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