Unusual thyroid function tests

• Ross McDougall– Nuclear Medicine Grand Rounds 3/18/2008

Overview of lecture

• “Normal” thyroid physiology• “Normal” patho-physiology• Unusual thyroid function tests

Pituitary

Hypothalamus

Thyrotropin releasing hormone

TRH

Thyrotropin

TSH

Thyroid hormones

Thyroxine T4 (free T4)

Triiodothyronine T3 (free T3)Iodine

trapping

Thyroid physiology

Thyroid patho-physiology

• Increased levels of thyroid hormones– Thyrotoxicosis

• (Hyperthyroidism)• Alternative source of thyroid hormones

» Iagaru and McDougall. J Nucl Med 2007:48:379-389» Mittra et al. J Nucl Med 2008;49:265-278

Patho-physiology

• In almost all situations where Free T4 and or Free T3 are above the normal range…..

• TSH is low and often suppressed (not measurable)– Conversely

• In almost all situations where Free thyroid hormones are low TSH is elevated

Patient 1

Laboratory test 11/15/2007

Free T4 1.5 ng/dl(0.6-1.6)

TSH 11.38 mIU/L(0.4-4.0)

Patient 1

• What could cause this combination of thyroid results?

Patient 1

1) Pituitary tumor secreting TSH2) TSH produced from an ectopic site3) Pituitary resistance to thyroid hormones4) Taking replacement levo-thyroxine

irregularly5) Other causes?6) Falsely elevated thyroid hormone levels

Patient 1: Case history

• 2008 patient is 80 years old• Diagnosed thyrotoxic due to toxic nodular goiter

at age 69 (1997 El Camino)• Free T4 2.4 (0.8-1.8 ng/dl) TSH suppressed• Treated by anti-thyroid medication• 1999 transferred care to Stanford

Patient 1

• Clinically well on antithyroid medication• Mass in left lobe of thyroid and palpable

lymph node• Review of scintiscan

Patient 1

• FNA of left sided nodule HÜrthle cell neoplasm

Patient 1

• Total thyroidectomy– Follicular carcinoma with angio-invasion

• Withdrawal of thyroid hormone for 4 weeks• Low iodine diet during weeks 3 and 4• What tests would you order?

Patient 1

• TSH• Thyroglobulin• Thyroid whole body

scan and uptake

• 9 mIu/l• 85 ng/ml• 23% at 48 hours

• What is unusual about these results?

Patient 1

• Now what?• Ultrasound

– Right lobe 3.2 x 1.2 x 1.1– Left lobe 3.1 x 1.1 x 0.7

• Nodule in right lobe

Patient 1

• Completion of thyroidectomy and I-131 therapy

• Follow-up scan after 1 year negative• Tg undetectable

Patient 1

Laboratory test 11/15/2007 11/26/2007

Free T4 1.5 1.6

TSH 11.3 28.5

Patient 1

12007

112007

112007

1 2008

1 2008

12008

22008

Free T4

1.2 1.5 1.6 1.6 2.1 1.9 1.7

TSH 3.77 11.38 28.53 13.85 6.82 3.82 2.78

Dr Google

15 Reasons Why Your TSH May Be Fluctuating Things to Consider When Your TSH Is Not Stabilized

Patient 1

Patient 1

• Patient was not taking medication regularly

• The TSH value does not respond immediately when there is a change in free thyroid hormones change

Patient 2

• 55 year old employee of Stanford Hospital

• Free T4 0.4 ng/dl (0.6-1.6)• TSH 0.25 mIU/L (0.4-4.0)

• What should be measured?• Free T3 10.2 pg/dl (2.3-4.0)

Patient 2

• Causes for T3 toxicosis– Functioning thyrotoxic nodule– Toxic multinodular goiter– Relapse of Graves’ disease– Taking cytomel (tri-iodothyronine)

• Sometimes this can be a cause of factitious thyrotoxicosis

Patient 2

• This patient has mild T3 toxicosis

Patient 3

• 46 year old man found to have a 5 cm thyroid nodule (1996)

• FNA follicular lesion• Total thyroidectomy: 5 cm follicular cancer• 100 mCi I-131 post operatively• How should he be followed?

Patient 3

• Clinical examination• Measurement of thyroglobulin• Thyroid function tests• Whole-body scan with radio-iodine• Ultrasound

Patient 3

• For 12 years Tg always undetectable (<0.5 ng/ml) irrespective of TSH value

• Primary physician calls patient “your thyroglobulin is 19 go and see your thyroid doctor”

• How do you resolve this?

Patient 3

• 19 is the value of anti-thyroglobulin NOT Tg• One well known clinical laboratory continues to

measure anti-thyroglobulin when thyroglobulin is requested

• Always look at the results yourself !

• However, when thyroglobulin is measured it is important to measure anti-Tg at the same time. Why?

Patient 3

• High Tg was not Tg but antibody to Tg

Patient 4

• 56 year old man– Proven thyroid cancer 3/94– Thyroidectomy in another hospital– I-131 therapy at Stanford– Follow-up scans with radio-iodine negative– Tg undetectable when TSH low, normal, or

high

Patient 4

• Bowel cancer– Neo-adjuvant chemotherapy and radiation

followed by surgery• Severe painful degenerative disease of

spine– Pain management

• Cymbalta

• Atrial fibrillation

Patient 4Free T4 (range 0.8-2.0 ng/dl) TSH (range 0.4-4.0 mIU/L)

2.1 1.2

1.8 9.77

1.5 6.52

2.3 6.49

2.7 3.38

2.3 2.13

1.6 4.88

2.2 1.5

2.4 1.54

Patient 4Free T4 (range 0.6-1.6 ng/dl) TSH (range 0.4-4.0 uU/L)

1.9 0.21

1.2 16.8

1.3 9.0

1.8 2.76

2.0 4.3

1.3 9.08

1.6 7.31

1.8 3.83

Patient 4

• How can a patient have both hyper and hypothyroidism?

• What could cause these disparate values?

TRRXR

HDAHistonedeacetylase activity“turned off”

Histone transacetylase

No T3presentRepressed

T3 presentActivated

TRRXRT3

HAT

1 52 120 370 410 492

Nuclear actions : Thyroid hormone receptors

Transactivation DNA Ligand binding/dimerization

binding

Alpha 1

Alpha 2

Beta 1

Beta 2

• How can a patient be hyper and hypothyroid at the same time?

• The relationship between free T4 and TSH depends on the function of the thyroid hormone receptors

Resistance to thyroid hormone

• Generalized resistance– TSH high– Thyroid hormones

high– No symptoms of

thyrotoxicosis– Goiter– Family history

• Resistance at the pituitary level– TSH high– Free hormones high– Symptoms of

thyrotoxicosis

Patient 4

• The plot thickens

Patient 4

• MRI of brain– Complication of duloxetine [cymbalta

antidepressant in a group of drugs called selective serotonin and norepinephrinereuptake inhibitors (SSNRIs)].

– 6 mm lesion in pituitary– How can we differentiate a TSH secreting

adenoma from resistance to thyroid hormone at the level of the pituitary?

Patient 4

• In pituitary tumor the concentration of TSH alpha -subunits in blood is above normal, as is the ratio of TSH alpha /TSH– TSH alpha 0.6 ng/ml (normal < 1.2 ng/ml)

• TSH level does not respond to changes in thyroid hormone values

Patient 4

• Resistance to thyroid hormone at the pituitary level

Patient 5

• 27 year old papillary thyroid cancer• Treated by thyroidectomy and I-131• Follow-up scan negative• For 2 years Tg always undetectable

(<0.5ng/ml) but she has high values of anti-Tg

Patient 5

• Physician calls her • Tg 24 contact your thyroid doctor• How do you resolve this?

Patient 5

• Look at the results

Patient 5

• In patient 3: the Tg result was actually anti-Tg

• In patient 5: TBG (Thyroxine Binding Globulin) was thought to be Tg

• Always look at the results yourself !– Value was 24 mcg/ml (normal 13.5-30.9)– Repeat Tg was <0.5 ng/ml

Patient 5

• The elevated Tg was not Tg but Thyroid Binding Globulin

Unusual thyroid function tests

• Dogma– Not all dogmas are correct

• Look at the results