Afternoon Delight

medchiefs.bsd.uchicago.edu

Afternoon Delight

afternoon delight

CLINICAL SKILLS

Interpretation of TFTs

November 11, 2010


Thanks for having me!


Goals and Objectives

Review thyroid hormone physiology and how

it relates to laboratory tests

Identify patterns of thyroid dysfunction in

examining clinical cases

Be able to appropriately choose tests to

evaluate thyroid dysfunction in inpatient and

ambulatory settings

Apply interpretation of thyroid function tests

to management decisions


A Brief Review

Pituitary thyrotropin (TSH) controls secretion

of thyroid hormones thyroxine (T4) and

triodothyronine (T3)

Regulated by negative feedback


HYPOTHYROID

•Hashimoto’s (chronic

autoimmune thryoiditis)*

•Iatrogenic (s/p

thyroidectomy, RAI or

external neck radiation)

•Iodine deficiency

•Iodine excess

•Drugs

•Lithium

•Antithyroid meds

•Other drug effects

on binding globulins

•Amiodarone

•Antithyroid action of

iodine

•In pts w/ preexisting

thyroid disease

•More in iodine

sufficient regions

•Infiltrative disease

•Congenital

•Secondary and tertiary

(central)

•Thyroiditis

•Subacute (painful)

granulomatous

•Subacute (painless or

silent) lymphocytic

•Reidel’s (fibrous)

•Infectious (suppurative)

•Postpartum

•Radiation induced

•Medication (Lithium,

tyrosine kinase inhibitors,

interferon alfa)

HYPERTHYROID

•Graves disease*

•Toxic adenoma

•Multinodular toxic goiter

•Iodine-induced

•Usually in pts w/

nodular goiter

•“Hashitoxicosis”

•Amiodarone

•Iodine load (contains

37% iodine)

•Thyroiditis

•More in iodinedeficient

regions

•Trophoblastic/germ cell

tumors

•Pituitary adenoma

•Thyroid receptor

resistance

•Ectopic

•Exogenous

*Most common causes

http://wikis.lib.ncsu.edu/images/a/ae/Hypohyper.jpg


Thyroid Function Tests (TFTs)

TSH

Highly sensitive third generation assay

Serum total T4 concentration

Thyroxine

>99.9% bound to thyroxine binding

globulin (TBG), transthyretin (AKA

thyroxine-binding prealbumin or TBPA),

or albumin

UCMC Normal Ranges

TSH

T4

T3

Free T4

FTI

Serum total T3 concentration

Triiodothyronine

Less tightly bound to TBG or TBPA, but stronger to albumin

Serum free T4 (or T3) concentration

Free thyroxine

0.3 - 3.8 mcU/mL

5 - 11.6 mcg/dL

80 - 195 ng/dL

0.9 - 1.7 ng/dL

6 - 10.5


Why is Free Important?

“Biologically active hormone”

Can be affected by drugs and illness

Free and total hormone concentrations may not

be concordant

E.g., estrogen-induced TBG excess

High serum total T4 due to high TBG bound T4

Physiologically important free T4 normal


What about the FTI?

T3-resin uptake

Traditional test to calculate free hormone index

Reported value is percent tracer bound to resin, which varies

inversely with number of available free sites of T3

Used to calculate thyroid hormone binding index (THBI)

THBI = Patient’s T3 resin / normal pool T3

Range 0.83-1.16

THBI used to calculate Free Thyroxine Index (FTI)

Helps to diagnose binding protein abnormality

FTI = total T4 x THBI

“Corrects” total T4 by the binding index

Example:

Total T4 = 10 FTI = total T4 * THBI

Free T4 = 1.78 12.8 = 10 * THBI

FTI= 12.8 THBI = 1.28

UCMC Normal Ranges

TSH

T4

T3

Free T4

FTI

High THBI means elevated T3 resin, which

indicates decreased available free sites of T3

c/w hyperthyroidism

0.3 - 3.8 mcU/mL

5 - 11.6 mcg/dL

80 - 195 ng/dL

0.9 - 1.7 ng/dL

6 - 10.5


Clinical use of FTI

Distinguish TBG excess and TBG deficiency

from hyper- and hypothyroidism

Total T4

T3 resin

uptake or THBI

Hyperthyroidism

TBG

excess

Hypothyroidism

TBG

deficiency

FTI Normal Normal


QuickTime and a

decompressor

are needed to see this picture.


Other TFTs

Reverse T3

Useful in diagnosing sick euthyroid

Antibodies

Thyroid stimulating immunoglobulin

Diagnostic of Graves’

But absent in 5-20% of patients with hyperthyroid Graves’ and may also

be present in Hashimoto’s

Thyroperoxidase (TPO) Antibodies (AKA microsomal antibodies)

Hashimoto’s

Postpartum Thyroiditis

Graves

Anti-thyroglobulin antibodies and TSH receptor antibodies

Hashimoto’s

Postpartum thyroiditis

Thyroglobulin

Useful in thyroid CA monitoring for persistent or recurrent disease


Cases

1. Describe the disorder

- Interpret basic TFTs

- History and physical

2. Diagnose the cause

- What disease is this?

- Use information from basic TFTs, physical

examination and additional tests


Case #1

34 yof with anxiety, palpitations presented with

tachycardia and symptoms of LV systolic heart

failure.

Exam: Sinus tachycardia, warm skin, proptosis and

stare, diffusely enlarged thyroid

TSH


Disorder?

Hyperthyroidism

TSH = low

Free T4 = high

T3 = high

Diagnosis?

Additional tests?

Hyperthyroidism


Radioiodine uptake and scan - diffusely

enlarged with high uptake

Diagnosis: Hyperthyroidism secondary to

Graves Disease


Lab Dx of Hyperthyroidism

TSH (+/- free T4) as initial screening test

TSH alone cannot determine degree of

biochemical hyperthyroidism

Overt hyperthyroidism TSH usually


Imaging in hyperthyroidism

Determine CAUSE of hyperthyroidism (i.e.,

the disease)

24-hour radioiodine uptake and scan

High uptake - de novo synthesis of hormone

Low uptake - inflammation and destruction of

tissue with release of hormone or extrathyroidal

source of hormone


Imaging in Hyperthyroidism

Where would these results go?

•Amiodarone, Grave’s, exogenous thyroid medication intake,

Autonomous tissue, external production from tumor, iodione

Induced?






High Uptake Low Uptake

de novo synthesis of hormone inflammation and destruction of tissue

with release of hormone or

extrathyroidal source of hormone


Imaging Results

High Uptake Low Uptake

de novo synthesis of

hormone

Autoimmune disease: Graves,

“Hashitoxicois”

Autonomous thyroid tissue: Toxic

adenoma, MNG

Trophoblastic disease and germ cell

tumors (due to stimulation of hCG)

TSH mediated hyperthyroidism:

pituitary adenoma, thyroid receptor

resistance

Iodine-induced: after iodine load once

it has cleared (e.g., CT contrast),

iodine-rich drugs (e.g., amiodarone)

inflammation and destruction of tissue

with release of hormone or extrathyroidal

source of hormone

Thyroiditis

Subacute granulomatous,painless,

postpartum, medication-induced with

inflammation (e.g., amiodarone),

radiation

Exogenous ingestion of thyroid

hormones: factitious, overdose

Ectopic hyperthyroidism: struma ovarii

Iodine-induced: if iodine continues to

be given or long half life


Not always so straightforward…

What about…

TSH


Low TSH with normal free T3

and T4

Central hypothyroidism

Low TSH and low/normal free T4 and T3

Recovery from hyperthyroidisim

Low TSH for months after normalization of T3/T4

After thyroiditis or treatment for hyperthyroidism

Sick Euthyroid

Subclinical hyperthyroidism


Subclinical Hyperthyroidism

Prevalence 0.7-12.4%

Transient - 40-60% have normal values upon recheck

Usually results from multinodular goiter or Graves’

Rate of progression to overt hyperthyroidism

In pts with MNG - 4-5% per year

Probably less common with Graves

Evaluation:

Repeat TFTs in 6-8 weeks

Radioiodine uptake imaging can help diagnose

Consider BMD, EKG


Should we treat subclinical

hyperthyroidism?

Risk factor for development of atrial fibrillation

TSH


Other unusual lab patterns in

hyperthyroidism

Normal/high TSH, high T4, high T3

TSH-induced hyperthyroidism

TSH-secreting pituitary adenoma (rare!)

Partial resistance of feedback of T4 and T3

(genetic abnormalities in thyroid receptors)


Case 2

75 yof with p/w weight loss, memory loss.

Had a “thyroid problem” years ago and was

on “medicine” since then.

Exam: MMSE=26, dry skin, no goiter.

TSH 112

Free T4 0.1

FTI 0.9 UCMC Normal Ranges

TSH

T4

T3

Free T4

FTI

0.3 - 3.8 mcU/mL

5 - 11.6 mcg/dL

80 - 195 ng/dL

0.9 - 1.7 ng/dL

6 - 10.5


Disorder?

Overt Primary Hypothyroidism

TSH = high

Free T4 = low

Additional studies?

Call the pharmacy - had been on levothyroxine 100mcg

longstanding and hadn’t filled it x6 months.

Diagnosis?

Overt Primary

Hypothyroidism

Iatrogenic primary hypothyroidism due to history of

radioiodine ablation


Approach to Hypothyroidism

Primary (95-99%)

Disease of gland - decreased secretion of thyroid

hormone

Manifests as overt or subclinical hypothyroidism

Secondary or Tertiary

Low T4 and TSH concentration that is not

appropriately elevated


Evaluation of Hypothyroidism

Confirm presence, establish primary vs

central, and identify cause

Use of thyroid antibodies in hypothyroidism

Not necessary to make diagnosis of Hashimoto’s

if overt hypothyroidism

Useful to predict progression to permanent overt

hypothyroidism

In pts with subclinical hypothyroidism

In pts with painless thyroiditis


How would you restart therapy?

What value should be used to titrate dose?

How frequently should you monitor dose

cahnges?


Levothyroxine Therapy

Start low, go slow!

Levothyroxine doses: 25, 50, 88, 100, 112, 125 mcg and so on

Titrate dose using TSH

Free T4 is insensitive for assessing dose!

Exception - secondary hypothyroidism due to pituitary or

hypothalamic disease - goal free T4 upper 50% of normal range

Goal

Normal - most cases

Suppression of TSH secretion

Prevent recurrence of thyroid cancer or regrowth of autonomous

tissue (MNG or toxic adenoma)

Undetectable or subnormal TSH concentrations

Monitoring

Takes 4-6 weeks to assess dose changes


Case #3

33 yof with h/o elevated TSH during

pregnancy, now postpartum x8 months.

Otherwise asymptomatic.

EXAM: Within normal limits. No goiter.

TSH 6

T4 5.1

Free Thyroxine 7.9

FTI 7.9

TSH

UCMC Normal Ranges

T4

T3

Free T4

FTI

0.3 - 3.8 mcU/mL

5 - 11.6 mcg/dL

80 - 195 ng/dL

0.9 - 1.7 ng/dL

6 - 10.5


Disorder?

Subclinical Hypothyroidism

TSH = high

Free T4 = Normal

Diagnosis?

Additional studies?

Subclinical

Hypothyroidism


Thyroid antibodies:

TPO antibodies - positive titer at 20480

Thyroglobulin Antibodies - negative

Diagnosis: Subclinical hypothyroidism

secondary to Hashimoto’s thyroiditis


Approach to Subclinical

Hypothyroidism

Elevated TSH (usually


QuickTime and a

decompressor

are needed to see this picture.


Should we treat subclinical

hypothyroidism?

Increased risk of cardiovascular disease

Possibly increased risk in pts 10

Patients


Case 4

19 yof with left sided neck mass that has

grown rapidly in last few days, presents to ER

before leaving for trip to South America in 3

days.

EXAM: 2cm right sided mass on thyroid,

moves up with swallowing. Otherwise normal.

TSH 6.17

Free T4 1.23

FTI 9.4

UCMC Normal Ranges

TSH

T4

T3

Free T4

FTI

0.3 - 3.8 mcU/mL

5 - 11.6 mcg/dL

80 - 195 ng/dL

0.9 - 1.7 ng/dL

6 - 10.5


Disorder?

Subclinical Hypothyroidism

TSH = high

Free T4 = Normal

Diagnosis?

Additional studies?

Should she still go to Peru?

Subclinical

Hypothyroidism


Ultrasound - heterogenous right thyroid

nodule with cystic degeneration measuring

3.1 x3.8 x1.8 cm.


Management of Thyroid

Nodules

Detected on physical examination or

“incidentalomas” on other imaging

Presence of thyroid CA - 4- 6.5% of nodules

Use of Thyroid Ultrasound

Can visualize structure as small as 2mm

Useful in following situation:

Supplement physical exam

Search for nonpalpable thyroid nodules in pts with h/o neck

radiation

Distinguish solid and cystic structures

Stratify nodule’s risk of cancer as low, medium or high

Increase accuracy of FNA


Approach to Patient with

Thyroid Nodules

Check TSH

If low, thyroid scintography

High uptake - “hot nodule”

No uptake - “cold nodule” or nonfunctioning --> FNA

Indeterminante --> FNA

If normal or high TSH - ultrasound


Use Thyroid Ultrasound to

guide FNA if normal/high TSH

High risk features of patient or nodule? --> FNA

High risk pt - h/o head/neck radiation, h/o CA, family h/o

thyroid CA or multiple CA syndromes, clinical features

High risk nodule

Size >1cm

Irregular margins or “halo”

Composition - solid

Echogenicity - hypoechoic

Microcalcifications

Presence of high central vascularity or vascular invasion

Presence of lymphadenopathy

Widely variable PPVs of these features


FNA

Most cost-effective and direct way to evaluate

23-27 gauge needle, adequate in 90-97% of

aspirations

The patient underwent FNA….

FNA: follicular cells with Hurthle cell change, few

clusters show features suggestive but not diagnostic

of thyroid carcinoma

Then…

Thyroidectomy: Right lobe -follicular adenoma measuring 4cm

in greatest dimension, completely excised. Three lymph

nodes negative for carcinoma. Left lobe with no specific

pathological change.


Case 5

89 yof with CHF p/w altered mental status x3

days. ER calls for “myxedema coma”.

33.6 108/64 78 16 100% RA

EXAM: Somnolent but arousable, no goiter or

scars

TSH 14.5

T4 5.3

Free T4 1.13

FTI 8.7

UCMC Normal Ranges

TSH

T4

T3

Free T4

FTI

0.3 - 3.8 mcU/mL

5 - 11.6 mcg/dL

80 - 195 ng/dL

0.9 - 1.7 ng/dL

6 - 10.5


Disorder?

Subclinical Hypothyroidism

TSH = high

Free T4 = Normal

Diagnosis?

Additional studies?

Subclinical

Hypothyroidism


Additional Studies

T3 48

Reverse T3 923 (normal 160-353)

+Urine and blood cultures

Prior records: normal TFTs and no prior

evidence of hypothyroidism

Diagnosis?

Sick euthyroid due to urosepsis

UCMC Normal Ranges

TSH

T4

T3

Free T4

FTI

0.3 - 3.8 mcU/mL

5 - 11.6 mcg/dL

80 - 195 ng/dL

0.9 - 1.7 ng/dL

6 - 10.5


Patterns of sick euthyroid

Alterations in TSH

Low - TSH usually 0.1-0.4 (rare to have


Sick Euthryoid/Nonthyroidal Illness

Changes in thyroid hormones, binding proteins, and

TSH concentrations

May have acquired central hypothyroidism

Explains pattern of low TSH and low T3/T4

Medications that affect thyroid function (amiodarone,

dopamine, steroids)

Decreased peripheral deiodination from T4->T3

Catalyzed by enzymes in liver and kidney

Decreases when caloric intake is low and in any

nonthyroidal illness


Diagnosis of Sick Euthyroid

Serum T3

Useful in hospitalized patients with low TSH to determine

hyperthyroidism vs euthyroid sick

Should be normal-high in hyperthyroidism, but low-normal

in euthyroid sick

Reverse T3

Product of deiodination of T4

Clearance is reduced in sick euthyroid due to inhibition of

enzyme activity

Elevated in patients with sick euthyroid

Possible exceptions: renal failure and AIDS

Can help distinguish between sick euthyroidism and

hypothyroidism

Reevaluate in 4-8 weeks


Treatment of Sick Euthyroid

Treatment

Little benefit and may be harmful

Changes may be protective - prevent excessive

tissue catabolism


Take Home Points

Look at whole TFT picture with TSH and T4/Free

T4/T3/FTI to avoid misinterpretation.

Radioiodide uptake scans used to diagnose cause

of hyperthyroidism

Antibodies not necessary for diagnosis in most

cases of overt hyper/hypothyroidism.

Subclinical hypo/hyperthyroidism exists and may

need treatment in some cases.

Thyroid nodules should be managed based on risk

factor for CA (both by pt and by nodule)

Remember what T3 can be used for - total T3 and

reverse T3 in sick euthyroid.


Thanks For Coming!

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