Top 3 Curbsides on Thyroid Disease · –no impact on circulating thyroid hormone levels • 552...
Transcript of Top 3 Curbsides on Thyroid Disease · –no impact on circulating thyroid hormone levels • 552...
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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
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Disclosures
• David S. Cooper, M.D. NONE
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Curbside consultation:
• An informal, unofficial “sidewalk” or
telephone consultation. Many physicians
refer to such consultations as “curbsides.”
• Nowadays, almost always by email.
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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”?
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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
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Weird TFT’s
Hi G:
Is the patient taking biotin?
David
G: I’ll find out
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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
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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
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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
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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
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*
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
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TSH
Total T3
Free T4
Biotin • 6 healthy
adults
• 10 mg biotin/d
for 7 days, then off for 7 days
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● Assays potentially affected by biotin
– TSH, FT4, T3, Free T3
– Parathyroid Hormone
– Prolactin
– Vitamin D
– NT-proBNP
● Not affected
– Ferritin
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Biotin Interference
● Unclear how much biotin causes interference
● Unclear how long it needs to be discontinued before retesting is possible
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Weird TFT’s
David:
All of the TFT’s were normal off biotin
Thanks
G
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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
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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.
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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?
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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”).
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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?
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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
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American Thyroid Association: www.thyroid.org
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Ultrasound or autopsy
Palpation
Mazzaferri, 1993
Prevalence of Thyroid Nodules
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Kwong et al.
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Chance of Malignancy by Age
Thyroid Nodules: Does Age Matter?
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P<0.02
P = NS
Thyroid Nodules: Does Size Matter?
10%
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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
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Normal thyroid: Transverse View
trachea
esophagus
carotid
carotid
jugular jugular
isthmus strap muscles
strap muscles SCM SCM
longus colli longus colli
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sagittal
Nonpalpable 2.1cm nodule
trachea
Head Feet
transverse
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sagittal
Nonpalpable 2.1cm nodule
trachea
Head Feet
transverse
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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)
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Benign Nodule
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Spongiform Nodule Lateral or Sagittal View
Head Feet
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Ultrasound Characteristics of Thyroid Nodules
• Ultrasound findings suggestive of
potential malignancy:
– Hypoechoic
– Solid
– Punctate calcifications
– Irregular margins
– Spherical in shape
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Thyroid Cancer
• Hypoechoic
• Irregular borders
• Microcalcifications
• “Taller than wide”
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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
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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.
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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)
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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?
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Controls
Thyroid cancer
Higher score = more dissatisfaction
with health
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Ito et al. Eur J Endocrinol 2012
TSH undetectable TSH subnormal TSH normal TSH elevated
before after
Serum Free T4
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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
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T3
T4
5’ – Deiodinase 1 and 2
DIO2
DIO1
T4 to T3 Conversion by Type 1 and Type 2 Deiodinases
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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
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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
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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
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Wiersinga WW Nat Rev Endocrinol 2014
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J Clin Endocrinol Metab 97: 2256–2271, 2012
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• 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
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• 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
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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.
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T3 profiles in patients taking T3 three times
a day Celi et al. Clin Endocrinol 2010
200 ng/dl
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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”?
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THANK YOU!