Use and Interpretation

of Thyroid Tests

Herbert L. Muncie, Jr., M.D.

You diagnosed hyperthyroidism 6 mos ago

Endocrine consult recommended 131I therapy

She completed 131I therapy 6 weeks ago

Labs: 1 week ago

TSH - < 0.1 mU/L (nl 0.45 – 4.5)

Free T4 - 0.5 ng/dL (nl 0.8 – 2.0)

Does she have persistent hyperthyroidism

requiring additional 131I therapy ?

36 Year Old Female

(Follow-up Visit)

At initial visit – gave a history of 3 weeks of mild anterior neck pain, palpitations

Mild jitteriness has been noted

Thyroid gland was diffusely tender, but not enlarged

Labs: 1 week ago TSH – 0.25 mU/L (nl 0.45 – 4.5)

Free T4 – 1.4 ng/dL (nl 0.8 – 2.0)

Should she be started on an anti-thyroid

medication for hyperthyroidism?

22 Year Old Female

(One Week Follow-up visit)

Seen last week for mild fatigue

No chest pain or history of CHF

Labs:

TSH – 5.6 mU/L (nl 0.45 – 4.5)

Free T4 - 1.6 ng/dL (nl 0.8 – 2.0)

Anti-TPO antibodies – positive

Should she be started on thyroid replacement?

66 Year Old Female

(Follow-up visit to review labs)

Thyroid Gland

Normal gland function is secretion of two hormones

– L- thyroxine (T4)

– 3,5,3'- triiodo-L-thyroxine (T3)

Normal functioning depends on exogenous iodine intake

– Iodine deficiency rare in developed country

Thyroid Gland

Two lobes joined

by isthmus

Lie anterior &

caudad to

cartilage of

larynx

Thyroid Hormones T4

– Only source is thyroid

T3

– Thyroid produces 20%

– Remaining 80% generated in extra glandular tissue by conversion of T4 to T3

Hormones half-life

– T4 - 1 week

– T3 - 1 day

Sun Mon Tues Wed Thu Fri Sat

X

X X X X X X X

Thyroid Hormones

T4 – 99.97% bound; T3 – 99.70% bound

Thyroid hormones bound to:

– Thyroxine-binding globulin (TBG)

– T4 binding prealbumin (TBPA)

– Albumin

TBG is dominant binding protein

– One binding site for T4 or T3

– 10 fold affinity for T4

Altered Concentrations TBG

Increased TBG

– Pregnancy

– BCP or estrogen

– Tamoxifen

– Hepatitis

– Biliary cirrhosis

– Acute intermittent porphyria

Decreased TBG

– Androgens

– High dose steroids

– Chronic liver disease

– Nephrosis

– Severe systemic illness

– Active acromegaly

Altered Concentrations TBG

Abnormalities of binding protein are associated with elevated or decreased totalT4 or T3

However, always accompanied by normal free T4, free T3 & euthyroid state

E.g. in pregnancy – increased TBG leads to less free T4 temporarily

– Stimulates increased production of total T4 but free T4 level remains normal

Thyroid Hormone Synthesis

T4

T3

Thyroid gland

Organic iodine

in Thyroglobulin

Hypothalamus

Ant. Pituitary

TRH

TSH

T4

T3

+TBGTBG + T4

TBG + T3

I- I- IPO

GI Tract

Iodine to

I-

T4

Thyroid Test Normal Range*

Test Normal Values

TSH 0.45 - 4.5 mU/L

Free T4 0.8 - 2.0 ng/dL

Free T3 0.71 - 1.85 ng/dL

*Confirm normal values for your lab

Are normal values normal?

An individual patient’s TSH remains in a much narrower range with repetitive testing

– Establishment of normal range may have included patients with occult thyroid disease

Results within upper limits of normal range are associated with adverse outcomes

– TSH 2.0 - 4.5 mU/L increased risk overt hypothyroidism over next 20 years

– TSH 4.0 - 4.5 mU/L associated with increased prevalence heart disease

Are normal values normal?

When corrected for underlying or occult thyroid disease

– Mean TSH 1.2 - 1.5 mU/L

– Upper limit for 97.5th percentile – 2.5 mU/L

National Academy of Clinical Biochemistry (NACB) recommends TSH normal to be 0.48 - 3.60 mU/L

– 95% of TSHs in this range

– No evidence thyroxine treatment is beneficial for TSH 3.61 - 4.5 mU/L

Follow-up Thyroid Tests

Radioisotope thyroid scan

– Use for hyperthyroid patient with nodule

– Can locate extra thyroidal tissue

– Can identify nodule function

Hot nodules < 1% cancer

Cold nodules – 20% cancer

However, FNA best for everyone

Follow-up Thyroid Tests

Radioactive iodine uptake (RAIU)

– Main indication is to differentiate between post-partum, silent & subacute thyroiditis

– Helps identify Graves disease unless clinically obvious Graves

Follow-up Thyroid Tests

Ultrasound

– Determines whether nodule solid or cystic

– Guides FNA if difficult to palpate

Follow-up Thyroid Tests(Rarely required)

Antithyroid peroxidase autoantibody (anti-TPO)

Antithyroglobulin antibodies

TBG level

Thyroglobulin level (only produced by thyroid)

– Measure f/u post thyroidectomy for cancer

– Thyroxine replacement lowers level but not thyrotoxicosis

Helps evaluate for thyrotoxicosis factitia

Thyroid nodules

Obtain ultrasound for all nodules

– Size is not predictive or risk of malignancy

Calcification within the nodule increases likelihood of malignancy

Almost all will require FNA

Routine measurement of thyroglobulin is not recommended (SOR F)

Thyroid Cancer Guidelines – American Thyroid Association - 2006

Thyroid nodules

Benign pathology on FNAB & biochemically normal

– No treatment is necessary

– Annual examination & repeat ultrasound

Thyroid Cancer Guidelines – American Thyroid Association - 2006

Reverse T3

What do you do if TSH is normal but Free T4 is below normal?

This can occur in medically ill patients with non-thyroidal illness (NTI)

– Measure reverse T3 to exclude subclinical hypothyroidism

Elevated in NTI

Low with hypothyroidism

Can You Really Exclude Thyroid

Dysfunction?

If clinically really suspect thyroid disease

– Order TSH, free T4, free T3

– TSH alone should not be used to make a diagnosis

If all three are normal – can confidently exclude clinical thyroid disease

TSH below normal, Free T4 elevated

(Hyperthyroidism)

DX: Primary hyperthyroidism

– Graves’ disease

– Multinodular goiter

– Toxic nodule

Gland usually nontender

– No definitive test to prove which it is

If clinically suspect hyperthyroidism & low TSH but normal FT4

– Measure FT3 for T3 hyperthyroidism

Primary Hyperthyroidism

Probably Graves if:

– Thyroid scan has homogeneous pattern

– Positive antithyroid antibodies

However, 10% of Graves are negative for antithyroid antibodies

– 24 hr RAIU normal or elevated

TSH below normal but Free T4 normal

(Subclinical hyperthyroidism)

No treatment indicated even though

– Increased risk of atrial fibrillation

But no increased mortality or other CVD

Repeat TSH, FT4 in 1 – 3 months

Treatment possibly indicated in:

– Early Graves’ Disease

– Multinodular goiter

– Fair evidence beneficial in slowing loss of bone mineral density (BMD)

Subclinical hyperthyroidism

(Follow-up testing)

If the repeat TSH = 0.1 – 0.45 & FT4 remains normal

– No treatment is necessary

– Monitor TSH in 3 – 12 months

If the patient has heart disease, osteoporosis or symptoms of hyperthyroidism

– Look for endogenous hyperthyroid disease

– Obtain thyroid scan, RAIu

If endogenous disease – treat

If no endogenous diesease – no treatment

Subclinical hyperthyroidism

(Follow-up testing)

If the repeat TSH = < 0.1 & FT4 remains normal

– Obtain thyroid scan, RAI uptake to look for endogenous disease

If diagnose is Graves disease or nodular goiter

– Consider treatment for patients with heart disease, osteoporosis, over age > 60 or with estrogen deficiency symptoms

– Otherwise monitor clinically with treatment optional

TSH Normal but Free T4 below

normal Consider pituitary disease – with 2o

hypothyroidism

– TSH usually in normal range when it should be elevated

Can occur within 2-3 months after treatment of hyperthyroidism with I131

May be hypothyroid phase of transient thyroiditis & will resolve spontaneously

TSH Elevated and FT4 below normal

(Primary hypothyroidism)

Common etiologies:

– Autoimmune thyroiditis

– Iatrogenic

Post radioiodine therapy/thyroidectomy

– Medications

– Thyroiditis – subacute, postpartum, silent

TSH Elevated but Free T4 Normal

(Subclinical hypothyroidism)

Affects 5-10% of women

– Transient elevations are common, especially with NTI & medications

– Consider repeating in 6 – 8 weeks

If TSH > 10.0

– Treatment is indicated

Subclinical hypothyroidism If TSH is 4.6 - 9.9, with normal FT4

– Clinical stratification

Consider T4 replacement No benefit to T4 replacement

Documented diastolic dysfunction Normal cardiac function

Diastolic hypertension Normal arterial pressure

Atherosclerotic risk factors No atherosclerotic risk factors

Dyslipidemia Normal lipid profile

Diabetes mellitus Normal glucose metabolism

Smoker Non-smoker

Symptoms of hypothyroidism No symptoms

Goiter No goiter

Positive anti-TPO antibodies No antibodies

Pregnancy Not pregnant

Infertility No infertility

Very elderly patient (> age 85)

Subclinical hypothyroidism

No randomized trials of treatment vs placebo

– Treatment has not been found to reduce adverse events

– Treatment can increase risk of hyperthyroidism, osteoporosis & atrial fibrillation (Clinical Evidence)

In 70-79 yo well functioning patients, TSH 4.5-7.0 mU/L, no increased risk of mobility problems

– Show slight functional advantage [Simonsick 2009]

Subclinical hypothyroidism

In patients > 85 yo condition associated with increased longevity

Positive anti-TPO antibodies associated with progression to overt disease

– However the presence of antibodies does not change management

TSH Normal & FT4 Elevated

Rare combination – consider:

– Intermittent T4 therapy or T4 overdose

– Acute psychiatric illness (first 1-3 weeks)

– Thyroid hormone receptor mutation and resistance to thyroid hormone

A 42 y.o. female diagnosed with primary

hypothyroidism. No other medical problems.

Ht 64”, Wt 156 (71 Kg), BMI 26.8.

Which initial levothyroxine dosage would you

recommend?

Audience Question

a) 25 mcg daily & repeat TSH in 4 weeks

b) 50 mcg daily & repeat TSH in 4 weeks

c) 75 mcg daily & repeat TSH in 4 weeks

d) 100 mcg daily & repeat TSH in 4 weeks

e) 112 mcg daily & repeat TSH in 4 weeks

Initiating Thyroid Replacement

Initiating treatment with full replacement dosage

(1.6 μg/kg) and no cardiac disease

– TSH normalizes in 4 weeks

– No cardiac complications [Roos 2005]

For pregnant patient at initial diagnosis

– Start with 100 – 150 μg daily & titrate every

4 weeks to keep TSH low normal

– If previously being treated with replacement

Increase daily dosage 30%

Initiating Thyroid Replacement

E.g. - for that 42 year old patient who weighed

71 Kg

– 1.6 μg/kg = 113.6 μg

– So 112 μg daily could be initial treatment & then

repeat the TSH in 4 weeks

– Although many physicians start with 50 – 75 μg &

titrate up

In elderly patients (> 60) or with heart disease

– Start with 25 - 50 μg daily & titrate slowly

Hypothyroidism Treatment

CAUTION if clinical state deteriorates shortly after

initiating thyroid replacement therapy suspect

Addison’s disease

– Patients with Addison’s disease can have

adrenal crisis if thyroxin introduced before

glucocorticoid replacement

– Do not screen everyone – too rare

Be suspicious if increased skin & mucosal

pigmentation, postural hypotension, weight

loss or hyperkalemia

Treating Hypothyroidism

TSH level assesses if adequate replacement

– Experts recommend TSH levels between 0.4-2.5 mU/L but pay attention to patients clinical condition

– After dosage adjustment, wait approximately 6 weeks to retest TSH

– A fully suppressed TSH (< 0.1 mU/L) should be avoided

FT4 assess for too much replacement dose

– Some patients feel better only if FT4 slightly elevated & TSH low or undetectable

Treatment Compliance

Stress importance of taking replacement even if not feel different with a missed dose

If miss a dose may double up the next day

– Small randomized trial found weekly dose (7x daily dose) safe [Grebe 1997]

Food & other medications may interfere with absorption

– LT4 should be taken alone on empty stomach with full glass of water at least 30 minutes before breakfast (Medical Letter 2009)

Treating Hypothyroidism - EBM

Adding T3 supplement does not improve QOL or cognitive function (SOR-B)

– Randomized controlled trials

http://www.infopoems.com/irsearch/search_details.cfm?ID=60325&ResultKey=E&title=Levothyroxine%20%2B%20liothyronine%20%3D%20levothyroxine%20alone&PrinterFriendly=1

Combination therapy (LT4 & LT3) Thyrolar®

– No significant benefit over LT4 alone

– Exception for patients with a genetic polymorphism that reduces their ability to convert T4 to T3 (16% of UK population)

Should you screen for thyroid

disease? - EBM

The evidence is insufficient to recommend for or against routine screening for thyroid disease in adults (SOR-I) USPSTF

Fair evidence it will detect patients without symptoms but poor evidence treatment improved outcomes

Potential for harm with false positive

In unselected medical or psychiatric patients TSH may have low yield for true positives and many false positives (SOR- C)

Screening for thyroid disease

Expert opinion recommendations – not EBM

American Thyroid Association – start age 35 & then every 5 years

American College of Physicians (ACP) – start at age 50 in women

– This is consistent with American Association of Clinical Endocrinologists (AACE)

American Academy of Family Physicians – start at age 60 for everyone

• Highest risk groups would be elderly women, pregnant women, diabetics & patients with hyperlipidemia

Amiodarone (Cordarone®, Pacerone®)

& Thyroid Thyroid abnormalities in up to 10% patients

– Hypothyroidism more common

Most are subclinical – approximately 3/4

If overriding indication for amiodarone provide thyroid supplements & continue amiodarone

– Amiodarone can induce thyroiditis & thyrotoxicosis

Almost all are subclinical [Batcher 2007]

If overriding indication for amiodarone give antithyroid medication or prednisone

Lithium & Thyroid

Lithium inhibits the secretion of T4 & T3

– Increases intrathyroidal iodine content

– Inhibits coupling of iodotyrosine residues to form T4 & T3

Can cause

– Goiter

– Hypothyroidism

– Chronic autoimmune thyroiditis

– And possibly hyperthyroidism

Lithium & Goiter

Approximately 50% of patients will develop goiter

Many patients (approximately 20 - 30%) with goiter develop hypothyroidism

– However, it is usually subclinical

Elevated TSH with normal FT4 & FT3

More commonly occurs during the first 2 years of therapy with lithium

Lithium & Autoimmune Thyroiditis

Many of the patients who develop hypothyroidism have an underlying chronic autoimmune thyroiditis

– Prevalence of antithyroid antibodies (anti-TPO) before therapy is higher in patients who become hypothyroid compared to patients who remain euthyroid

Lithium & Hyperthyroidism

The incidence is higher than in the general population

Lithium & Thyroid abnormalities –

Treatment

Continue the lithium if medically necessary

Treat hypothyroidism with replacement therapy

– Continue lithium if providing replacement therapy

– If patient has subclinical hypothyroidism

Then manage as any other patient with that condition

If antithyroid antibodies are present before therapy with lithium monitor TSH every 3 months

– If no antithyroid antibodies are present before therapy monitor TSH every 6 – 12 months.

Key Points - Thyroid Tests

If low likelihood of thyroid disease order:

– TSH only

If really suspect thyroid disease

– TSH & FT4 initially

Initiate full thyroid replacement (1.6 μg/kg) in patients with no known cardiac disease

Key Points - Thyroid Tests

Subclinical hypothyroidism (elevated TSH & normal FT4) or subclinical hyperthyroidism (low TSH & normal FT4) do not usually require treatment

– Monitor frequently

In monitoring thyroid replacement measure TSH to determine if giving enough and FT4 if suspect giving too much

You diagnosed hyperthyroidism 6 mos ago

Endocrine consult recommended 131I therapy

She completed 131I therapy 6 weeks ago

Labs: 1 week ago

TSH - < 0.1 mU/L (nl 0.45 – 4.5)

Free T4 - 0.5 ng/dL (nl 0.8 – 2.0)

Does she have persistent hyperthyroidism

requiring treatment?

36 Year Old Female

(Follow-up Visit)

36 Year Old Female

(Follow-up Visit)

No! Profoundly hypothyroid!!

She will need thyroid replacement therapy

At initial visit – history of 3 weeks of mild anterior neck pain

Otherwise feels fine

Thyroid gland was diffusely tender, but not enlarged

Labs: 1 week ago TSH – 0.25 mU/L (nl 0.45 – 4.5)

Free T4 – 1.4 ng/dL (nl 0.8 – 2.0)

Should she be placed on anti-thyroid medication

for hyperthyroidism?

22 Year Old Female

(Follow-up visit)

22 Year Old Female

(Follow-up visit)

No, probably self-resolving thyroiditis

– Just do follow-up testing

Seen last week for mild fatigue

No chest pain or history of CHF

Labs:

TSH - 5.6 mU/L (nl 0.45 - 4.5)

Free T4 - 1.6 ng/dL (nl 0.8 - 2.0)

Anti-TPO antibodies – positive

Should she be placed on thyroid replacement?

66 Year Old Female

(Follow-up visit to review labs)

66 Year Old Female

(Physical Exam)

Should she be placed on thyroid replacement?

No treatment is indicated

– Treatment would only increase risk of osteoporosis & atrial fibrillation

What Questions do

you have?