Pearls and Pitfalls of Thyroid Diagnosis Todd W. Frieze, MD, FACP, FACE, ECNU, CCD Endocrine Care, Hattiesburg Clinic Biloxi MS
Thyroid Anatomy Isthmus of gland located 1 fingerbreadth below cricoid cartilage Average thyroid size is 15-20 grams with each lobe being size of thumb Cartilage, lymph nodes, carotid bulb often mistaken for thyroid tissue
Thyroid Physiology Iodine used for substrate Thyroid gland produces 20-fold more T4 than T3 15-20% of circulating T3 made by thyroid gland 80-85% of T3 comes from deiodination 2-3 months of hormone stored in thyroid T4 has long t 1/2 = 7 days T3 has short t 1/2 = 24 hrs and is active hormone 99.7+% of all hormone is bound to proteins
Thyroid Regulation Thyrotropin Stimulating Hormone (TSH) stimulates thyroid growth, production and release of T4 and T3 TSH increased by small decreases in T4 and T3 TSH decreased by small increases in T4 and T3, octreotide, steroids, and dopamine TSH secretion is pulsatile
Measurement of tropic and peripheral hormones facilitates diagnosis
Thyroid Function Tests (TFTs) Know specifically what tests you are ordering The more the better is not always true Often, 3rd generation TSH is only test needed
Measurement of the tropic hormone, TSH, usually suffices for diagnosis Secondary thyroid dysfunction is rare The pituitary TSH response to changing thyroid hormone levels is double-exponential Thus, TSH the most sensitive and discriminatory marker for thyroid function status in most patients
TSH as Screening Test Changes may occur before symptoms Not affected by changes in binding proteins Equilibration of TSH levels Occurs after changes in T4 and T3 May take 4-12 weeks (longer with aging given slowed thyroid metabolism)
TSH is Not Reliable in Certain Clinical Conditions Pituitary or Hypothalamic disease Rapidly changing thyroid hormone levels (e.g. thyrotoxicosis during treatment) Severe illness Certain medications = amiodarone, high-dose glucocorticoids, dopamine, dobutamine, octreotide (somatostatin analogs [SSAs])
Evolution of TSH Testing Figure 6-8. The effect of serum TSH assay sensitivity on the discrimination of euthyroid subject (Euth) from those with thyrotoxicosis (Toxic). (From C. Spencer, Clinical Diagnostics, Eastman Kodak Co., 1992).
TSH Variability 10 min sampling for 24 hrs 8 mild hypothyroidism 38 healthy volunteers 8 severe hypothyroidism Roelfsema et al, JCEM 2010 95:928
Distribution of second TSH results compared with initial measurement Second TSH level test result Patients, % n=669 n=3775 n=7533 n=334,572 First TSH level test result, % Meyerovitch et al 2007 Arch Intern Med 167: 1533-8
Thyroid hormone levels Total thyroid hormones (T4 and T3) Less accurate due to highly protein-bound states Altered by Pregnancy and drugs that affect TBG Free thyroxine (T4) levels Directly measured Free T4 (FT4) = standard Equilibrium dialysis Used during pregnancy as trimester-specific ranges Also useful if protein abnormalities or discordant results Free Thyroxine Index (FTI) - calculated by using total T4 and the amount of binding proteins using T3RU
T3 Testing No utility in primary hypothyroidism T3 Resin Uptake (T3RU) functional T3 test Choice between FT3 or TT3 Use of oral estrogen FT3 Hepatic disease or meds affecting liver FT3 Reverse T3 No clinical utility in outpatient setting Use limited to inpatients, as elevated in euthyroid sick syndrome (but long turnaround)
T4 and T3 assays (non)-harmonization TT4 & TT3 assays fairly well harmonized FT4 & FT3 assays poorly harmonized Range of result-differences on aliqotes of the same sample measured with 15 different Immunoassays 70% 60% 50% Difference between highest & lowest result (%) 40% 30% 20% 10% 0% TT4 TT3 FT4 FT3
Thyroid screening guidelines 3rd generation TSH if suspect thyroid disease If normal: no further work up If high: FT4 for degree of hypothyroidism If low: FT4 + Free/Total T3 for degree of thyrotoxicosis FT4 and TSH ordered Hypothalamic or pituitary disease suspected Severe symptoms and discordant TSH Inpatients (reverse T3 and T3 may also be helpful) Thyroid cancer suppression testing
Thyroid Antibodies (1) Anti-Thyroid Peroxidase (TPO) Confirm diagnosis of Hashimoto s thyroiditis Aids in determining who has highest risk of progression to overt hypothyroidism Higher risk of recurrent postpartum thyroiditis Thyroid Stimulating Immunoglobulin (TSI) Highly specific, 2 nd generation more sensitive Predictor of ophthalmopathy risk pre I 131 therapy Crosses placenta useful to determine risk of neonatal thyrotoxicosis
Thyroid Antibodies (2) Thyroglobulin antibody (TgAb) Second line testing for autoimmune process Some TPO(-) but TgAb(+) Thyroid cancer evaluation: Interferes with thyroglobulin test Need to have negative antibody levels in order to interpret thyroglobulin level, or use Tg via LCMSMS TSH Receptor antibodies (TRAb) More specific than TSI, less available
Other Thyroid Labs Thyroglobulin Main utility in thyroid cancer Distinguishes b/w factitious disease and all other causes of thyrotoxicosis 24-hr urine Iodine Critical if suspect iodine deficiency Determine if iodine excess present via dietary or medical exposure (amiodarone, CT/cath dyes) Serum/plasma iodine for metabolism defects
Imaging Studies Thyroid ultrasound Radioactive Iodine ( 123 I or 131 I) Uptake: determines thyroid activity Scan: functional thyroid picture 99m Tc pertechnetate CT: anatomic detail MRI: esp. orbits PET: functional study
Prevalence of Thyroid Abnormalities N=24,337 Percentage of patients Canaris et al 2000 Arch Intern Med 160: 526-534
Hypothyroidism Prevalence of 2-4% of population Risk factors: female, goiter, increasing age, thyroid surgery, neck irradiation, family hx of autoimmune thyroid dz, other autoimmune dzs Symptoms are not sensitive or specific 12-15% of the general public, with normal TSH and FT4, have at least two hypothyroid complaints Increased likelihood with constellation of sxs No pathognomonic signs e.g. Queen Anne s sign
Hypothyroidism Subclinical Hypothyroidism: Elevated TSH without symptoms + normal FT4 More prevalent than overt disease Higher progression to overt disease if positive antibodies or goiter Evaluation of overt or subclinical process: Rule out other causes of increased TSH Assess for symptoms and signs Repeat TSH within 2-4 weeks for persistency If persists, check TPO, TgAb, and ultrasound
TSH Distribution vs. Age NHANES III Thyroid Disease-free 97.5 %ile by age: 20-29 = 3.56 miu/l 80+ = 7.49 miu/l Reference population 70% of 80+ age group with TSH > 4.5 miu/l were within age-specific reference group Surks & Hollowell; JCEM 2007; 92:4575
TSH Distribution vs. Age Surks & Hollowell; JCEM 2007; 92:4575
Local TSH Normal Ranges Garden Park 0.35-4.94 Hancock 0.34-5.60 Memorial 0.49-4.67 Merit Biloxi 0.34-5.60 SRHS 0.36-3.74 LabCorp 0.40-4.50 Quest Diagnostics 0.40-4.50
Thyrotoxicosis Definition = any condition in which there is an excess of circulating thyroid hormone Prevalence in U.S. 0.5% overt and 0.7% subclinical Male 25% of female Development of various forms dependent on iodine intake of population and age Elderly have less obvious presentation than younger patients
Apathetic Thyrotoxicosis Up to 55% of elderly pts had 2 symptoms 1 Lack typical adrenergic features Present with Depression or apathy Weight loss Atrial fibrillation Congestive heart failure Increased risk of osteoporosis 1. Boleart et al, J Clin Endocrinol Metab 2010; 95 (6): 2715-2726
TSH Screening If normal = euthyroid Pursue with T4/T3 only if patient toxic Causes of toxicosis with normal TSH TSH-secreting pituitary adenoma Thyroid hormone resistant states Rule out other causes of TSH suppression Euthyroid sick syndrome/non-thyroidal illness Drugs e.g. dopamine, glucocorticoids, SSAs Central hypothyroidism Normal pregnancy
Caution about Biotin!!! Hot issue in lab testing Recommend daily intake is 30 mcg OTC hair/skin/nail supplements have as much as 10 mg (>300X RDI) Many FDA immunoassays use biotin Lowers TSH and elevates T4/T3 levels Recommendations: Hold biotin for at least 48 hours Hold longer if higher intake or CKD
Thyroid Hormone Testing If suppressed TSH = thyrotoxic Obtain FT4 (if not reflexive) Obtain T3 if FT4 normal as 1% with T3-toxicosis Free >> total thyroid hormone levels Acute and inpatient settings = TBG & albumin Pregnant/estrogen = TBG T3:T4 > 20 in Graves and toxic nodular goiter T3:T4 < 20 in thyroiditis
Confirmation of Diagnosis Always repeat testing within short timeframe e.g. 2-4 weeks to confirm persistent process Thyroid antibodies (TSI, TPO) usual next step Thyroid ultrasound more critical to assess for concomitant nodular disease Nuclear study only if unclear picture 24-hr urine iodine if known/possible exposure Thyroglobulin if suspect factitious process
Two Categories of Causes Hyperthyroidism Source of thyroid hormone excess is high synthesis and secretion from the thyroid gland Elevated Radioactive iodine uptake (RAIU) Thyrotoxicosis without true hyperthyroidism Source of thyroid hormone excess is not due to production problem within the thyroid Low RAIU
Causes of Thyrotoxicosis High Radioiodine Uptake: Graves Disease Toxic Nodule(s)/MNG 90% TSH-secreting tumors hcg-induced Low Radioiodine Uptake: Thyroiditis (subacute, painless) Factitious Iodine-induced 10%
Graves : Nuclear Imaging Increased RAI Uptake Diffuse/homogeneous pattern
Toxic Nodular Goiter: Nuclear Imaging Toxic MNG Minimal-moderately increased RAIU Patchy scan pattern Toxic Adenoma Increased RAIU Hyperfunctional/ hot nodule on scan Other tissue cold / suppressed
Subacute Thyroiditis Low RAIU (<5%) No/minimal image on scan
Subclinical Thyrotoxicosis Prevalence ~1% in general population TSH level below LLN in sensitive assay Not necessarily below the limit of detection Normal T4 and T3 levels Some patients may have symptoms Repeat levels within 3-6 months unless risks
Prevalence of Endocrine Disorders in U.S. Adults Endocrine Condition Prevalence Metabolic syndrome 35-40% Obesity 25-50% Diabetes 5-25% Hyperlipidemia 15-20% Osteoporosis 7% Thyroid nodules 30-70% Golden SH., et al. J Clin Endo Metab 2009; 94:1853-78 Mazzaferri M. New England Journal Medicine 1993; 328:553-558 Guth S., et al. Eur J Clin Invest 2009; 39:699-706
Thyroid Nodules: Epidemiology Palpation: 4-7% U.S. Ultrasound: 30% pts Autopsy: 50% of suspected normal thyroid glands Female/Male ratio 5:1 Incidence increases linearly with age Autopsy/Ultrasound Ultrasound Palpation Palpation More common in areas of low iodine intake Mazzaferri. N Engl J Med. 1993 Feb 25;328(8):553-9
How good are we at finding nodules? Ultrasound vs. Palpation 35 Nodules MISSED by palpation Nodules FOUND by palpation # Nodules found by US 30 25 20 15 10 5 94% 50% 42% 0 <1cm 1-2cm >2cm Nodule size by US Brander 1992 J Clin Ultrasound 20: 37-42
Concerning Clinical Features Rapid tumor growth Very firm nodule (rock hard) Fixation to adjacent structures Vocal cord paresis Enlarged regional lymph nodes Family history of PTC or MEN 2 Distant metastases History of radiation exposure to the head/neck Positive Predictive Value (PPV) good (70-75%) Negative Predictive Value (NPV) unacceptable (85%) Hamming JF., et al. Arch Int Med 1990; 150:1088 Rago T., et al. Clin Endo 2007; 66:13
Evaluation of Thyroid Nodule(s) Assess thyroid cancer risk factors TSH as first line screening test If suppressed/low: Complete TFTs for thyrotoxicosis evaluation Nuclear study for toxic/autonomous nodule(s) No biopsy if functional nodule(s) If normal or elevated/high, assess size and features to determine biopsy vs. surveillance Calcitonin use by specialist only
Thyroid/Neck Ultrasound RECOMMENDATION 6: Thyroid sonography with survey of the cervical lymph nodes should be performed in all patients with known or suspected thyroid nodules Strong Recommendation, High-quality evidence Haugen et al 2016 Thyroid 26: 12
Radionuclide Thyroid Imaging ATA 2015 RECOMMENDATION 2(C): If serum TSH is normal or elevated, a radionuclide scan should not be performed as the initial imaging evaluation Strong Recommendation, Moderate-quality evidence Haugen et al 2016 Thyroid 26: 10
Sonographic Pattern/Risk Haugen et al 2016 Thyroid 26: 14
Indications for FNA Haugen et al 2016 Thyroid 26: 14
Thyroid FNA Cytology Bethesda Category Risk of Malignancy I. Non-diagnostic 5-10% II. Benign 0-3% III. AUS (atypia undetermined significance)/ FLUS (follicular lesion undetermined significance) 10-30% IV. Follicular Neoplasm (FN)/ Suspicious for FN 25-40% V. Suspicious for malignancy 50-75% VI. Malignant 97-99% Adapted from Ali and Cibas, TBSRTC 2017.
Thyroid Nodule Algorithm Haugen et al 2016 Thyroid 26: 13
History, Physical TSH High or Normal TSH Low TSH (Thyrotoxic) Ultrasound FT4 + FT3/TT3, Nuclear study U/S guided FNA based on size & features Surveillance/ monitoring Functioning Hot Nonfunctioning Cold/warm No FNA, Rx hyperthyroidism Ultrasoundguided FNA
Questions???