Overview of Thyroid Disease and Top Thyroid Myths 46 th Annual Winter Refresher Course Adrienne Barnosky, DO Endocrinologist Wheaton Franciscan Medical Center Review lab tests used in thyroid disease Review hypothyroidism Review hyperthyroidism Discuss utility of imaging testing in thyroid disease Discuss thyroid myths commonly encountered in clinic practice Disclosures I have no financial or pharmaceutical affiliations. Best screening test for thyroid status Low in hyperthyroidism High in hypothyroidism Free T4 used most commonly Total T4 used during pregnancy (goal 1.5x upper end of normal reference range) 1
ONLY helpful in hyperthyroidism Can use total or free T3 Low in nonthyroidal illness/euthyroid sick syndrome Generally not clinical useful Helpful for hyperthyroidism receptor antibodies (TRAb) Thyroid stimulating immunoglobulins (TSI) Not usually helpful Thyroid peroxidase (TPO) antibodies Anti thyroglobulin antibodies* Hypothyroidism *Used in thyroid cancer Hypothyroidism Diagnosis relies on lab tests due to low specificity of symptoms Subclinical High TSH Normal free T4 Treat for TSH values >10 (unless plans for pregnancy) or high TSH values <10 with symptoms Overt disease High TSH Low free T4 Central hypothyroidism Low free T4 Low or inappropriately normal TSH 2
Screening for Hypothyroidism Who should be screened? Screening for asymptomatic patients is controversial American Academy of Family Physicians (AAFP): Periodic assessment of thyroid function in older women 1 The American College of Physicians (ACP): office screening of women older than 50 years 2 The American Thyroid Association (ATA) and the American Association of Clinical Endocrinologists (AACE): measurement of TSH in any individual at risk for hypothyroidism and in patients over the age of 60 years 3 The United States Preventive Services Task Force: insufficient evidence to assess the benefits and harms of screening 4 1. American Academy of Family Physicians. Summary of policy recommendations for periodic health examinations 2002. 2. Screening for thyroid disease. American College of Physicians. Annals Internal Medicine 1998. 3. Garber et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012. 4. Rugge et al. Screening and treatment of thyroid dysfunction: an evidence review for the U.S. Preventive Services Task Force. Annals Internal Med. 2015. Screening for Hypothyroidism Who should be screened? Those at highest risk: Type 1 DM or other autoimmmune disease, family history of thyroid disease, history of neck radiation, history of thyroid surgery or radioiodine therapy, known pituitary or hypothalamic disorders (FT4) Screen for those with lab or imaging abnormalities that could be caused by hypothyroidism: Significant hyperlipidemia Hyponatremia High serum muscle enzymes Macrocytic anemia Pericardial or pleural effusions Antibodies in Hypothyroidism Serum TPO antibodies are elevated in > 90% Not needed in overt hypothyroidism May be considered in: Goiter Painless thyroiditis Postpartum thyroiditis Hyperthyroidism Mariotti et al. Antithyroid peroxidase autoantibodies in thyroid diseases. JCEM 1990; 71:661. Symptoms Anxiety Emotional lability Tremor Palpitations, tachycardia, atrial fibrilllation Heat intolerance Increased sweating Weight loss (some patients gain weight due to excessive appetite) Increased frequency of stools Oligo or amenorrhea Gynecomastia Some patients may have no symptoms 3
Evaluation FT4 Total or FT3 +/ TSH receptor ab or TSI Thyroid Imaging Radioactive iodine uptake/scan Used for differential diagnosis of hyperthyroidism Not helpful in hypothyroidism or euthyroidism Sometimes mentioned as a next test in US reports (know the TSH!) Thyroid Imaging Thyroid Ultrasound Used to evaluate s Not generally helpful in hypothyroidism Limited utility in hyperthyroidism Increased vascularity can aid in diagnosis Interpretation can be complicated Causes of Thyrotoxicosis by Radioiodine Uptake Normal or elevated RAI uptake Graves disease* Toxic adenoma* Toxic multinodular goiter* Trophoblastic disease TSH producing pituitary adenoma Resistance to thyroid hormone Low RAI uptake Painless (silent) thyroiditis Amiodarone induced thyroiditis Subacute (de Quarvain s) thyroiditis Factitious ingestion of thyroid hormone Struma Ovarii Acute thyroiditis Extensive metastases from follicular thyroid cancer Treatment Depends on cause Graves disease Radioactive iodine ablation Surgery Antithyroid medication (ATDs) Toxic MNG or Toxic adenoma Radioactive iodine ablation Surgery Remission does not occur therefore ATDs not routinely recommended (elderly with increased surgical risk, limited life expectance, patient preference) Thyroiditis Beta blockade ATDs not beneficial Antithyroid Medications Methimazole: Blocks new hormone synthesis Drug of choice Preferred in pregnancy other than 1 st trimester Side effects: agranulocytosis, liver toxicity, rash Propylthiouracil Blocks new hormone synthesis Blocks T4 to T3 conversion Drug of choice only for 1 st trimester pregnancy Black box warning: hepatotoxicity, liver failure 4
Thyroid Function Testing Approach to thyroid function testing FT4 High TPO ab (rarely needed) Check TSH Normal: No further workup FT4 & Free or total T3 Low TSH receptor ab Thyroid stimulating Ig NM uptake/scan 1. Why are you testing? Hypothyroidism: TSH, free T4 Hyperthyroidism: TSH, free T4, total T3 Screening for high risk individuals: TSH, free T4, can add T3 if TSH comes back low 2. If TSH returns low, add TRab and/or TSI 3. If TSH returns low, consisder NM uptake/scan When to Refer Hypothyroidism: Difficulty achieving therapeutic target Unclear diagnosis Pregnancy Hyperthyroidism: Most cases To discuss pros/cons of treatment options Pregnancy Case #1 45 year old female presents for evaluation of fatigue, difficulty losing weight, dry skin. TSH checked by primary care physician and found to be 7.6 uiu/ml, FT4 1 ng/dl. On recheck 1 month later TSH found to be 6.9 uiu/ml. Started on levothyroxine 50 mcg daily. TSH now 1.5 uiu/ml. She still reports the same symptoms. Has requested endocrinology consultation. Case #1 She has done some reading and thinks addition of T3 would be helpful. Myth #1: T4+T3 is better Insufficient evidence to support routine use of T4 + T3 Research needed for those with normal TSH and low T3 on monotherapy with levothyroxine 5
Thyroid Physiology Case #2 60 year old female presents for evaluation of hypothyroidism. She was diagnosed with hypothyroidism 2 years ago. TSH was checked because of fatigue, difficulty with weight loss, cold intolerance. She was started on levothyroxine 75 mcg daily and the dose was increased to 88 mcg daily 6 months ago due to persistent symptoms. Wiersinga W. Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism. Nature Reviews Endocrinology. Vol 10, 164 174. 2014. Case #2 Labs at diagnosis: TSH 14.2 uiu/ml, FT4 0.6 ng/dl On LT4 75 mcg daily: TSH 3 uiu/ml, FT4 0.8 ng/dl On LT4 88 mcg daily: TSH 2.2 uiu/ml, FT4 0.9 ng/dl She is wondering if her symptoms will improve with further dose increases. Myth #2: Titration of levothyroxine within the normal range improves symptoms Anectodal evidence for symptom improvement with fine tuning LT4 dosage Double blind randomized, crossover study N=56 with primary hypothyroidism on LT4 of at least 100 mcg daily, stable dosing for at least 2 months, with a TSH 0.2 4.8 mu/l Randomized to a low, middle, or high dose each for 6 weeks Baseline dose + placebo Baseline dose + 25 mcg daily Baselind dose + 50 mcg daily Walsh et al. Small changes in thyroxine dosage do not produce measurable changes in hypothyroid symptoms, wellbeing, or quality of life: results of a double blind, randomized clinical trial. JCEM 91:2624 2630. 2006. Myth #2: Titration of levothyroxine within the normal range improves symptoms Walsh et al. Small changes in thyroxine dosage do not produce measurable changes in hypothyroid symptoms, wellbeing, or quality of life: results of a double blind, randomized clinical trial. JCEM 91:2624 2630. 2006. Case #3 31 year old female presents for evaluation of thyroid lab abnormalities. She saw her PCP for evaluation of weight gain 20 lbs in the past 6 months. She is recently married 10 months ago and had done a liquid diet prior to her wedding. Thyroid function testing was performed. TSH is 1.4 uiu/ml, FT4 0.9 ng/dl. TPO antibodies are checked and positive at 353 IU/mL (normal <9 IU/mL). 6
Antibodies in Hypothyroidism Chronic autoimmune hypothyroidism (Hashimoto s thyroiditis) is the most common cause of primary hypothyroidism in the U.S. Pathology shows lymphocytic thyroiditis Presence of antibodies to thyroid peroxidase (TPO) and thyroglobulin Antibodies in Hypothyroidism Serum TPO antibodies are elevated in > 90% Not needed in overt hypothyroidism May be considered in: Goiter Painless thyroiditis Postpartum thyroiditis Mariotti et al. Antithyroid peroxidase autoantibodies in thyroid diseases. JCEM 1990; 71:661. TPO ab Positivity with Normal TSH N = 1184, FT4, TPO ab, TG ab in 1981 and 1994 If TPO ab or TG ab positive: Baseline TSH <2.5 mu/l, 12% hypothyroid Baseline TSH 2.5 4 mu/l, 55.2% hypothyroid Baseline TSH >4 mu/l, 85.7% hypothyroid Management of Thyroid Nodules 46 th Annual Winter Refresher Course Kimberly LaMack, MD Endocrinologist Wheaton Franciscan Medical Center Walsh et al. J Clin Endocrinol Metab, March 2010, 95(3):1095 1104 Disclosures No financial or pharmaceutical affiliations Discuss the initial evaluation of a thyroid Discuss when to consider a biopsy of a thyroid Discuss treatment of a thyroid Discuss when to refer to Endocrinology 7
Background Thyroid s are common Palpable thyroid s are present in approximately 5% of women and 1% of men in iodine sufficient areas (1,2) Thyroid s are present on 19 67% of thyroid ultrasounds (3,4) Thyroid s are present in autopsy in up to 8 65% of cases (5,6) Discuss the initial evaluation of a thyroid Discuss when to consider a biopsy of a thyroid Discuss treatment of a thyroid Discuss when to refer to Endocrinology 1. Turnbridge WMG et al. (1977) Clinical Endocrinology, 7, 481 493. 2. Vander JB et al (1968) Annals of Internal Medicine, 69, 537 540. 3. Mazzaferrri EL (1992) American Journal of Medicine, 93, 359 362. 4. Tan, GH, Gharib H. (1997) Annals of Internal Medicine, 126, 226 231. 5. Mortensen JD, Woolner LB, Bennett WA. (1955) Journal of Clinical Endocrinology and Metabolism, 15, 1270 1280. 6. Dean, DS, Gharib, H (2008) Best Practice & Research Clinic Endocrinology & Metabolism, 22: 901 911. Initial Evaluation of Thyroid Nodules History Personal history of radiation exposure Family history of thyroid s, hyperthyroidism or thyroid cancer Compressive symptoms (globus sensation, swallowing difficulty, hoarseness) Symptoms of hyperthyroidism (heat intolerance, weight loss/gain, palpitations, tremors, loose stools, anxiety, sleep disturbance, fatigue) Initial Evaluation of Thyroid Nodules Physical exam Vitals (tachycardia, fever, hypertension) Eyes (proptosis, periorbital edema, conjunctival injection) Focal or diffuse thyroid enlargement Cervical lymphadenopathy Heart (tachycardia, atrial fibrillation) Neurologic (hand tremor, rapid relaxation phase of reflexes) Skin (warm skin, thyroid dermopathy) Initial Evaluation of Thyroid Nodules Laboratory TSH (Thyroid stimulating hormone) Imaging Thyroid ultrasound is the best imaging technique Size Benign versus concerning features Echogenicity, vascularity, microcalcifications, irregular borders, taller than wide Incidenalomas Initial Evaluation of Thyroid Nodules If TSH is suppressed Iodine uptake and scan A toxic/hot is a benign A cold should be evaluated for biopsy 8
Discuss the initial evaluation of a thyroid Discuss when to consider a biopsy of a thyroid Discuss treatment of a thyroid Discuss when to refer to Endocrinology When to Consider a Thyroid Biopsy When the TSH is normal or high and Any thyroid (s) > 1 cm in size Any thyroid (s) < 1 cm in size with concerning features Thyroid (s) of any size with: Family history of thyroid cancer, MEN (Multiple Endocrine Neoplasia) syndrome or Familial polyposis Personal history of radiation exposure Any PET positive thyroid 1 2% of FDG PET scans show an incidental thyroid (1) Risk of malignancy 23% (2) to 42% (3) Neck lymphadenopathy (thyroid bed, ipsilateral/unilateral anterior cervical) 1. Are, C et al. (2007) Annals of Surgical Oncology, 14, 3210 3215. 2. Bae, JS et al. (2009) World Journal of Surgical Oncology, 7, 63. Kang et al. (2003) Journal of Clinic Endocrinology and Metabolism, 88, 3. K 4100. American Thyroid Association (ATA) Guidelines for Management of Thyroid Nodules First published in 2006 Revised in 2009 Currently undergoing revision When to Consider a Thyroid Biopsy www.thyroid.org Cooper, R.S. et al. (2009) Thyroid, 19: 1167 1214. Cooper, R.S. et al. (2009) Thyroid, 19: 1167 1214. When to Consider a Thyroid Biopsy Hypoechoic Thyroid Nodule (1) Isoechoic Thyroid Nodule (2) Discuss the initial evaluation of a thyroid Discuss the when to consider a biopsy of a thyroid Discuss treatment of a thyroid Discuss when to refer to Endocrinology Hyperechoic Thyroid Nodule (3) Spongiform Nodule (4) 1. Vandermeer, FQ, Cheong JWY (2007) Applied Radiology, 2. http://www.ultrasoundcases.info/slide View.aspx?cat=276&case=249 3. http://posterng.netkey.at/esr/viewing/index.php?module=viewing_poster&task=viewsection&pi=108804&ti=342810&searchkey= 4. Kim, JY (2015) Ultrasonography, 34, 304 311. 9
Treatment of Thyroid Nodules Surveillance Repeat ultrasound in 6 18 months (1) If stable, then repeat every 3 5 years False negative rate of benign thyroid biopsies is about 5% (2,3) Surgery Compressive symptoms even if biopsy proven benign disease Toxic solitary Abnormal thyroid biopsy 1. Cooper, R.S. et al. (2009) Thyroid, 19: 1167 1214 2. Carmeci, C et al (1998) Thyroid, 8: 283 289. 3. Ylagan LR et al (2004) Thyroid, 14:35 41. Treatment of Thyroid Nodules Biopsy results Benign Malignant (risk of malignancy > 95%) Suspicious for maligancy (risk of malignancy 50 75%) Follicular neoplasm (risk of malignancy 15 25%) Follicular lesion of undetermined significance [FLUS] or Atypia of unknown significance (risk of malignancy 5 10%) Non diagnostic Baloch, ZW et al. (2008) Diagnostic Cytopathology, 36: 42 437. Treatment of Thyroid Nodules Biopsy results Benign Malignant (risk of malignancy > 95%) Suspicious for maligancy (risk of malignancy 50 75%) Follicular neoplasm (risk of malignancy 15 25%) Follicular lesion of undetermined significance [FLUS] or Atypia of unknown significance (risk of malignancy 5 10%) Non diagnostic Treatment of Thyroid Nodules Afirma Used for FLUS, atypia of unknown significance, follicular neoplasm Gene Expression Classifier Measures the expression of 142 genes Risk of malignancy in a benign Afirma sample the same as for a benign biopsy (1) Benign Afirma has a NPV of 94 96% on indeterminate biopsy samples (2) Baloch, ZW et al. (2008) Diagnostic Cytopathology, 36: 42 437. 1. Alexander EK, et al (2012) NEJM, 367: 705 715. al 2010) Journal of Clinical Endocrinology & Metabolism, 2. Chudova D, et ( 95; 5296 5304. Discuss the initial evaluation of a thyroid Discuss the when to consider a biopsy of a thyroid Discuss treatment of a thyroid Discuss when to refer to Endocrinology When to consider an Endocrine Referral for a Thyroid Nodule(s) Any time you would consider a thyroid biopsy Any thyroid (s) with a suppressed TSH Any biopsy proven thyroid cancer Any thyroid (s) 10
Summary Thyroid s are common Check a TSH before considering a biopsy Ultrasound is the best imaging modality Biopsy based on size, concerning features or patient risk A referral to Endocrinology is always appropriate Myth #1 If a patient has a negative thyroid biopsy, no further assessment is needed False negative rate of benign thyroid biopsies is about 5% (1,2) Repeat thyroid ultrasound in 6 18 months and then every 3 5 years if stable (3) Monitor for development of compressive symptoms or change in TSH Annual thyroid function tests and exam 1. Carmeci, C et al (1998) Thyroid, 8: 283 289. 2. Ylagan LR et al (2004) Thyroid, 14:35 41. 3. Cooper, R.S. et al. (2009) Thyroid, 19: 1167 1214. Myth #2 If a patient has a thyroid and hyperthyroidism, no further assessment is needed. Nonfunctioning thyroid with background Graves disease Cold on uptake and scan would require a biopsy 11