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Top 3 Curbsides on Thyroid Disease David S. Cooper, M.D., MACP Division of Endocrinology, Diabetes, and Metabolism The Johns Hopkins University School of Medicine
Top 3 Curbsides on Thyroid
Disease
David S. Cooper, M.D., MACP
Division of Endocrinology,
Diabetes, and Metabolism
The Johns Hopkins University
School of Medicine
Disclosures
• David S. Cooper, M.D. NONE
Curbside consultation:
• An informal, unofficial “sidewalk” or
telephone consultation. Many physicians
refer to such consultations as “curbsides.”
• Nowadays, almost always by email.
My Top 3 Thyroid Curbside
Consultations
• Weird Thyroid function tests
• What to do about a thyroid nodule
• Is T4 + T3 combination therapy for
hypothyroidism reasonable or
“crazy”?
Weird TFT’s • David: Let me run a case by you.
• 33 yo female I am treating for
microprolactinoma for 12 months on
Cabergoline. She now has new onset mild
hyperthyroidism. First set of labs:
• Free T4 2.05 (0.8-1.8), T3 315 (80-200) and
TSH .78 (0.5-4.5)
• second set Free T4 1.85, T3 251 and TSH
.45; TSI normal.
• 24h uptake upper limit of normal.
Best, G
Weird TFT’s
Hi G:
Is the patient taking biotin?
David
G: I’ll find out
Unusual Thyroid Function Tests • Commonly, TSH or FT4 levels in some normal individuals
mimic the presence of thyroid or pituitary disease: quite
common and not “unusual”
• “Weird”, “Challenging”, “Do not make sense”, “Funny” TFT’s
are not common:
– TFT’s that do not “fit” with the clinical picture or form an
unusual nonphysiologic pattern
– Typically, the serum TSH is high in the face of normal FT4
levels.
– Drugs are also a common cause of challenging TFT’s
– When the FT4 is also high, this suggests a TSH secreting
pituitary tumor or thyroid hormone resistance.
– Need to think about role of T4 therapy
Surks, M. I. et al. J Clin Endocrinol Metab 2007;92:4575-4582
TSH distribution by age groups in the United States
excluding individuals with +FH, +AB, or goiter TSH 97.5%iles
Age 20-29 3.56 mU/l
Age 50-59 4.03 mU/l
Age 80+ 7.5 mU/l
Log Linear Relationship between
FT4 and TSH
Free T4
(ng/dl)
ULN
LLN
TSH secreting
tumor, Thyroid
Hormone
Resistance,
Weird TFT’s
Weird
TFT’s
Weird
TFT’s
Effects of Drugs on Thyroid Function Tests
and on Thyroid Function
• Changes in TFT’s: Patient is euthyroid
• Estrogen
• Amiodarone
• Dilantin, carbamazepine
• Heparin
• Biotin
• True Changes in Thyroid Function
• Iodine, lithium, interferon-alfa, amiodarone,
sorafenib and other TKI’s, Ipilimumab,
bexarotine
*
Strepavidin coated microparticle
bound to magnetic solid phase
Biotinylated anti T4 antibody
* Radiolabeled T4
Serum Free T4
The higher the FT4
in the serum, the less
bound radioactivity
Biotin in serum
Biotin in serum binds to
Strepavidin and mimics
a high FT4 level with less
bound radioactivity
Biotin and falsely high Free T4
TSH
Total T3
Free T4
Biotin • 6 healthy
adults
• 10 mg biotin/d
for 7 days, then off for 7 days
● Assays potentially affected by biotin
– TSH, FT4, T3, Free T3
– Parathyroid Hormone
– Prolactin
– Vitamin D
– NT-proBNP
● Not affected
– Ferritin
Biotin Interference
● Unclear how much biotin causes interference
● Unclear how long it needs to be discontinued before retesting is possible
Weird TFT’s
David:
All of the TFT’s were normal off biotin
Thanks
G
Curbside #2: What to do about thyroid nodules
• Have a patient S.L. with 2.3 cm solid nodule (solitary) which radiology is recommending be biopsied………I know how tough it is to get appts. so I thought I’d email to see if you had time in the next several weeks to fit her in. Can you look at the images?
• Thank you so much
L
What is an “Incidentally” discovered
nodule?
• We call a nodule discovered “incidentally”
on imaging that is not palpable an
“incidentaloma”
• But, in my opinion, it is wrong to say, for
example: “ A 2 cm nodule was discovered
“incidentally on physical examination”.
• A nodules should be evaluated by
sonographic criteria, not by whether it is
“incidentally” discovered or not.
Thyroid Nodules: Questions to be Answered
• What studies should be ordered after an
abnormal thyroid exam/incidental radiologic
finding (thyroid incidentaloma)?
• Should all such patients have a thyroid
ultrasound?
• How do you interpret thyroid ultrasound
findings?
• When should thyroid FNA be done and what
do the results mean?
Thyroid Nodules
• Extremely common
• Almost always benign
• Always require evaluation,
whether found
– “incidentally”
– on routine PE
– by the patient themselves (“I feel a
lump in my neck”).
Thyroid Nodules
The Three Big Questions
• Is it associated with thyroid
dysfunction?
• Is it cancer?
• Is it causing compressive
symptoms such as choking,
hoarseness, or dysphagia?
Thyroid Nodules
The Three Big Questions
• Is it associated with thyroid dysfunction?
– Answer: serum TSH
• Is it cancer?
– Answer: Fine Needle Aspiration
• Is it causing compressive symptoms such as
choking, hoarseness, or dysphagia?
– Answer: Patient history, CT or MRI, pulmonary
function tests
American Thyroid Association: www.thyroid.org
Ultrasound or autopsy
Palpation
Mazzaferri, 1993
Prevalence of Thyroid Nodules
Kwong et al.
Chance of Malignancy by Age
Thyroid Nodules: Does Age Matter?
P<0.02
P = NS
Thyroid Nodules: Does Size Matter?
10%
Thyroid Nodule Evaluation
Discover a nodule >1 cm
Serum TSH
TSH low
US and Scan
TSH normal or high
Ultrasound
Nodule not seen Nodule(s)
seen
Normal thyroid: Transverse View
trachea
esophagus
carotid
carotid
jugular jugular
isthmus strap muscles
strap muscles SCM SCM
longus colli longus colli
sagittal
Nonpalpable 2.1cm nodule
trachea
Head Feet
transverse
sagittal
Nonpalpable 2.1cm nodule
trachea
Head Feet
transverse
Ultrasound Characteristics of Thyroid Nodules
• Ultrasound findings that are more
reassuring:
– Iso- or Hyperechoic
– “Spongiform” appearance
– “halo sign” (sonolucent rim)
– Low blood flow
– Cystic (the greater the cystic component, the les likely to be malignant)
Benign Nodule
Spongiform Nodule Lateral or Sagittal View
Head Feet
Ultrasound Characteristics of Thyroid Nodules
• Ultrasound findings suggestive of
potential malignancy:
– Hypoechoic
– Solid
– Punctate calcifications
– Irregular margins
– Spherical in shape
Thyroid Cancer
• Hypoechoic
• Irregular borders
• Microcalcifications
• “Taller than wide”
US Pattern and suggested FNA cutoffs
Sonographic
Pattern
Estimated
malignancy
risk
FNA size
cutoff Strength
Quality of evidence
High suspicion >70-90% > 1 cm Strong Moderate
Intermediate
suspicion 10-20% > 1 cm Strong Low
Low suspicion 5-10% > 1.5 cm Weak Low
Very low
suspicion
< 3% > 2 cm Weak Moderate
One option is surveillance
Benign < 1% No biopsy Strong Moderate
TIRADS: Background Horvath et al. 2009
• TIRADS 1: normal thyroid gland.
• TIRADS 2: benign conditions (0% malignancy).
• TIRADS 3: probably benign nodules (<5% malignancy).
• TIRADS 4: suspicious nodules (5–80% malignancy rate). A subdivision into
4a (malignancy between 5 and 10%) 4b (malignancy between 10 and 80%) was optional.
• TIRADS 5: probably malignant nodules (malignancy >80%).
• TIRADS 6: biopsy proven malignant nodules.
Thyroid Nodule Evaluation
Discover a nodule >1 cm
Serum TSH
TSH low
US and
Scan
TSH normal or high
Ultrasound
Nodule not seen Nodule(s)
seen
FNA (depending on
size and US
characteristics)
Curbside #3: Is T4 + T3 combination therapy for hypothyroidism reasonable or “crazy”? • David: Julie is here and has a TSH of
0.27 …..she is 4 months out from total thyroidectomy and went to 175 of Synthroid but still feels very hypothyroid. Can we cut back on the Synthroid and add a bit of Cytomel?
Controls
Thyroid cancer
Higher score = more dissatisfaction
with health
Ito et al. Eur J Endocrinol 2012
TSH undetectable TSH subnormal TSH normal TSH elevated
before after
Serum Free T4
Ito et al. Eur J Endocrinol 2012
TSH undetectable TSH subnormal TSH normal TSH elevated
Serum Free T3
TSH elevated TSH normal TSH subnormal TSH undetectable
T3
T4
5’ – Deiodinase 1 and 2
DIO2
DIO1
T4 to T3 Conversion by Type 1 and Type 2 Deiodinases
Personalized Medicine: Potential Role of
Genetics
• Type 2 deiodinase gene polymorphism Thr92Ala – present in 16% of study population
– no impact on circulating thyroid hormone levels
• 552 patients in a combination therapy study were genotyped
• Genotype was retrospectively associated with – worse scores in General Health Questionnaire while
taking LT4 compared with other genotypes
– better response to combination therapy (50 mcg LT4 replaced with 10 mcg T3) than other genotypes
Panicker et al, JCEM 94: 1623-1629, 2009
Panicker, V. et al. J Clin Endocrinol Metab 2009;94:1623-1629
Response to therapy by genotype (TT, TC, CC) in the Deiodinase gene as measured by GHQ (A), Thyroid Symptom Questionnaire (B), and satisfaction score (C)
T4/T3
T4 Lower score
better
Lower score
better
Higher score
better
TT TC CC
TT TC CC
TT TC CC
Meta analysis of combination therapy Grozinsky-Glasberg et al, JCEM 91: 2592-2599, 2006
Randomized trials of
combination therapy
vs monotherapy
--11 studies
--1216 patients
Relative risk of
adverse events
1.19 (95% CI -0.63-
2.24)
STANDARDIZED MEAN DIFFERENCE
Bodily Pain
Depression
Anxiety
Fatigue
Quality of Life
-0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4
Favors combination Favors monotherapy
Wiersinga WW Nat Rev Endocrinol 2014
J Clin Endocrinol Metab 97: 2256–2271, 2012
• LT4 monotherapy cannot assure a euthyroid state in all tissues,
and a normal serum TSH levels in patients receiving LT4 reflect
pituitary euthyroidism, but not necessarily all tissues
• LT4 plus LT3 combination therapy is gaining in popularity;
although evidence suggests it is generally not superior to LT4
monotherapy,
• Disappointing results with combination therapy could be related to
use of inappropriate LT4 and LT3, resulting in abnormal serum
free T4:free T3 ratios.
• Alternatively, its potential benefit might be confined to patients
with specific genetic polymorphisms in thyroid hormone
transporters and deiodinases that affect the intracellular levels of
T3.
• LT4 monotherapy remains the standard treatment for
hypothyroidism. However, in selected patients, new guidelines
suggest that experimental combination therapy might be
considered. Wiersinga WW Nat Reviews Endocrinol 2014
• Recommendation: For patients with primary
hypothyroidism who feel unwell on levothyroxine therapy
alone, there is currently insufficient evidence to support the
routine use of a trial of a combination of levothyroxine and
liothyronine therapy outside a formal clinical trial or N of 1
trial
• …due to uncertainty in long-term risk benefit ratio of the
treatment and uncertainty as to the optimal definition of a
successful trial to guide clinical decision making.
Jonklaas et al. Thyroid 2014
T4 plus T3: How to do it
• Many complex recommendations based
on molar ratio of secreted T4 and T3
• Simplest:
– T3 is about 3 times as metabolically active as
T4 (Celi F et al. Clin Endocrinol 2010)
– Therefore, substitute ~25-50 mcg of T4 with
T3 (liothyronine) as 5 mcg twice a day
– Check TFT’s in 6 weeks.
T3 profiles in patients taking T3 three times
a day Celi et al. Clin Endocrinol 2010
200 ng/dl
Top 3 Curbside consultations: • Weird Thyroid function tests
• What to do about a thyroid nodule
• Is T4 + T3 combination therapy for hypothyroidism reasonable or “crazy”?
THANK YOU!
