH (uU/ml)**

**RELATIVE RISK**

**SUBCLINICAL HYPERTHYROIDISM**

**ATRIAL FIBRILLATION**

**SAWIN CT et al NEJM 331:1249-52, 1994**

**Framingham**

**28%/10 yrs**

## Survival vs Serum TSHAge >60yrs

**Parle J et al Lancet 358:861,2001**

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- 80

- 60

- 45

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_**TSH**_

**>5.0**

**2.1-5.0**

**1.3-2.0**

**0.5-1.2**

## 45 Subclinical Hypo Patients 
     TSH = 6.3 uU/ml 

32 matched controls 
     TSH = 1.2 
     (gender, age, BMI)

No obesity, smokers, DM.
Blinded RCT

**45 Subclinical Hypo Patients **
**     ****TSH = 6.3 uU/ml**** **
**32 matched controls **
**     ****TSH = 1.2 **
**     ****(gender, age, BMI)**
**No obesity, smokers, DM.**
**Blinded RCT**

**Minimally Elevated TSH and Lipids**

**Monzani F et al. **_**JCEM**_** 89(5):2099-2106. 2004.**

**0**

**50**

**100**

**150**

**200**

**250**

**Chol**

**LDL**

## Carotid Artery Intimal Media ThicknessSCHypo and Increased IMT

**45 SCHypo Patients**
**78% with TSH <10**
**32 matched euthyroid controls (gender, age, BMI)**
**No obesity, smokers, DM.**
**Double Blind RCT**
**Carotid Artery IMT by US as**
**a marker of early atherosclerosis**

**Monzani F et al. **_**JCEM**_** 89(5):2099-2106. 2004.**

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**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1**

**Mean IMT**

**Max IMT**

## Subclinical Hypothyroidism and Atherosclerosis

- The Rotterdam Study

**Random sample = 1149 females**
**Age = 69 +/- 7.5 yrs**
**TSH Elevated = 10.8% (>4 uU/ml)**
**End Points = Aortic Atherosclerosis (Aortic Calcification)**
**	****             ****Myocardial Infarction ( EKG)**
**Methods = Cross-sectional**** **

**Hak AE et al Annals Int Med 132:270, 2000**

## Subclinical Hypothyroidism and Atherosclerosis

**0**

**1**

**2**

**3**

**4**

**Aortic**

**Ca++**

**MI**

**Odds Ratio**

- The Rotterdam Study

**Hak AE et al Annals Int Med 132:270, 2000**

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

## “Minimally” Elevated TSH CV Disease + Mortality 

## Conclusions

**TSH is the most Sensitive Measure of Thyroid Hormone Action**

**TSH is the most Sensitive Pharmacodynamic measure of LT4**

**TSH should be used in Combination with TT4 for future analyses**
**of LT4 Bioequivalence**

**TT4 levels are not Sensitive Pharmacodynamic measures of LT4**