Top 3 Curbsides on Thyroid Disease · –no impact on circulating thyroid hormone levels • 552...

transcript

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

Is the patient taking biotin?

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)

TSH secreting

tumor, Thyroid

Hormone

Resistance,

Weird TFT’s

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

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

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

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?

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)

Normal thyroid: Transverse View

trachea

esophagus

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

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

TSH normal or high

Ultrasound

Nodule not seen Nodule(s)

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

5’ – Deiodinase 1 and 2

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 Lower score

better

Lower score

better

Higher score

better

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-

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

• 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

• …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!

Top 3 Curbsides on Thyroid Disease · –no impact on circulating thyroid hormone levels • 552...

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