THYROID DISORDERS Too Hot, Too Cold or Just Right

THYROID DISORDERSToo Hot, Too Cold or Just Right

Uzma Khan, MD.Associate Professor of Clinical Internal Medicine

University of Missouri-ColumbiaACP 2012

On her show, Oprah Winfrey admitted a thyroid problem was the cause of her tiredness

Simple case

• 45 year old lady, mother of two teenagers, works at Wal-Mart pharmacy

• Presents with tiredness, sleepy all the time, weight gain of 10 lbs. over the last 5 years, skin and hair is dry

• Her hair dresser advised her to get her thyroid checked

History- Questions to ask

• No history of radiation to head and neck• No personal history of thyroid problems

– During pregnancy?• No family history of thyroid problems --“

goiter”

Work up

• Lab tests• TSH• Free T4• Total T4• Free T3• Total T3• TPO antibodies• Thyroglobulin• Thyroglobulin Antibodie

s

• Imaging studies• Thyroid uptake and

scan• Thyroid ultrasound• CT scan of neck• PET scan

• Fine needle aspiration

Endocrine Review, 2008

The percentage of subjects with an elevated TSH level by sex and decade of age. Percentages of hypothyroidism ranged from 4% to 21% in women and from 3% to 16% in men.

Canaris et al, The Colorado Thyroid Disease Prevalence Study, 2000

The percentage of euthyroid subjects compared with those with an elevated TSH level who reported each symptom.

The proportions of elevated, normal, or low lipid levelsaccording to thyroid function status.

TSH T4 T3Subclinical N N

Mild N or N or

overt

• Medical situations where T4 medication may be affected.

• Estrogen: Pregnancy, OCP, HRT• Drugs that interfere with T4 absorption

• Iron, Calcium• Cholestyramine (cholesterol resin Rx)• At least 4h between T4 and these drugs!

• Increase TBG: estrogen, heroin, methadone• Decrease TBG: depakote, dilantin, androgens

Levothyroxine (T4)

• Thyrolar, Armour thyroid• Combo pill of T3 and T4• Ratio of T4:T3 = 4:1 (not 14:1)• T3 still not slow release• Few small studies showing benefit

• 1999 NEJM study 33 patients• Benefit: mood & cognitive function

• Cytomel is only T3………..limited use

• Only check a TSH…do not check T4 or T3

T3/T4 CombosParameter T3 T4

Production rate nmol/day 50 110

-Fraction from thyroid 0.2 1.0

Relative metabolic potency 1.0 0.3

Serum concentration

- Total (nmol/L) 1.8 100

-Free (pmol/L) 5 20

Fraction of total hormone in free form 0.3 0.02

Fraction intracellular 0.64 0.15

Half-life (days) 0.75 6.7

Complex Case

• 42 year old female presents with left thyroid nodule detected during annual physical exam

• She is a country singer , has no medical problems, takes no medications, and has a healthy 2 year old son

• There is no history of head and neck irradiation, her mother has hypothyroidism, there is no family history of thyroid cancer

• She denies dysphagia, ROS is negative, and states” I did not even know it was there”

Thyroid Incidentaloma

Palpable:5% women

1% men

Ultrasound:19-67%

Thyroid Nodules PrevalenceAutopsy Data

Autopsy data from 821 patients at the Mayo clinic with “normal” thyroids on clinical examination◦ 49% had thyroid nodules

12 % had single nodule 37% had multiple

nodules◦ 35.5% of these nodules

were >2 cm

3751

12

Single NoduleMultiple NoduleNo Nodules

Mortensen et al. J Clin Endocrinology, 1955

Common Varieties of Thyroid Nodules

• Anterior approach • Posterior approach

TechniqueThe location of the thyroid is identified by inspection.

Using the anterior or posterior approach, palpate the thyroid to identify nodules

Note the size and number of nodules. Note the consistency of the nodule.

Palpate regional lymph nodes for consistency and mobility.

The Pemberton sign

Wallace C , Siminoski K Ann Intern Med 1996;125:568-569

Work up

• Lab tests• TSH• Free T4• Total T4• Free T3• Total T3• TPO antibodies• Thyroglobulin• Thyroglobulin Antibodies

• Imaging studies• Thyroid uptake and sca

n• Thyroid ultrasound• CT scan of neck• PET scan

• Fine needle aspiration

Work up- Next step

• Lab tests• TSH: 0.2 mIU/L• Free T4: Normal• Total T4• Total T3• Free T3• TPO antibodies• Thyroglobulin• Thyroglobulin Antibodies

• Imaging studies• Thyroid uptake and sca

n• Thyroid ultrasound• CT scan of neck• PET scan

• Fine needle aspiration

Work up- Next step

• Lab tests• TSH: 0.2 mIU/L• Total T4• Free T4• Total T3• Free T3• TPO antibodies• Thyroglobulin• Thyroglobulin Antibodies

• Imaging studies• Thyroid uptake and scan

? Toxic multinodular goiter? • Thyroid ultrasound• CT scan of neck• PET scan

• Fine needle aspiration

Work up- Next step

• Lab tests• TSH: 0.2 mIU/L• Total T4• Free T4• Total T3• Free T3• TPO antibodies• Thyroglobulin• Thyroglobulin Antibodies

• Imaging studies• Thyroid uptake and scan

? Toxic multinodular goiter? • Thyroid ultrasound

– Multiple thyroid nodules with concerning features in left thyroid nodule

• CT scan of neck• PET scan

• Fine needle aspiration

Work up- Next step

• Lab tests• TSH: 0.2 mIU/L• Total T4• Free T4• Total T3• Free T3• TPO antibodies• Thyroglobulin• Thyroglobulin Antibodies

• Imaging studies• Thyroid uptake and scan

? Toxic multinodular goiter? • Thyroid ultrasound

– Multiple thyroid nodules with concerning features in left thyroid nodule

• CT scan of neck• PET scan

• Fine needle aspiration– Indeterminate!

Genetic medicine Era…New tools!!

• She declines surgery, wants to know if we can be more “sure” about cancer

• The endocrinologist says “ will assess the cells for mutations”……?

Work up- Next step

• Lab tests• TSH: 0.2 mIU/L• Total T4• Free T4• Total T3• Free T3• TPO antibodies• Thyroglobulin• Thyroglobulin Antibodies

• Imaging studies• Thyroid uptake and scan

? Toxic multinodular goiter? • Thyroid ultrasound

– Multiple thyroid nodules with concerning features in left thyroid nodule

• CT scan of neck• PET scan

• Fine needle aspiration– Indeterminate!

Work up- Next step

• Lab tests• TSH: 0.2 mIU/L• Total T4• Free T4• Total T3• Free T3• TPO antibodies• Thyroglobulin• Thyroglobulin Antibodies

• Imaging studies• Thyroid uptake and scan

? Toxic multinodular goiter? • Thyroid ultrasound

– Multiple thyroid nodules with concerning features in left thyroid nodule

• CT scan of neck• PET scan

• Fine needle aspiration– Indeterminate!

Davies, L. et al. JAMA 2006;295:2164-2167.

Thyroid Cancer Incidence and Mortality, 1973-2002•10th leading cancer type in women•22590 new cases/year•2400 deaths/year•50% increase in incidence in 25 years

Davies, L. et al. JAMA 2006;295:2164-2167.

Trends in Incidence of Thyroid Cancer (1973-2002) and Papillary Tumors by Size (1988-2002) in the United States

812

48

15

44

13

0

10

20

30

40

50

Perc

enta

ge

<0.5 cm 0.5-1 cm > 1 cmSize of incidentaloma

% Patients % Papillary Thyroid Cancer

Risk of Malignancy

Nam-Goong et al. Clinical Endocrinolog. 2004

A study of 317 thyroid incidentalomas by Nam-Goong et al in 2004

Radioactive iodine management

• Consensus: – Fine needle aspiration---if shows malignancy– Total thyroidectomy– Ablative doses of radioiodine– Suppressive treatment– Periodic follow up with thyroglobulin and imaging

with radioiodine scans

Close follow up

rhTSH

• recombinant form of human TSH• Thyrogen® (thyrotropin alfa for injection)

is a highly purified• Thyrotropin alfa is synthesized in a

genetically modified Chinese hamster ovary cell line

• Can be used for– Remnant ablation– Follow up WBS/thyroglobulin

Scheduling of rhTSH Doses and Diagnostic Procedures

• Recommended dose: 0.9mg IM q24 hr x 2 doses• Serum Tg protocol is identical for both Tg alone

testing and when combined with WBS• 4 mCi 131I should be used for scans; which should be

acquired for 30 minutes and/ or 140,000 counts

Day 1 Day 2 Day 3 Day 4 Day 5

rhTSH0.9 mg

rhTSH0.9mg

131I(if WBS isperformed)

Serum Tg withor without WBS

Monday Tuesday Wednesday Thursday Friday

Maximum Percent Change from Baseline in the Sum of the Longest Diameters (SLD) of Target Lesions

Sherman S et al, NEJM, July 2008

Motesanib Diphosphate in Progressive Differentiated Thyroid Cancer

Know the thyroid well!!

You may need it as the next White House Physician

TSH : first line test◦ 2nd generation: good

immunometric, sandwich assays: up to 0.1

◦ 3rd generation: ? Varying sensitivity

immunochemiluminometric Assays: up to 0.01

TSH: 6.1 mIU/ l ( 0.40-4.5)• TSH: normal range: 0.40 -4.5

m IU/L

• <0.1: Hyperthyroidism• 0.1 – 0.3: subclinical

hyperthyroidism• 0.32-5.6: normal vs central

hypothyroidism• 6-10: subclinical

hypothyroidism• > 10: primary hypothyroidism

Know what you are “fishing for”……………………………………………..

Free T4 : normal • T4– Free T4 : good– Total T4: make sure you

know about TBG• T3

– FT3: very minute amounts

– TT3: helpful in T3 thyrotoxicosis, remember TBG!

T4 or T3

T4

T380% (peripheral)

20%

Protein* binding + 0.03% free T4

Protein* binding + 0.3% free T3

* Thyroid hormone Binding:

TBG 75%Transthyretin 15%Albumin10%

Thyroid Function

Ratio of T4:T3-stored in thyroglobulin: 15:1-secreted in blood: 10:1

Increased production due to any reason Leads to an increase in T3

Hollowel et all, NHANES III survey, JCEM 2002

Serum TSH range in the US population

Not a Gaussian curve…………… Tail

• Thyroglobulin– Large glycoprotein– Only source: thyroid

follicular cell- Assay limitation:

- Tg Ab- >variability 25%

- Know why you are doing it- Thyroid cancer- Exogenous TH?

• Antibodies– 10% of general

population– TPO> Hashimotos– TSI > Graves– Tg> non specific

• Remember PGAs

Thyroid tests

RAIU RAIU

Grave’s Thyroiditis

Toxic MNG Exogenous

Toxic adenoma Iodine ingestion

Hyperemesis gravidarum

Strumaovarii

Trophoblastic tumor

Metastatic thyroid Ca

Utility of Radioactive Iodine Uptake (RAIU)

Your Interpretation

24 hour RAIU = 25%. TSH 0.2 mU/L. Thyroid palpably “cobblestone” texture.

Thyroid Ultrasound (US)Normal Ultrasonographic Anatomy

Transverse right lobe of the thyroid gland

• Current resolution of US allows demonstration of thyroid nodules as small as 1 mm.

Features of a Benign Nodule

• Hyperechoic nodule• Halo sign or a smooth margin• Thin walled cyst without solid

component• Calcification with acoustic

shadowing• Colloid within nodule • Low vascularity• Multiple nodules

Longitudinal image of thyroid nodule with peripheral calcification and halo

Features of a Malignant nodule• Hypoechoic or

heterogeneous nodule• Microcalcification without

shadowing• Increasing size on TSH

suppression• Cervical lymphadenopathy

Intranodular vascularization• Invasion of muscle• Irregular border• Thick walled cyst

Longitudinal image of a solid thyroid nodule with incomplete halo and coarse calcifications

Your interpretation

Left thyroid longitudinal

TSH: 0.2 mIU/L ( 0.40-4.5)

Higher Serum Thyroid Stimulating Hormone Level in Thyroid Nodule Patients Is Associated with Greater Risks of Differentiated Thyroid Cancer and Advanced Tumor Stage

• The likelihood of thyroid cancer increases with higher serum TSH concentration: 29 % ( 241 of 843 patients)

• Even within normal TSH ranges, a TSH level above the population mean is associated with significantly greater likelihood of thyroid cancer than a TSH below the mean.

• Higher TSH level is associated with advanced stage DTC– Stage III/IV---- mean TSH was 4.9 ± 1.5 mIU/ml– Stage I/II--- mean TSH was 2.1 ± 0.2 mIU/ml .

Haymart et al, 2008

Not useful

Techniques for FNA

Manual Ultrasound-Guided

Management Guidelines for thyroid cancer

Cooper et al, 2006surgeryrepeat

Not helpful

results

• Mutational analysis : shows: positive for BRAF: V 600 E mutation

Asa S, Ezzat S, and Kondo T, 2006

Three distinct pathways lead to neoplastic proliferation of thyroid cells

BRAF Mutation

-One of the three RAF genes ( ARAF and CRAF)-Mutated in about 7% of human cancers-- V600E is the most common mutation---oncogene-Most common mutation in PTC-Unique to PTC

- Santisteban, 2007

-BRAF mutations are not a major event in post-Chernobyl childhood thyroid carcinomas. Lima J, et al. 2004

-Low frequency of BRAF mutations in childhood thyroid carcinomas. Kumagai A, et al. 2004

-Low prevalence of BRAF mutations in radiation-induced thyroid tumors in contrast to sporadic papillary carcinomas. Nikiforova MN, et al. 2004

BRAF negative PTC

• Thyroglobulin– Large glycoprotein– Only source: thyroid

follicular cell- Assay limitation:

- Tg Ab- >variability 25%

- Know why you are doing it- Thyroid cancer- Exogenous TH?

• Antibodies– 10% of general

population– TPO> Hashimotos– TSI > Graves– Tg> non specific

• Remember PGAs

Thyroid tests

Work up- Next step

• Lab tests• TSH: 0.2 mIU/L• Free T4: Normal• Total T4: normal• Total T3: Normal• Free T3• TPO antibodies• Thyroglobulin• Thyroglobulin Antibodies

• Imaging studies• Thyroid uptake and sca

n• Thyroid ultrasound• CT scan of neck• PET scan

• Fine needle aspiration