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 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

Surks, M. I. et al. J Clin Endocrinol Metab 2007;92:4575-4582 Log Linear Relationship between FT4 and TSH

TSH secreting tumor, Thyroid Hormone Free T4 Resistance, (ng/dl) Weird Weird TFT’s TFT’s ULN Weird TFT’s LLN 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 boundto magneticsolidphase Strepavidincoated microparticle

Serum Free T4 Biotinylatedanti antibody T4

boundradioactivity in the serum,the less The higherthe FT4

Biotin and falsely high Free T4 highfalsely Biotinand

RadiolabeledT4

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boundradioactivity a highFT4 level lesswith Strepavidinand mimics Biotinin serum bindsto

Biotin in serum Biotin in

Biotin Total T3 • 6 healthy adults

• 10 mg biotin/d for 7 days, then off for 7 days Free T4 TSH ● 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 Prevalence of Thyroid Nodules

Ultrasound or autopsy

Palpation

Mazzaferri, 1993 Kwong et al. Thyroid Nodules: Does Age Matter?

Chance of Malignancy by Age Thyroid Nodules: Does Size Matter?

P = NS

P<0.02

10% Thyroid Nodule Evaluation

Discover a nodule >1 cm

Serum TSH

TSH normal TSH low or high

Ultrasound US and Scan

Nodule not seen Nodule(s)

seen Normal thyroid: Transverse View

strap muscles isthmus SCM strap muscles SCM

trachea jugular jugular carotid carotid esophagus longus colli longus colli Nonpalpable 2.1cm nodule transverse

trachea sagittal

Head Feet Nonpalpable 2.1cm nodule transverse

trachea sagittal

Head Feet 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

Estimated Sonographic FNA size Quality of malignancy Strength Pattern cutoff risk evidence

High suspicion >70-90% > 1 cm Strong Moderate Intermediate 10-20% > 1 cm Strong Low suspicion Low suspicion 5-10% > 1.5 cm Weak Low

Very low < 3% > 2 cm Weak Moderate suspicion 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 normal TSH low or high

US and Ultrasound Scan 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 Serum Free T4

TSH undetectable TSH subnormal TSH normal TSH elevated

before after

Ito et al. Eur J Endocrinol 2012 Serum Free T3

TSH undetectable TSH subnormal TSH normal TSH elevated

TSH undetectable TSH subnormal TSH normal TSH elevated

Ito et al. Eur J Endocrinol 2012 T4 to T3 Conversion by Type 1 and Type 2 Deiodinases

T4

DIO1

5’ – Deiodinase 1 and 2

DIO2

T3 Panicker et al, JCEM 94: 1623-1629, 2009 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

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) Panicker, V. et al. J Clin Endocrinol Metab 2009;94:1623-1629

TT TC CC T4/T3 Lower score T4 better

TT TC CC

Lower score better

CC TT TC

Higher score better

Meta analysis of combination therapy Grozinsky-Glasberg et al, JCEM 91: 2592-2599, 2006

Quality of Life Randomized trials of combination therapy Fatigue vs monotherapy --11 studies Anxiety --1216 patients

Depression Relative risk of adverse events Bodily Pain 1.19 (95% CI -0.63- 2.24) -0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4

Favors combination Favors monotherapy STANDARDIZED MEAN DIFFERENCE 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 Jonklaas et al. Thyroid 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. 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!