Primary Care Internal Medicine Workshop. Thyroid Disease. Douglas S. Ross MD October 2018

Transcription

1 Primary Care Internal Medicine Workshop Thyroid Disease Douglas S. Ross MD October 2018

2 Disclosures Medullary Thyroid Cancer Registry Consortium Abbott India Shire Spectrix Therapeutics Quest

3 Topics How to order thyroid function tests Thyrotoxicosis: Assessment and management Subclinical hyperthyroidism Hypothyroidism: It s not your thyroid Hypothyroidism: Does T3 matter? Subclinical hypothyroidism Thyroid Nodules: Managing the epidemic

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5 Negative Log-linear Relationship between TSH and free T4 Very small changes in T4 result in large changes in TSH

6 Does Serum TSH Accurately Reflect Tissue Levels of Thyroid Hormone?

7 Uncertainty due to T4 is a prohormone that gets converted into T3 in all tissues in the body The deiodinases in the pituitary differ from those in many peripheral tissues, e g. heart, liver Heterogeneity of T3 Receptors and their response to T3

8 Case 1 26 year old woman with hyperthyroidism treated with radioiodine 6 weeks ago Free T4 0.5 ng/dl TSH 0.2 uu/ml ( ng/dl)

9 Limitations of TSH measurement During acute therapy of hyperthyroidism Acquired central hypothyroidism Occurs in 90% of patients and lasts 25 days (14-47 days) Uy et al Am J Med 1995

10 Limitation of TSH measurement During initial treatment of hypothyroidism Case 2 52 year old woman TSH 62, free T4 <0.4 Started on levothyroxine 75 mcg 3 weeks later TSH 20, free T4 1.5 ng/dl Still fatigued, bloated, brain fog

11 Before you order TFTs Ask yourself: Steady State Conditions: TSH Non-steady state conditions: TSH, free T4 Possible pituitary/hypothalamic disease: TSH, free T4

12 Case 3 62 year old woman c/o fatigue Screening TSH <0.01 Free T4 > 7.5 ng/dl, T3 420 ng/dl (81-180) No palpitations, no tremulousness, no weight loss She takes a dozen supplements daily

13 Biotin RDA approximately 300 mcg Common concentration in supplements 5-10 mg ( mcg) Interferes with biotin-avidin separation techniques when biotinylated antibodies are used Immunometric (sandwich assays) low Competitive binding assays high

14 Case 4 42 year old woman with palpitations, insomnia, 8 pound weight loss No proptosis, thyroid 25 g TSH <0.01, free T4 2.6 ng/dl ( ), T3 360 ng/dl (81-180)

15 Assessing Etiology of Thyrotoxicosis High radioiodine uptake Graves disease Toxic adenoma Toxic multinodular goiter Trophoblastic disease TSH-mediated Low radioiodine uptake Painless or postpartum thyroiditis Subacute thyroiditis Factitious ingestion of thyroid hormone Amiodarone induced Struma ovarii

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19 Assessing Etiology of Thyrotoxicosis Paradigm shift Measurement of thyrotropin receptor antibodies Obtain radioiodine uptake/scan (Measure blood flow in thyroidal arteries)

20 Antibodies in Graves Disease Thyrotropin Receptor Antibodies (TRAb) TSI: Thyrotropin Stimulating Antibodies TBI: Thyrotropin Binding Inhibitory Imunoblobulins Anti-thyroid Peroxidase (TPO) Antibodies

21 Automated 3 rd Generation TRAb Assays Meta-analysis of automated 3G assays Sensitivity Specificity Odds Ratio for diagnosis GD 3129 (95% CI ) Tozzoli et al Autoimmun Rev 2012

22 Impact of TSI versus RAIU scan 47 % cost savings * 46 % faster time to diagnosis No radiation exposure to patient * Analysis does not include indirect costs to patient (e.g. time lost from work) McKee & Peyerl Am J Manag Care 2012

23 If TRAb negative Radioiodine uptake or uptake/scan T3/T4 ratio in appropriate setting (total T3/total T4 ng/dl/mcg/dl) Postpartum thyroiditis T3/T4 < 20

24 Treatment of hyperthyroidism Beta-adrenergic blocking agents unless contraindicated, start before referral to endocrine Choice of agent Propranolol inhibits T4 to T3 conversion at very high doses Atenolol, Metoprolol more convenient

25 Case 4 continued 42 year old woman with palpitations, insomnia, 8 pound weight loss No proptosis, thyroid 25 g TSH <0.01, free T4 2.6 ng/dl ( ), T3 360 ng/dl (81-180) TSI 2.2 (normal <1.3)

26 Choice of Therapy 2016 American Thyroid Association Guidelines for Management of Hyperthyroidism Patients with Graves disease can be treated with any of the following modalities: 131I therapy, antithyroid medications, or thyroidectomy.

27 Choice of Therapy The long term quality of life following treatment for GD was found to be the same in patients randomly allocated to one of the 3 treatment options. Abraham-Nordling M 2005 Thyroid

28 Choice of Therapy? Radioiodine Favor Definitive pre-pregnancy treatment Elderly, comorbidities Poor surgical candidate, surgical contraindications, lack of surgical expertise Oppose Pregnancy, lactation Orbitopathy Nodules suspicious for thyroid cancer Inability to comply with radiation precautions

29 Favor High remission chance Elderly, co-morbities Poor surgical candidate, surgical contraindications, lack of surgical expertise Orbitopathy Unable to follow RAI precautions Choice of Therapy? Methimazole Oppose Prior adverse reactions Agranulocytosis Abnormal liver tests PTU if first trimester pregnancy

30 Choice of Therapy? Surgery Favor Large glands / nodules Suspicious nodules Hyperparathyroidism Orbitopathy Definitive pre-pregnancy treatment Low RAIU Oppose Elderly, co-morbidities Poor surgical candidate, surgical contraindications, lack of surgical expertise Pregnancy

31 Choice of Therapy Once the diagnosis has been made, the treating physician and the patient should discuss each of the treatment options including the logistics, benefits, expected speed of recovery, drawbacks, potential side effects, and cost.allows the final decision to incorporate the personal values and preferences of the patient.

32 Long-term methimazole therapy In USA patients were discourage from using antithyroid drugs for greater than months because of side effects Recent data suggest long-term safety

33 Agranulocytosis Two studies from Japan Retrospective study 50,385 subjects 50 agranulocytosis 5 pancytopenia 1 death Incidence 0.29 % Mean onset 69 days ( days) Registry (30 years) 754 cases 89 % agranulocytosis 11 % pancytopenia 30 deaths Incidence % 7% > 120 days Watanabe et al JCEM 2012 Nakamura et al JCEM 2013

34 Hepatotoxicity 73,000 patients from Taiwan Cholestasis approx 3.5 / 1000 patient years Liver failure approx 0.5 / 1000 patient years All cases occurred in the first 180 days of therapy Wang et al Br J Clinical Pharmacology 2014

35 Physician Preference for Radioiodine USA EUROPE ASIA Solomn et al JCEM,1990; Burch et at JCEM 2012

36 Case 5 42 year old woman with palpitations, insomnia, 8 pound weight loss No proptosis, thyroid 25 g TSH <0.01, free T4 2.6 ng/dl ( ), T3 260 ng/dl (81-180) TSI <1.0 (normal <1.3) RAIU <1%

37 Painless thyroiditis (silent or lymphocytic thyroiditis) 6-12 weeks hyperthyroid phase 1-5 months hypothyroid phase 90% recover, 10% permanent hypothyroidism Beta-blockers only No role for methimazole

38 Case 6 32 year old woman with hyperthyroid symptoms TSH <0.01, free T4 2.8, T3 360 Treatment options discussed She would like to get pregnant next year

39 TSH during pregnancy High levels of HCG stimulate small changes in free T4 within the normal range TSH is subnormal in up to 20% of women during the first trimester

40 Free T4 in pregnancy non-pregnant 1 st 2 nd 3 rd Total T Free T4 index Free T4 A Free T4 B Lee et al Am J Obstet Gynecol 2009

41 Teratogenesis from Anti-thyroid drugs Methimazole (MMI) and carbimazole (CMZ) have been associated with embryopathy Previously, reports of birth defects with PTU were rare But PTU has been associated with fulminant hepatocellular necrosis 2011 ATA guidelines: PTU first trimester, then MMI

42 Birth Defects with ATDs Danish Nationwide Study no ATDs 5.7 % controls PTU MTZ / CMZ 9.1 Control group: use of ATD > 12 months before or after the pregnancy Andersen et al JCEM 2013

43 Methimazole Embryopathy Choanal atresia Esophageal atresia Omphalocele Omphalomesenteric duct anomalies Aplasia cutis

44 Birth Defects after PTU Face and neck periauricular cysts Urinary tract congenital hydronephrosis Most required a surgical procedure Additional cases identified after age 2 Andersen et al Thyroid 2014

45 Patients switching ATDs per 2011 ATA Guidelines Based on prescriptions filled up to 10 th week 159 patients (149 MMI to PTU) 10.1% had birth defects Defects include those from both groups of embryopathy Does switching expose the fetus to the risks of both drugs?

46 Impefect strategies 2016 ATA guidelines Women with Graves hyperthyroidism who are planning a pregnancy could consider: 1) Changing to PTU prior to conception 2) Changing to PTU when hcg positive 3) Stopping ATD when hcg positive 4) Definitive therapy before conceiving Insufficient evidence

47 Factors favoring timing of switching or stopping ATD first trimester SWITCHING STOPPING Young fertile woman: Favor change to PTU preconception Older less fertile woman: Favor switch as soon as pregnancy diagnosed Mild hyperthyrodism, low dose MMI, > 6 months on MMI, TRAb normal: favor stopping

48 2016 ATA Guidelines Insufficient Evidence Patients started on or switched to PTU during the first trimester could consider: 1) Switch to MMI at the beginning of the second trimester 2) Continue PTU as long as ATD treatment is needed for the duration of the pregnancy.

49 Case 7 64 year old woman c/o fatigue Screening TSH 0.09 uu/ml Free T4 1.3 ng/ml ( ) T3 118 ng/ml (81-180) No hyperthyroid symptoms

50 Subclinical Hyperthyroidism Subnormal serum TSH Normal serum free T4 and T3

51 Subclinical Hyperthyroidism Prevalence 0.7 % of 16,533 people had TSH < % had TSH <0.4 NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY (NHANES III) JCEM 2002, 2004

52 Subclinical Hyperthyroidism Natural History 323 patients mean follow-up 32 months TSH % TSH < % Das et al Clin Endocrinol 2012

53 Subclinical Hyperthyroidism Natural History HMO Database 422,242 patients with TSH measured Patients on thyroid medications excluded 1.2 % with low TSH 51.2 % Became Normal Spontaneously

54 Subclinical Hyperthyroidism Total mortality 1.24 ( ) CHD mortality 1.29 ( ) Risk of atrial fibrillation TSH ( ) TSH < ( ) Risk of congestive heart failure TSH ( ) TSH < ( ) Collet et al Arch Intern Med 2012; Gencer et al Circulation 2012 Thyroid Studies Collaboration

55 Risk for Fractures in Subclinical Hyperthyroidism 70,298 subjects, 13 studies 2975 hip fractures Subclinical hyperthyroidism TSH <0.1 HR 1.36 ( ) HR 1.60 ( ) Endogenous subclinical hyperthyroidism HR 1.52 ( ) Blum et al JAMA 2015

56 Subclinical Hyperthyroidism Recommendations TSH Low Risk High Risk Observe Consider treatment <0.1 Consider treatment Treat High Risk: Age > 65; cardiac risk factors, heart disease, osteoporosis; postmenopausal women who are not on estrogens or bisphosphonates; patients with symptoms

57 Case 8 36 year old woman with 5 year history of hypothyroidism TSH on 100 mcg levothyroxine in past TSH 20.2, free T4 0.8

58 Changing thyroid hormone requirements Compliance Weight (1.6 ug/kg) Age (lower levels in elderly) Estrogens: pregnancy, OC, postmenopausal rx Gastrointestinal disease: reduced absorption celiac, gastritis, bypass, achlorhydria Drugs

59 Drugs that increase T4 requirements Reduce Absorption Proton pump inhibitors Sulcrafate ** Calcium Phosphate binders Iron ** Bile acid sequestrants orlistat Increased Metabolism Barbiturates Carbamazepine Phenytoin Rifampin Tyrosine kinase inhibitors

60 Changing T4 requirements Other considerations Take on an empty stomach Morning versus evening dosing Generics versus brands Levothyroxine gel caps

61 Case 9 52 year old woman with fatigue Recent diagnosis of menopause Screening TSH 7.6 Started on levothyroxine 50 mcg 6 weeks later TSH 0.98, free T4 1.6 She has gained 5 pounds, hair is dry, skin is dry, c/o fatigue, constipation and brain fog

62 Studies of Patients with Hypothyroid Symptoms Hypothyroid patients do not feel well Hypothyroid symptoms do not change with changes in TSH within the normal range

63 Psychological Well-being in Patients on Adequate Doses of Thyroxine 397 patients on thyroxine with normal TSH 551 age- and sex-matched controls General Health Questionnaire (GHQ-12) Thyroid Symptom Questionnaire (TSQ) Saravanan et al 2002

64 Psychological Well-being in Patients on Adequate Doses of Thyroxine Percent with distressed scores on GHQ-12 Controls 25.6% Patients with normal TSH 34.4 * Saravanan et al 2002

65 Psychological Well-being in Patients on Adequate Doses of Thyroxine Percent with distressed scores on TSQ Controls 35.0% Patients with normal TSH 48.6 * Saravanan et al 2002

66 Do we select unhappy patients for T4 treatment? Unhappy Patient Symptoms not improved TSH checked T4 prescribed 5 % Subclinical hypothyroidism

67 Psychological Well-being in Patients on Adequate Doses of Thyroxine Do hypothyroid patients have genetic or acquired defects in psychological wellbeing? Does thyroxine therapy fail to provide adequate treatment of hypothyroidism? Is there a role for T3?

68 Effects of altering T4 dose on QOL, mood and cognition 138 subjects, age 27-70, stable T4 dose Dose altered to aim for: TSH low normal high normal mildy elevated Samuels et al JCEM 2018

69 Effects of altering T4 dose on QOL, mood and cognition NO DIFFERENCE Billewicz Thyroid Quality of Life SF-36 Profile of Mood (POM) Executive Function Declarative Memory Motor Learning

70 Effects of altering T4 dose on QOL, mood and cognition Patients could not determine what dose they were taking But they felt best on the dose they thought was the highest dose Samuels JCEM 2018

71 Does levothyroxine mimic normal physiology? T4 range is shifted right, 7.2% above normal T3 range in shifted left, 15.2% below normal Gullo et al PLoS One 2011 After thyroidectomy, in order to bring post-op T3 levels equal to pre-op T3 levels, T4 must be given in a dose that results in TSH 0.1 Mitsuru Ito et al. Eur J Endocrinol 2012

72 Combined T4 and T3 Therapy Physiology Pharmacology T4:T3 = 14:1 T4:T3 = 4:1

73 Trials of T4/T3 versus T4 alone Escobar-Morreale et al Ann Int Med women on stable 100 mcg T4 RCT Changed to 5 mcg T3 and 75 mcg T4 Resulted in a slight rise in TSH 1.95 to 2.56 Add-on Changed to 7.5 mcg T3 and 87.5 mcg T4 Resulted in over-treatment (low TSH) in 38%

74 Trials of T4/T3 versus T4 alone Escobar-Morreale et al Ann Int Med 2005 Changed to 5 mcg T3 and 75 mcg T4 No change in QOL, mood, or psychometric testing Changed to 7.5 mcg T3 and 87.5 mcg T4 Slight improvement in psychometric testing

75 Trials of T4/T3 versus T4 alone Patient Preference Combined therapy 69 % 5/75 46 % 7.5/ % T4 alone 8 % No preference 23 % Escobar-Morreale et al Ann Int Med 2005

76 Thyroid Extract 1 grain = 38 mcg T4 and 9 mcg T3 T4:T3 ratio 4.2:1 T4:T3 ratio in rats 4:1 T4:T3 ratio in humans 14:1

77 Extract versus L-T4 Extract (also) does not mimic normal physiology extract L-T4 normal mg mcg Free T T TSH

78 Extract versus L-T4 Weight was 2.86 lb lower on extract No change in BP, heart rate No change in GHQ-12, TSQ-36 No change in Weschler memory scale No change in cholesterol, SHBG No adverse effects

79 Extract versus L-T4 Patient Preference Extract 49 % L-T4 19 % P>0.02 No preference 23 % Hoang et al JCEM 2013

80 Thyroid Extract Potential Harm Transient hypertriiodothyronemia arrhythmia skeletal effects? Fetal type 2 deiodinase converts maternal T4 to T3, maternal T4 is the primary source of thyroid hormone through week 16 of gestation

81 Suggested Candidates for a Trial of Combined Therapy YES Patients who have never felt well after a thyroidectomy or after ablative therapy with radioiodine NO Pregnant or planning a pregnancy Elderly or patients with cardiovascular disease Patients who previously felt well on L-T4

82 Examples of T4/T3 at approximately14:1 T3 T4 T4 alone

83 Cost Issues Generic levothyroxine 137 approx $ 60 / 90 d Generic liothyronine 5 approx $ 80 / 90 d T4/T4 $ 880 / year versus T4 alone $ 240 / year

84 Case 9 Revisited 52 year old woman with fatigue Recent diagnosis of menopause Screening TSH 7.6 Started on levothyroxine 50 mcg 6 weeks later TSH 0.98, free T4 1.6 She has gained 5 pounds, hair is dry, skin is dry, c/o fatigue, constipation and brain fog

85 Case year old woman complains of fatigue TSH 6.40, free T4 1.2 ng/dl ( ) TPO antibodies borderline positive Thyroid not enlarged

86 SUBCLINICAL HYPOTHYROIDISM ELEVATED SERUM TSH NORMAL FREE T4 AND T3

87 PREVALENCE OF SUBCLINICAL HYPOTHYROIDISM % WOMEN % MEN UP TO 15% OF WOMAN OVER 60 TUNBRIDGE ET AL CLINICAL ENDOCRINOLOGY 1977; BAGCHI ET AL ARCH INTERN MED 1990

88 NATURAL HISTORY OF SUBCLINICAL HYPOTHYROIDISM PROGRESSION TO OVERT HYPOTHYROIDISM WOMEN ELEVATED TSH ALONE: ELEVATED TSH, POSITIVE ANTIBODIES: 2.6% / YR 4.3% / YR VANDERPUMP ET AL CLIN ENDOCRINOL 1995

89 SUBCLINICAL HYPOTHYROIDISM NATURAL HISTORY HMO DATABASE 422,242 PATIENTS WITH TSH MEASURED PATIENTS ON THYROID MEDS EXCLUDED 3.0 % WITH HIGH TSH 62 % BECAME NORMAL SPONTANEOUSLY MEYEROVITCH ET AL 2007

90 Subclinical Hypothyroidism There is not a single randomized blinded study that has shown improved symptoms or cognitive function in patients whose TSH values were under 10 after treating with levothyroxine.

91 SUBCLINICAL HYPOTHYROIDISM RISK of CAD and MORTALITY CAD EVENTS MORTALITY TSH ( ) 1.09 ( ) TSH ( ) 1.42 ( ) TSH ( ) 1.58 ( ) N= 3450 subclincial hypo versus 51,837 euthyroid from 11 studies Rodondi et al JAMA 2010

92 Subclinical Hypothyroidism Mortality Age Elevated TSH associated with a lower mortality Hazard Ratio 0.77 ( ) for each 1 SD change in TSH (2.7 mu/l) GUSSEKLOO ET AL JAMA 2004

93 Subclinical Hypothyroidism and Functional Mobility: Age TSH > 4.5 to <7.0 miu/l Better mobility (faster usual and rapid gait speed) Improved cardiorespiratory fitness TSH > 7 to < 20 miu/l same as euthyroid controls Simonsick et al Arch Intern Med 2009

94 Thyroid Function and Non-vertebral Fracture 1278 healthy postmenopausal women 6 year prospective study Patients with elevated TSH had a 35% reduction in fracture Murphy E et al JCEM 2010

95 Subclinical Hypothyroidism Treatment: Cardiovascular Events UK General Practitioner Database TSH Age individuals treated 4.2% untreated 6.6% * Age > individuals treated 12.7% untreated 10.7% Razvi et al Arch Intern Med 2012

96 Why would there be a benefit in young patients, but not old patients?

97 Risk of Over-treatment Colorado health fair (n=25,862) 21.6% taking T4 had TSH <0.3 General practice in England (n=7640) 23 % had TSH < 0.3 Thyroid Clinic Mass General 14% had TSH <0.4 Canaris et al 2000; Dewhallep 1995; Ross 1990

98 Risk of Over-treatment in the Elderly Atrial fibrillation Reduced bone density Cognitive impairment

99 TSH: UPPER LIMIT OF NORMAL 13,444 SUBJECTS: NO THYROID HISTORY, DRUGS, NEG TPO ABS AGE MEAN TSH 97.5 %ILE > SURKS & HOLLOWELL JCEM 2007

100 Case 10 Revisited 79 year old woman complains of fatigue TSH 6.40, free T4 1.2 ng/dl ( ) TPO antibodies borderline positive Thyroid not enlarged

101 Case year old woman with neck pain MRI cervical spine incidental 7 mm thyroid nodule Ultrasound-7 mm hypoechoic nodule with possible microcalcifications

102 SEER INCIDENCE RATES FOR THYROID CANCER / 100, / 100, / 100,000

103 SEER DEATH RATES FOR THYROID CANCER / 100, / 100,000

104 2015 ATA Guidelines for Biopsy Pattern Risk of cancer Biopsy Solid portion, hypoechoic with suspicious features > 70 % > 10 mm no suspicious features > 10 Isoechoic, hyperechoic no suspicious features 5-10 > 15 Spongiform / cystic < 3 > 20 * * or observe without biopsy

105 Do we need to diagnose papillary thyroid cancer under 10 mm?

106 PERCENTAGE OF MICROCARCINOMAS % QUEEN ELIZABETH HOSPITAL HONG KONG 1348 PATIENTS CHOW ET AL CLIN ONC 2003; 15:329

107 PERCENTAGE OF MICROCARCINOMAS UNIVERSITY WISCONSIN 42 % UNIVERSITY FERRARA 40 % JEWISH GENERAL, MONTREAL 50 % CHEEMA ET AL ANN SURG ONC 2006;13:1524 ROTI ET AL JCEM 2006;91:2171 PAKDAMAN ET AL OTOLARYNGOLOGY 2008;139:218

108 MICROPAPILLARY CANCER CANCERS 10 MM OR LESS PREVALENCE AT AUTOPSY % IN SURVEYS DONE IN THE UNITED STATES AS HIGH AS 36 % IN PARTS OF EUROPE

109 NATURAL HISTORY POSSIBLE INSIGHTS BASED ON AUTOPSY AND SEER DATA US POPULATION 300 MILLION ASSUME 6% HAVE MICROPAPILLARY CANCER CALCULATED PREVALENCE 18,000,000 OBSERVED PREVALENCE ALL THYROID CANCER 539,973 CANCERS FOUND <3.0 %

110 OBSERVATIONAL TRIAL KUMA HOSPITAL JAPAN 1235 PATIENTS OBSERVATION 75 (18-227) MONTHS 10 YEARS ONLY 8% of CANCERS GREW BY 3 MM 10 YEARS ONLY 3.8% DEVELOPED NODES ITO ET AL, THYROID 2014

111 DON T ASK, (DON T TELL?) OBSERVATION IS THE STANDARD OF CARE FOR NON- PALPABLE THYROID NODULES UNDER 10 MM

112 Case year old man 2.5 cm thyroid nodule TSH 1.8 Ultrasound hypoechoic, solid, no calcifications Biopsy: Follicular lesion of undetermined significance (FLUS)

113 Evaluation of the Thyroid Nodule Malignancy risk and age <20 YEARS 6.5 % YEARS 2.9 % YEARS 3.9 % YEARS 16.4 % Belfiore et al Am J Med 1992

114 Initial Thyroid Nodule Management: TSH and ultrasound TSH normal or high TSH subnormal Consider FNA based on size and ultrasound characteristics ATA, SRU, TIRADS Obtain thyroid scan Autonomous nodules do not need biopsy Non-functional nodules: consider FNA

115 FNA Diagnostic Categories 1 Non-diagnostic 2 Benign Macrofollicular, Hashimotos 3 FLUS or AUS 4 Follicular Neoplasm Microfollicular 5 Suspicious for malignancy 6 Malignant Papillary, Medullary, Anaplastic, Lymphoma

116 When FNA helps us 2 Benign Macrofollicular, Hashimotos 5 Suspicious for malignancy 6 Malignant Papillary, Medullary, Anaplastic, Lymphoma

117 I don t understand doctor, why did I have the biopsy if you can t tell whether its cancer? 3 FLUS or AUS 4 Follicular Neoplasm (Microfollicular)

118 Bethesda 3: The good, the bad, and the ugly FLUS AUS Equal proportion of macro- and microfollicules Poor fixation or obscuring blood Mild nuclear atypia Extensive Hurthle cells Baloch et al Diagn Cytopath 2008 Layfield et al Diagn Cytopath 2009

119 Bethesda 3 : The bad FLUS / AUS intended to be no more than 7% of biopsies It is being used much more frequently with reported use up to 29% of biopsies

120 Bethesda 3: The ugly An epidemic of thyroid surgery Before FLUS 9 % surgery n=3751 After FLUS 37 % surgery n=3308 Locarno, Switzerland; Reggio Emilia and Desio, Italy; MGH, UPenn Bongiovanni et al Cancer Cytopath 2011

121 Molecular Markers for Indeterminate Cytology FLUS AUS Follicular Neoplasm

122 Molecular Analysis Thyroseq Thyroseq v2 Thyroseq v3 Afirma Gene expression classifier GEC Genomic Sequencing Classifier GSC Xpression Atlas Platform ThyrGen X / Thyra MIR

123 Thyroseq v 3 Mutations, insertions/deletions, fusions, gene expression, and copy number variations in 112 thyroid-related genes 238 surgically removed tissue samples were used as a training set and 175 indeterminate FNAs were used as a validation set Nikiforova et al Cancer 2018

124 Thyroseq v s Sensitivity 98 % Specificity 82 % Accuracy 91 % Nikiforova et al Cancer 2018

125 mrna Expression Analysis Using a Gene Classifier (Afirma) mrna from 167 genes 2646 FNAs used to train the classifier 265 indeterminate nodules of which 85 were malignant 78 of the 85 were suspicious on the classifier FLUS/AUS NPV 95 % n=129 Follicular neoplasm NPV 94 % n= 81 Suspicious NPV 85 % n= 55 Missed cancers n=7 Alexander et al NEJM 2012

126 mrna Expression Analysis Using a Gene Classifier mrna from 167 genes 2646 FNAs used to train the classifier 265 indeterminate nodules of which 85 were malignant 78 of the 85 were suspicious on the classifier FLUS/AUS NPV 95 % (85-99%) Follicular neoplasm NPV 94 % (79-99%) Suspicious NPV 85 % (55-98%) Missed cancers n=7 Alexander et al NEJM 2012

127 Hurthe cell lesions Afirma GEC 17 of 21 benign nodules had suspicious GEC 1 of 10 cancers had benign GEC Alexander et al NEJM 2012 Afirma GSC Sensitivity 89 % Specificity 59 % Unpublished data Thyroseq v 3 Sensitivity 93 % Specificity 69 % Nikiforova et al Cancer 2018

128 Impact of Gene Classifier Managing the Surgical Epidemic? Before using the classifier 74 % of indeterminate bx went to surgery After using the classifier 7.6 % of indeterminate bx went to surgery Duick et al. Thyroid 2012

129 Redefining Non-invasive follicular variant papillary cancer NIFTP Follicular Neoplasm invasive Follicular Cancer Non-invasive follicular tumor with papillary nuclear features encapsulated / circumscibed invasive Follicular Variant PTC

130 Recommendations Benign Reassess at 6-18 months If growth > 20% in 2-3 dimensions, consider repeat biopsy

131 Recommendations Suspicious or Malignant Thyroidectomy

132 Recommendations Follicular Neoplasm FLUS If TSH low or low normal consider scan (if not previously done) If TSH low or low normal consider scan (if not previously done) Molecular testing Surgery Repeat biopsy with or without molecular testing

133 Recommendations AUS nuclear atypia AUS Hurthle cells Consider repeat biopsy with molecular testing Surgery Consider repeat biopsy with mutational testing (GEC not useful) (new GSC better) Surgery

134 Key Points Order TSH alone only if steady-state conditions exist and no pituitary disease. Order TRAb (TSI, TBII) rather than a scan when Graves is the expected cause of hyperthyroidism. Order a scan if the patient has a nodule or if thyroiditis is likely. Patients with slightly high TSH levels will not feel better when treated with T4. Most subcentimetric nodules do not need a biopsy.

135 Next Best Steps Hyperthyroid patients: Begin beta-blocker and order TRAb or a scan; refer to endocrine. Hypothyroid patients: Most patients do not require endocrine referral. Thyroid nodules: Subcentimetric nodules repeat imaging in 6-12 months. Larger nodules refer to endocrine.