THYROID DISORDERS
Too Hot, Too Cold or Just Right
Uzma Khan, MD.
Associate Professor of Clinical Internal Medicine
University of Missouri-Columbia
ACP 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
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Lab tests
TSH
Free T4
Total T4
Free T3
Total T3
TPO antibodies
Thyroglobulin
Thyroglobulin Antibodies
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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 levels
according to thyroid function status.
TSH
Subclinical
T4
N
T3
N
Mild
N or
N or
overt
Levothyroxine (T4)
• 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
Parameter
T3/T4 Combos
Production rate nmol/day
T3
T4
50
110
• Thyrolar,
Armour thyroid
-Fraction from thyroid
0.2
• Combo pill of T3 and T4
1.0
• Relative
Ratiometabolic
of T4:T3potency
= 4:1 (not 14:1)
• Serum
T3 still
not slow release
concentration
• Few small studies showing benefit
- Total
(nmol/L)
• 1999
NEJM study 33 patients 1.8
• Benefit: mood & cognitive function
-Free (pmol/L)
5
• Cytomel is only T3………..limited use
Fraction of total hormone in free form
0.3
• Only check a TSH…do not check T4 or T3
1.0
0.3
100
20
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 Prevalence
Autopsy 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
Single Nodule
Multiple Nodule
No Nodules
12
51
37
Mortensen et al. J Clin Endocrinology, 1955
Common Varieties of Thyroid Nodules
Technique
The 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.
• Anterior approach
• Posterior approach
The Pemberton sign
Wallace C , Siminoski K Ann Intern Med 1996;125:568-569
Work up
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Lab tests
TSH
Free T4
Total T4
Free T3
Total T3
TPO antibodies
Thyroglobulin
Thyroglobulin Antibodies
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•
•
•
•
Imaging studies
Thyroid uptake and scan
Thyroid ultrasound
CT scan of neck
PET scan
• Fine needle aspiration
Work up- Next step
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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 scan
Thyroid ultrasound
CT scan of neck
PET scan
• Fine needle aspiration
Work up- Next step
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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
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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
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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
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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
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•
•
•
•
•
•
•
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!
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
Davies, L. et al. JAMA 2006;295:2164-2167.
Risk of Malignancy
A study of 317 thyroid incidentalomas by Nam-Goong et al in 2004
48
50
Percentage
40
44
% Patients
% Papillary Thyroid Cancer
30
20
10
0
8
12
<0.5 cm
15
13
0.5-1 cm
> 1 cm
Size of incidentaloma
Nam-Goong et al. Clinical Endocrinolog. 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
rhTSH
0.9 mg
rhTSH
0.9mg
131
I
(if WBS is
performed)
Monday
Tuesday
Wednesday
Day 4
Day 5
Serum Tg with
or without WBS
Thursday
Friday
Maximum Percent Change from Baseline in the Sum of the Longest Diameters (SLD) of Target Lesions
Motesanib Diphosphate in Progressive Differentiated
Thyroid Cancer
Sherman S et al, NEJM, July 2008
Know the thyroid well!!
You may need it as the next White House Physician
TSH: 6.1 mIU/ l ( 0.40-4.5)
 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: 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”……………………………………………..
T4 or T3
 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!
Thyroid Function
T4
Protein* binding
+ 0.03% free T4
Protein* binding
+ 0.3% free T3
80% (peripheral)
20%
T3
* Thyroid hormone Binding:
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
TBG
75%
Transthyretin 15%
Albumin10%
Serum TSH range in the US population
Not a Gaussian curve…………… Tail
Hollowel et all, NHANES III survey, JCEM 2002
Thyroid tests
• 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
Utility of Radioactive Iodine Uptake (RAIU)
RAIU
RAIU
Grave’s
Thyroiditis
Toxic MNG
Exogenous
Toxic adenoma
Iodine
ingestion
Struma
ovarii
Metastatic
thyroid Ca
Hyperemesis
gravidarum
Trophoblastic
tumor
Your Interpretation
24 hour RAIU = 25%. TSH 0.2 mU/L.
Thyroid palpably “cobblestone” texture.
Thyroid Ultrasound (US)
Normal Ultrasonographic Anatomy
• Current resolution of US allows demonstration of thyroid nodules as small
as 1 mm.
Transverse right lobe of the thyroid gland
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
repeat
surgery
Cooper et al, 2006
Not helpful
results
• Mutational analysis :
shows: positive for
BRAF: V 600 E
mutation
Three distinct pathways
lead to neoplastic
proliferation of thyroid
cells
Asa S, Ezzat S, and Kondo T, 2006
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 negative PTC
-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
Thyroid tests
• 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
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 scan
Thyroid ultrasound
CT scan of neck
PET scan
• Fine needle aspiration