Nodules and Thyroid YRIGHT Dysfunction 2019 · 2020-01-02 · Thyrotoxicosis Etiology Continued 3. Painless and Subacute Thyroiditis (SAT) – Inflammation of thyroid tissue ® TH

Thyroid Disease:Nodules and Thyroid

Dysfunction 2019

James V. Hennessey MDAssociate Professor of Medicine

Harvard Medical School

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Case 1

● 28 year old woman sees OB for routine visit● ROS:

– Negative except for occasional dysphonia● PE: BP 122/78, HR 72 BPM, 5’ 5”, 120 lbs.● Thyroid Exam: 2.5 cm smooth nodule left

– Moves easily with swallowing– 1 cm left SCM lymph node palpable

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Thyroid Nodule Prevalence

Mazzaferi EL. NEJM. 1993;328:553-559.

•Detected by ultrasound/autopsyq Detected by palpation

• By age 30, ~20% of the population has a thyroid nodule (women>men)

• Likely hood of malignancy is higher in the extremes of age (<20 years, >70 years)

• Lifetime likelihood of a nodule is ~ 60%

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15 X ↑

Ahn HS et al. 2014 NEJM 371(19):1765-1767

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Thyroid Cancer• THYROID CANCER FACTS

• 53,990 cases in U.S. 2018 (Estimate)• 3 Women : 1 Man

• @ 0.005% of U.S. population

• < 4% fatal (2060 deaths in 2018 estimated)• 1.1 Women : 1 Man• @ 0.3% cancer deaths in US (27.5% are aged 75-84)

Cancer Facts and Figures 2018 American Cancer Society

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Risk Factors for malignancy: Patient History● Surgical Dx of thyroid cancer in contralateral lobe

● Ionizing Irradiation (XRT) as child/adolescent

● Calcitonin > 100 pg/mL

● PET positive thyroid nodule

● Low dietary iodine intake

● Thyroid cancer in first degree relative

http://www.cancer.org/cancer/thyroidcancer/detailedguide/thyroid-cancer-risk-factors

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Thyroid Nodule Laboratory Diagnosis

● TSH– Suppressed C/W thyrotoxicosis

● Malignancy unlikely– Elevated C/W hypothyroidism

RADIONUCLIDE SCANNINGIndication:

•Thyrotoxic nodule identification (TSH < normal)•99mTc (False +s), 131-I (Rads) or 123-I (Std)

Haugen BR et al. 2016 Thyroid 26(1):1-133

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Thyroid UltrasoundIndication: normal to TSH–Defines a distinct nodule vs. abnormal parenchyma–Role to guide FNA (cystic, posterior)–MNG nodule selection–Useful in f/u of low risk patient, incidentaloma

● MRI / CT SCANNING–Offer little in pre-operative diagnosis–Contrast administration may delay Dx &/or Rx


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Papillary Thyroid Cancer Appearance on U/S

Tae et al. Thyroid 2007 17:461-466

58 male, 10 mm mass+ microcalcifications

39 female, 9 mm mass+ irregular margins

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Ultrasound Pattern = Risk●High Suspicion = 70-90% Cancer Risk

●Intermediate suspicion = 10-20% Risk

●Low Suspicion = 5-10% Risk of cancer

●Very Low suspicion = <3% Risk cancer

●Benign (Purely cystic)Haugen BR et al. 2016 Thyroid 26(1):1-133

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Who to Biopsy? R8Sonographic Risk Pattern Estimated

Malignancy Risk

Consider Biopsy

Strength of Recommendation

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

Benign < 1% No Strong Low

FNA NOT recommended for nodules not meeting above criteria, including ALL nodules < 1cm

Strong Moderate


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Multiple Nodules R20

● When multiple nodules > 1 cm are present, FNA based upon US pattern– Strong Recommendation, Mod Qual evidence

● If multiple sonographically similar low or very low risk nodules are present, malignancy risk is low, reasonable to FNA largest (1.5-2.0 cm) and observe others.– Weak Recommendation, Low Qual evidence


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Malignancy Prediction: Bethesda System

● Category Malignant risk What next?● Non-Diagnostic 1-4+% Re-do (U/S)● Benign 0-3% Clinical F/U● Atypical 5-15% Re-do (U/S)● Follicular Neoplasm 15-30% Lobectomy● Suspect malignancy 60-75% Total Tx● Malignant 97-99% Total Tx In

determinate

FNA = fine needle aspiration

Cibas ES et al. Am J Clin Path.2009(132):658-65

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Indeterminate: What Next?● Mutation Panel

– BRAF, RET, RAS, RET/PTC, PAX8/PPARγ etc. – High Positive Predictive value (60+%)– High Negative Predictive value (90+%)

● Multigene classifier: identify benign nodule– High Negative predictive value (94-95+%)

● TSH Receptor mRNA in circulation– High Positive Predictive value (96%)

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FNA Disposition

IndeterminateInadequate

MalignantBenign

Repeat FNAUS guidance

Inadequate

Close F/USurgery?

Surgery Repeat FNACytogenetics?

FollowSurgeryT-Tx?

Surgery ?Hemi Tx

Mutation Mut. Neg. “B9”@

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Case 2● 72-year-old man

– palpitations over 2 months– 14 lb. weight loss over 6 months– recent insomnia

PE: BP 152/84, P 112 BPM, irregular● Eyes: alert stare present● Thyroid: 3.5 cm left nodule, freely movable● Cor: Irregularly irregular rhythm, no M/G/R● Lungs: bibasilar rales, LE: 1+ edema

What additional work-up is needed?

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Case 2: Next Steps

ECG Results: Atrial fibrillation with ventricular response of 110 BPM

Lab Results:● TSH <0.05 (0.4-4.2 mIu/mL)● FT4 2.1 (0.8-1.8 ng/dL)● TT3 345 (80-200 ng/dL)

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Thyrotoxicosis Classification and Etiology● Classification: all may have signs & symptoms1

– Overt T-Tox: ↓ TSH, ↑ FT4, ↑ T3– Subclinical T-Tox: ↓ TSH, normal FT4 and T3

● Etiology:1. Graves’ disease (GD), autoimmune, stimulating TSH-receptor antibodies (TRAbs)2. Toxic Nodular disease, growth and autonomomy2

● Multinodular (TMNG) or Adenoma (TA) ● TAs have somatic TSH receptor activating mutations3

● Both susceptible to iodine induced T-Tox● TMNG Incidence increases with age and in Iodine deficiency4

1. Bahn RS, et al. Thyroid. 2010;21(6):593-646. 2. Berghout A, et al. Am J Med. 1990;89:602. 3. Martin FI, et al. Med J Aust. 1996;164:200-

203. 4. Laurberg P, et al. J Intern Med. 1991;229:415.

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Thyrotoxicosis Etiology Continued

3. Painless and Subacute Thyroiditis (SAT)– Inflammation of thyroid tissue ® TH release– Painful SAT: post viral ® fever, thyroid pain1

– Painless SAT underlies 10% “hyperthyroidism”2

● Occurs postpartum3 (PPT), with lithium4, cytokines5 (Interferon alpha), and 5-10% of amiodarone6 T-Tox

– Results in changing Thyroid function abnormalities– May spontaneously resolve to euthyroidism

1. Fatourechi V, et al. JCEM. 2003;88:2100. 2. Williams I, et al. J EpidemiolCommunity Health. 1983;37:245. 3. Gerstein HC. Arch Intern Med. 1990;150:1397.

4. Miller KK, et al. Clin Endo. 2001;55:501. 5. Roti E. Am J Med. 1996;101:482. 6. Cohen-Lehman J, et al. Nat Rev Endocrinol. 2010;6:34-41.

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Clinical Evaluation● Comprehensive H&P, VS: PR, BP, RR, BMI

– Thyroid: +/- tender, symmetry, nodularity– Gen PE: Pulmonary, Cardiac, Neurologic

● +/- Edema, eye signs, pretibial myxedema● Biochemical evaluation:

– TSH most sensitive and specific (intact pituitary)– FT4 and TT3 simultaneously with high suspicion

● Otherwise reflex FT4 and TT3 for suppressed TSH

Bahn RS, et al. Thyroid. 2010;21(6):593-646. de los Santos ET, et al. Arch Intern Med. 1989;149:526-532.

Spencer CA, et al. JCEM. 1990;70:453.

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Determination of Etiology

● Radioactive Iodine uptake (RAIU) – Should be performed when the clinical presentation

(ophthalmopathy, PTMyx) is not diagnostic of Graves’● Exception

– Pregnancy (TSH R antibodies)– Obvious signs and symptoms of Graves’ disease

● Radioactive Iodine thyroid scan– Should be added in the presence of thyroid nodularity

Ross DS, et al. Thyroid. 2016 26(10):1343-1421.

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Hyperthyroidism-Differential Diagnosis

(RAIU)

Increased AbsentGraves� DiseasehCG mediated

Hot NoduleMultinodular Goiter

ThyroiditisIodine excess

Exogenous THEctopic TH

Radioactive Iodine Uptake

TSH < 0.01

Slide courtesy of A Hollenberg M. D.

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Management of Hyperthyroidism

● Symptomatic Management:– Beta-adrenergic blockade

● For elderly, resting HR >90, coexistent CV Disease● All with symptomatic thyrotoxicosis

●Directed Interventions based on Etiology


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Who Should be Treated?● Overt hyperthyroidism due to Graves’

– Treatment with any of the following● 131-I, antithyroid medication (ATD), thyroidectomy

● Overt hyperthyroidism due to TMNG/ TA– Treatment with any of the following

●131-I, thyroidectomy, ATD (occasionally)

●Subclinical hyperthyroidism?


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Subclinical Thyrotoxicosis Rx?Factor TSH (<0.1 mUL) TSH (0.1 – 0.5

mU/L)Age >65 Yes Consider treating

Age <65 with comorbidities

Heart disease Yes Consider treating

Osteoporosis Yes NoMenopausal Consider treating Consider treating

Hyperthyroid symptoms Yes Consider treating

Age <65, asymptomatic Consider treating No


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Anti-Thyroid Drug Recommendations● PTU not be considered 1st line ATD therapy

– Methimazole (MMI) preferred in children and adults

● PTU may be considered over MMI:– 1st Trimester of pregnancy

● Until more is known with potential MMI embryopathy● Consider switch to MMI in 2nd and 3rd to ¯ risk liver dz

– In Thyroid Storm● Advantage T4®T3 conversion inhibition

– Reaction to MMI (NOT AGRANULOCTOSIS) in whom 131-I or surgery are not possible


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Case 3● 73 year old woman presents with a 3 year

history of cold intolerance, constipation, dry skin and feeling very tired.

● Her TSH values have been 4.5-5.6 mIu/ml.● ROS now includes increasing fatigue, hair loss,

and a new worry of “brain fog”.● She asks if she should be on thyroid hormone

replacement as she now has all of the hypothyroid symptoms and shares an article on bio-identical hormone replacement therapies.

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But What is an Upper Normal TSH?

NHANES III: 4.12 mU/L (Thyroid risk free)1

NHANES III: Age adjusted (Thyroid risk free)2

Age group 97.5 centiles % > 4.5 mU/L20–29 years 3.56 mIU/liter 2.4%70-79 years 5.9 mIU/liter 9.9%>80 years 7.49 mIU/liter 12.0%

Not all elevations of TSH levels = Hypothyroidism!!!!1. Hallowell JG et al. 2002 JCEM 87:489-992. Surks et al. 2007JCEM 92: 4575–4582

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Differential Dx: Tiredness in 1° Care● Meta-analysis of 26 studies for diagnosis● Prevalence of diagnoses:

– Anemia- 2.8% Malignancy- 0.6%– Somatic Dz- 4.3% Depression- 18.5%

● In studies with control groups (no tiredness), prevalence of somatic Dz (Diabetes, anemia, hypothyroidism) was identical to those with tiredness. Hence association may not be causal– Depression more frequent with tiredness

Stadje R et al. 2016 BMC Family Practice 17:147

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Canaris GJ, et al. Arch Intern Med. 2000;160(4):526-534.

Reported Symptoms and TSH Levels

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Carle A et al. Am J Med 2016;129(10):1082-92

Subjects < 50 years

Subjects > 50 yearsCOPYRIG

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HypothyroidismOvert: Elevated TSH, low FT4

Non-specific symptomsCardiovascular manifestations

CVD risk, Hypertension, Hyperlipidemia, CHFPulmonary, Musculoskeletal, Neurologic, PsychiatricSkin/connective tissue, Renal/electrolyte abnormalitiesGastrointestinal/liver, Hematologic and HemostaticPituitary and adrenal dysfunction

Subclinical: Elevated TSH, normal FT4Little to no symptoms, milder metabolic changes

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Hypothyroidism Etiology● Iodine deficiency (most common world wide)

● Chronic autoimmune thyroiditis (Hashimoto’s)– More frequent in women than men– Increases in frequency with age

● Iatrogenic– 131-I or surgical treatment, external beam irradiation– Drugs: thionamides, lithium, amiodarone, interferon-alfa,

interleukin-2, tyrosine kinase inhibitors (sunitinib)

● Central hypothyroidism: insufficient active TSH– Tumors: pituitary, hypothalamus Drugs: Rexanoids (Bexarotene)– Infiltrative, inflammatory, surgical, irradiation

Andersson M, et al. Pub Health Nutr. 2007;10:1606. Vanderpump MP, et al. Clin Endocrinol (Oxf). 1995;43:55-68.Hollowell JG, et al. JCEM. 2002;87(2):489-499. Huber G, et al. JCEM. 2002;87:3221.

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Who to Treat● TSH > 10 mIu/ml considered for Rx

– Due to risk of CHF and CV mortality

● TSH > upper “normal” & < 10 mIu/ml– Treatment based on individual factors

● Positive TPO antibodies● ASCVD, CHF or risk of same● Symptoms c/w hypothyroidism ????

Garber JR, et al. Thyroid. 2012;22:1200-1235.

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Who to Treat● TSH > 10 mIu/ml considered for Rx

– Due to risk of CHF and CV mortality

● TSH > upper “normal” & < 10 mIu/ml– Treatment based on individual factors

● Positive TPO antibodies● ASCVD, CHF or risk of same● Symptoms c/w hypothyroidism ???

● Thyroid hormones should NOT be used to treat “hypothyroid symptoms” without biochemical confirmation of hypothyroidism


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Subclinical Hypothyroidism: Systematic Review and Meta-analysis

§ 21 RCTs comparing thyroid hormone therapy with placebo or no therapy in nonpregnant adults with SCHypothyroidism.

§ 2192 adults randomized, followed 3-18 mos., TSH lowered to 0.5-3.7 mIu/L with LT4 and essentially unchanged (4.6-14.7) without.

§ Assessment of general quality of life (QOL) and thyroid related symptoms (TRS).

Feller M et al. JAMA 2018;320(13):1349-1359

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Results: Benefit (95% CI)

Feller M et al. JAMA 2018;320(13):1349-1359

QOL

TRS

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Bekkering et al. 2019 BMJ doi:10.1136/bmj.l2006

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● 1. Dx of TSH in nonpregnant adult● 2. Confirmation of persistent SCHypo

– TSH 4.5-14.9 mU/L: Repeat with FT4, 1-3 mo.– TSH > 15 mU/L: Repeat with FT4, 1-2 weeks

● 3. Indications for treatment

Biondi B et al. JAMA 2019 322(2):153-60

Subclinical Hypothyroidism

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1. Dx of TSH in nonpregnant adult2. Confirmation of persistent SCHypo

• TSH 4.5-14.9 mU/L: Repeat with FT4, 1-3 mo.– TSH > 15 mU/L: Repeat with FT4, 1-2 weeks

3. Indications for treatment4. Treatment follow up

– If Rx initiated, F/U TSH in 6 weeks– Once TSH at target, F/U TSH Q year

Biondi B et al. JAMA 2019 322(2):153-60

Subclinical Hypothyroidism

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What Should We Treat With?

● Hypothyroidism should be treated with L-thyroxine monotherapy


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What Should We Treat With: 2● The evidence does NOT support using L-

thyroxine and L-triiodothyronine (T4/T3) combinations to treat hypothyroidism

● However, a Randomized Double Blind X-over trial of TH extract vs. LT4 at euthyroid doses2

● NS difference in Symptoms or Neurocognitive function● TH extract was preferred by 48.6% of participants2

Garber JR, et al. Thyroid. 2012;22:1200-1235Jonklass J et al. 2018 Thyroid 28(11):1416-14242-Hoang TD et al. 2013 JCEM 98(5):1982-90.

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Therapy Targets for LT4 Replacement

●Replacement Doses: – 1.6-1.7 mcg/kg/day (0.8 mcg/lb.)– Lower start doses:

● Elderly, symptomatic CAD (12.5-15 mcg/d)

– Initial full replacement for :● Younger and without cardiac symptoms.

● Best outcomes when taken fasting, with water only, 30-60 minutes before breakfast– Alternative, at bedtime 4 hours after last meal


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Follow up of LT4 RxTitrate TSH into the “normal range”

-- Walsh JP et al. 2006 JCE&M 91(7):2624-30-- Samuels MH et al. 2018 JCEM 103(5):1997-08

●Pregnancy Goal ● 1st Trimester < 2.5 mIU/L● 2nd Trimester < 3.0 mIU/L● 3rd Trimester < 3.5 mIU/L

– Frequency of pregnancy sampling Q 4 weeks 1st ½● > X 1 @ 26-32 wks


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Nodules and Thyroid YRIGHT Dysfunction 2019 · 2020-01-02 · Thyrotoxicosis Etiology Continued 3. Painless and Subacute Thyroiditis (SAT) – Inflammation of thyroid tissue ® TH