Thyroid Diseases Scott Urquhart, PA-C Clinical Instruct., George Washington Univ. PA Program Adjunct Clinical Prof., James Madison Univ. PA Program Diabetes and Thyroid Associates. Fredericksburg, Virginia Q1: The most common thyroid function disorder is? • • • • 1) Graves’ disease 2) Hypothyroidism 3) Sub-acute thyroiditis 4) Thyroid cancer Q2: The most sensitive test for thyroid function is? • • • • 1) Free T4 2) Free T3 3) TSH 4) Thyroid ultra sound Q3: The best assay to confirm that a patient’s hypothyroidism is autoimmune in nature? • • • • 1) 2) 3) 4) Thyroid stimulating immunoglobulins Anti-nuclear antibody TSH Thyroid peroxidase antibodies Q4: The best assay to confirm that a patient’s hyperthyroidism is autoimmune in nature? • • • • 1) 2) 3) 4) Thyroid stimulating immunoglobulins Anti-nuclear antibody TSH Thyroid peroxidase antibodies Q5: Which is the best study to confirm the etiology of a patient’s thyrotoxicosis? • • • • 1) 2) 3) 4) I123 thyroid scan/uptake Neck CT or MRI Thyroid ultrasound Fine needle aspiration of the thyroid Q6: Which is the best study to make the initial evaluation for thyroid nodules discovered on routine physical exam? • • • • 1) 2) 3) 4) I123 thyroid scan/uptake Neck CT or MRI Thyroid ultrasound Fine needle aspiration of the thyroid Q7: Patient has a thyroid U/S showing a solid dominant (>10mm) nodule and normal thyroid function, what is your next step? • • • • 1) 2) 2) 4) Re-check thyroid U/S in 1 year Fine needle aspiration of the thyroid Neck CT or MRI I123 thyroid scan/uptake Q8: Thyroid U/S shows homogeneous increased radiotracer uptake, the diagnosis is? • • • • 1) 2) 3) 4) Metastatic thyroid cancer Graves’ disease Toxic multi-nodular goiter Toxic thyroid nodule Q9: Methimazole or propylthiouracil and used to treat hypothyroidism? • 1) True • 2) False Q10: Which in not an appropriate treatment for Graves’ disease? • 1) Thyroidectomy • 2) Anti-thyroid medications such as propylthiouracil or methimazole • 3) Levothyroxine sodium • 4) I131 radioactive iodine OBJECTIVES • Order and interpret appropriate labs and studies necessary for the diagnosis of the thyroid disorders discussed in this lecture. • Describe the common signs and symptoms of hyper/hypothyroidism, work-up, treatment, and follow-up. • Provide a practical approach to the work-up and diagnosis of thyroid nodules. • Know when to refer. Thyroid Diseases Scott Urquhart, PA-C Clinical Instruct., George Washington Univ. PA Program Adjunct Clinical Prof., James Madison Univ. PA Program Diabetes and Thyroid Associates. Fredericksburg, Virginia Major Thyroid Abnormalities Functional / Biochemical • Hypothyroidism • Hyperthyroidism Structural / Anatomy • Thyroid – Goiter – Nodules • Cold • Warm or Hot – Cysts – Malignancies At Risk Population for Thyroid Dysfunction • Women, elderly, postpartum 4-8 months. • FamHx of Hashimoto’s or Graves’ dz. • PMHx or FamHX autoimmune diseases – SLE, RA, DM1, Addison’s, vitiligo, pernicious anemia. • Type 1 DM: ~20% increase risk for thyroid dysfunction, mainly hypothyroid. • Patients treated with amiodarone, lithium, others. Am. Thyroid Association, postpartum thyroiditis, accessed 6/4/2011 AACE Thyroid Guidelines, Endocr Pract. 2002;8(No. 6) Basic and Clinical Endocrinology, Lange Series, 7th edition HYPOTHALAMIC / PITUITARY THYROID AXIS • TRH: stimulate anterior pituitary to release TSH. • TSH: stimulate thyroid for synthesis and release of T4 and T3. • Low T4, Low T3: stimulate TSH and TRH. • High T4, High T3: inhibit TSH and TRH. Basic and Clinical Endocrinology, Lange Series, 7th edition THYROID HORMONES • • • • T4 to T3 secretion ratio of 10:1. T3 is 4X more biologically active than T4. T1/2: T4 = 7days, T3 = 1 day. T4,T3: 99% bound to protein, i.e. metabolically inactive. • From thyroid: 100% - T4, 20% - T3 remainder of T3 is from T4 to T3 conversion in peripheral tissues. Basic and Clinical Endocrinology, Lange Series, 7th edition THYROID TESTING Biochemical 1) TSH - highly sensitive, best test for thyroid function. 1) Free T4 (FT4)- biologically active. 2) Free T3 (FT3) - biologically active. - rarely need to check unless, TSH is low or undetectable with a normal FT4. THYROID TESTING (more specific) • Thyroid Peroxidase Antibodies (TPO-Ab’s) - Hashimotos Thyroiditis • Thyroid Stimulating Immunoglobulins (TSI’s) or TSH receptor antibodies (TRAb). - Unique to Graves’ disease • I-123 RAIU (Radio Active Iodine Uptake) evaluation for thyrotoxicosis, shape, size. Don’t use to confirm hypothyroidism. DON’T FORGET THE BASICS • History of present illness and ROS. • PMHx – postpartum – Past Hx of thyroid pain/tenderness/nodule/ enlargement or goiter – H/O autoimmune diseases • FamHX – thyroid dysfunction, thyroid cancer, Autoimmune diseases. • Medications • Systematic physical exam Hypothyroidism HYPOTHYROIDISM • Prevalence: 4 - 8% general population. • Mean age of Dx: 5th decade of life • Female to male ratio: 10:1 Endocrine Secrets. McDermott, 4rd Edition PRIMARY HYPOTHYROIDISM • Identification on clinical basis can be challenging. • Symptoms generally vague. • Frequently goes unnoticed, confused as other health problems. • Insidious onset + poor index of suspicion = misdiagnosis ETIOLOGY • Autoimmune: - Chronic lymphocytic thyroiditis = Hashimoto’s - positive TPO-Ab’s - remember postpartum thyroiditis • Iatrogenic: I-131 RAI, total/subtotal thyroidectomy, neck irradiation. • Congenital: agenesis, dysgenesis. • Drug induced: lithium, amiodarone, chemotherapy, others. Endocrine Secrets. McDermott, 4rd Edition Basic and Clinical Endocrinology, Lange Series, 7th edition Clinical Symptoms of Hypothyroidism • Fatigue • Lethargy • Arthralgias • Hoarseness • Cold intolerance • Heavy menstrual flow • Constipation • Decreased memory • Paresthesias • Sleepiness • Depression • Weight gain ,edema • Mental Impairment • Muscle cramps AACE Thyroid Guidelines, Endocr Pract. 2002;8(No. 6) Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. Clinical Signs of Hypothyroidism • • • • • • • • • • • Bradycardia Coarse hair, hair loss Delayed relaxation phase of deep tendon reflexes Dry, cool, pale skin Goiter Hoarseness Non-pitting edema (myxedema) Puffy eyes and face Slow movements Slow speech Thinning lateral third of eyebrows AACE Thyroid Guidelines, Endocr Pract. 2002;8(No. 6) Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clin. Text. 8th ed. 2000. Example of Clinical Manifestations of Hypothyroidism • Patient example – Fatigue (“no energy”), cold intolerance, constipation, weight gain, fatigue, problems with concentration (“mental clouding”), dry skin CLINICAL MANIFESTATONS EXAM • NECK: thyroid may be normal, enlarged, symmetric/asymm., smooth or lumpy. • HEART: bradycardia. • EXTREMS: pretibial/ankle edema, dry cool skin, brittle nails. • NEURO: DTR’s with delayed relaxation phases • HEENT: periorbital puffiness, loss of lateral eyebrows, coarse/thinning hair. LABORATORY EVALUATION • TSH - high • Free T4 - low • Check both if new diagnosis to make sure PITUITARY-THYROID AXIS intact. • Consider TPO-Ab Levothyroxine Sodium (LT4 ) • Exogenously administered LT4 hormone • Indistinguishable from endogenous T4, both in its physiologic effects and its quantification as measured in blood • LT4 is the treatment of choice as replacement or supplemental hormone therapy • Branded preparations are preferred Levothyroxine Bioequivalence Briefing Document. Available at: http://www.fda.gov/ohrms/dockets/ac/03/briefing/3926B1_02_A-abbott.pdf TREATMENT • Levothyroxine (LT4), narrow therapeutic range – 0.3 – 3.0 IU/mL, caution in lower range TSH. • Brand vs. generic vs. T4 + T3 combination. • Lifelong treatment, most cases • Dosing: 1.6 mcg/kg/day = ~100 - 125 mcg/day. • Compliance, empty stomach, competing agents for absorption (Iron, Calcium ) • Check TSH no sooner than 6 weeks after initial start of LT4 or any adjustment. AACE Thyroid Guidelines, Endocr Pract. 2002;8(No. 6) Therapy Monitoring • Clinical and laboratory monitoring enable – Evaluation of the clinical response – Assessment of patient compliance – Assessment of drug interactions, if applicable – Adjustment of dosage, as needed • Clinical and laboratory evaluations should be performed – At 6- to 8-week intervals while titrating – Annually once a euthyroid state is established Factors That May Reduce Levothyroxine Effectiveness • Malabsorption Syndromes – Post jejunoileal bypass • Drugs That Increase Clearance surgery – Short bowel syndrome – Celiac disease – Rifampin – Carbamazepine – Phenytoin • Reduced Absorption – – – – – – – • Factors That Reduced T4 Colestipol hydrochloride to T3 Clearance Sucralfate – Amiodarone Ferrous sulfate – Selenium deficiency Food (eg, soybean formula) • Other Mechanisms Aluminum hydroxide – Lovastatin Cholestyramine – Sertraline Sodium polystyrene sulfonate Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. 2000. Synthroid® [package insert]. Abbott Laboratories; 2003. Thyroid Hormone Therapy Special Treatment Populations • Patients 50 years of age or with underlying cardiac disease – Initial dose of LT4 - 25 to 50 mcg/d • Elderly patients with cardiac disease – Initial dose of LT4 - 12.5 to 25 mcg/d • Patients with heart failure – Both hypo- and hyperthyroidism can worsen heart failure Levothyroxine Bioequivalence Briefing Document. Available at: http://www.fda.gov/ohrms/dockets/ac/03/briefing/3926B1_02_A-Abbott.pdf Treating Hypothyroidism Before and During Pregnancy • Encourage adherence with LT4 replacement therapy before conception • Monitor TSH levels before conception and during first trimester • Consider increase of LT4 dosage in athyreotic patients by 25% - 50% when pregnancy is confirmed • Monitor TSH levels every 6 to 8 weeks throughout pregnancy • Reinstate pre-pregnancy LT4 dosage immediately following delivery Gharib H, et al. Endocr Pract. 1999;5:367-368. Mandel SJ, et al. N Engl J Med. 1990;323:91-96. Over-Replacement Risks • Switching a narrow therapeutic index drug, such as LT4, without retesting and re-titrating can cause inconsistent TSH control, resulting in over-replacement • Over-replacement risks (TSH <0.5 IU/mL) – Iatrogenic thyrotoxic state – Increased heart rate and myocardial contractility – For cardiac patients, increased risk of angina and MI – Reduced bone density/osteoporosis – Psychiatric symptoms, such as anxiety, sleep disturbance, irritability, and fatigue Synthroid® [package insert]. Abbott Laboratories; 2003. Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. Felicetta JV. Consultant. 2002;1597-1606. Available at: www.consultantlive.com. Accessed July 1, 2003. Case 1 46 y.o. female presents with a 3 - 4 month history of heavier than usual menstrual cycles, fatigue, “feeling sleepy all of the time”, depressed, constipation, problems concentrating, cold intolerance. • PMHx: unremarkeable • FAMHx: Adopted. Case 1 continued • P.E. : DTR’s show delayed relaxation phases of biceps and brachioradialis, non tender symmetric goiter @ 2 times normal size without nodules. • LABS : TSH 77.02 (0.45-4.50) Free T4 0.38 (0.8 – 1.50) TPO-Ab 267 reactive greater 40. Case 1 continued • Dx: Hashimoto’s Thyroiditis • Tx: 100 mcg qd, non-generic LT-4 Follow-up in 6 weeks and recheck TSH • F/U: Feeling “90% better” TSH 7.62 Increase to 112mcg qd. Follow-up in 2 months. • 2 months later TSH – 2.11 (0.50 - 3.00). Plan: follow and adjust LT-4 based on TSH SUBCLINICAL HYPOTHYROIDISM • Very difficult to diagnose clinically • High index of suspicion, may be asymptomatic • 4 -15% of general population* • 20% of pts. over 60 y.o. (esp. women)** • LABS: TSH - minimally high (6 - 10 IU/mL) Free T4 – low normal • TREATMENT: controversial, consider if symptoms, lipid abnormality, if TPO-Ab positive • Low dose LT-4 vs. surveillance, education. *US Endocrinology Volume 4 Issue 1 *www.aace.com accessed 6/4/2011 Mild Thyroid Failure and Neurobehavioral Abnormalities • Conditions reported to occur more frequently in patients with mild thyroid failure – Depression – Anxiety – Somatic complaints – Cognitive abnormalities Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. Cooper DS. N Engl J Med. 2001;345:260-264. Rationale for Treating Mild Thyroid Failure • Potential benefits from treatment – Prevent progression to overt hypothyroidism – Improve serum lipid profile, which may reduce the risk of death from cardiovascular causes – Reduce symptoms, including psychiatric and cognitive abnormalities Cooper DS. N Engl J Med. 2001;345:260-264. Case 2 • Hx: 32 y.o. women referred for mildly increased TSH 8.69 (0.46-4.68) • Symtoms: mild fatigue, dry skin, “not feeling my usual self” • PMHx: no H/O thyroid disorders, or recent of remote thyroid pain/tender. • FAMHx: Mother, two maternal aunts with hyperthyroidism. Case 2 continued • P.E. : Thyroid minimally enlarged and nontender, no nodules. remainder of exam unremarkable. • Labs: TSH 7.5 (.46 – 4.68) FREE T4 0.82 (0.80-1.50). TPO-Ab 317 reactive greater than 40 Case 2 continued • DX: Subclinical Hypothyroidism • Hashimotos thyroiditis • Tx: “Brand LT4” 25 mcg q.d. Follow-up and TSH in 2 months. • Follow-up: patient feeling better without complaints TSH 1.89 (0.5 – 3.0) Education, need to follow Hyperthyroidism HYPERTHYROIDISM ETIOLOGY • Graves’ disease ( autoimmune ). • Toxic multi-nodular goiter ( toxic MNG ). • Toxic nodule (hot or warm nodule) Common Symptoms and Signs of Thyrotoxicosis Signs Symptoms • • • • • • • • Nervous / shaky Fatigue Muscle weakness Increased perspiration Heat intolerance Tremor Palpitations Appetite/weight changes Menstrual disturbances • • • • • Goiter Hyperactivity Tachycardia / arrhythmia Systolic hypertension Warm, moist, or smooth skin • Stare and eyelid retraction • Tremor • Hyper-reflexia Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. GRAVES’ Dz • ~75% of cases of hyperthyroidism. • Thyroid Stimulating Immunoglobulins (TSI’s) and / or TSH receptor antibodies (TRAb) levels usually increased • Incidence 2nd – 4th decade of life. • ~5 times more likely in women. Basic and Clinical Endocrinology, Lange Series, 7th edition Thyrotoxicosis - work-up • Labs- demonstrate thyrotoxicosis. – TSH - Low or undetectable – Free T4 and/or Free T3 – Increased I123 thyroid scan / uptake • Uptake is increased. – 4 hour: normal ref. (5 – 15%) – 24 hour: normal ref. (6 - 30%) • Scan (anatomical findings via radiotracer uptake) – Homogeneous ( Graves’ Dz) – multiple areas (Toxic MNG) – single area (Hot or warm nodule) Hyperthyroidism Management Guidelines, Endocr Pract. 2011;17(No. 3) PATIENT EXAMPLE GRAVES’ • 30 y.o. female with nervousness, shakiness, heat intolerance, “fast / pounding heart beat”, wt loss, light menses, and muscle weakness for 3 months. • P.E. HR=118 – – – – Eyes—lid lag, stare, Skin: warm/moist Thyroid: large symmetric non-tender gland Neuro—tremors, DTR’s – brisk, hyper-reflexic • LABS: TSH: < 0.03 (0.45 – 4.50) FT4: 2.8 (0.8-1.8) Graves’ Work up Cont. • I123 thyroid S/U 4hr = 28% (5 - 15%) 24hr = 76% (6 - 30%) diffuse homogeneous uptake. TREATMENT options Treatment Options for Thyrotoxicosis • I131 RAI thyroid ablation • Anti-Thyroid Drugs (ATD’s) – Methimazole – Propylthiouracil (PTU) • Surgery: very rarely indicated Hyperthyroidism Management Guidelines, Endocr Pract. 2011;17(No. 3) Treatment with 1131 RAI • Treatment of choice – Goal is complete ablation i.e. hypothyroid – Hypothyroid about 3-5 months post I131 Tx • Follow Free T4 q 4-6 weeks until low – Treatment: “brand” LT4 – Follow and treat as you would for hypothyroid – Exception: the low TSH usually lags behind, often for months, the normalization of the Free T4. – Check Free T4 and TSH until the TSH becomes normal or high, then only follow the TSH. AACE Thyroid Guidelines, Endocr Pract. 2002;8(No. 6) Treatment with ATD’s • Anti-Thyroid Drugs (ATD’s) – Methimazole: 10 – 60 mg/day, first choice – PTU: 100 – 600 mg/day in 2-3 divided doses • Only recommended for first trimester pregnancy then change to methimazole • Risk for liver failure with PTU – Follow CBC – risk for agranulocytosis with either. – Hepatic function panel – esp. with PTU • Check TSH, Free T4 four weeks after start of Tx. • Once patient stable and TSH normalized, check TSH q 3-4months. AACE Thyroid Guidelines, Endocr Pract. 2002;8(No. 6) Hyperthyroidism Management Guidelines, Endocr Pract. 2011;17(No. 3) Thyroid Nodules How thyroid nodules or masses are found? • By HCP: palpation on routine exam • By patient: rarely • Incidentally – CT scan or MRI of chest / neck – Carotid Dopplers • Thyroid Ultrasound • I123 thyroid scan / uptake Thyroid Nodules • 5 categories: – – – – – Benign Non-diagnostic Follicular neoplasm/lesion Suspicious Malignant. • Size - >1cm “dominant nodule” AACE/AME/ETA Thyroid Nodule guidelines, Endocr Pract. 2010;16 (Suppl 1) Thyroid Nodules • I123 thyroid scan / uptake – Hot or warm – hormone secreting nodules – Cold nodules can be: • Cysts • Benign adenomas • Malignant tumors • others AACE/AME/ETA Thyroid Nodule guidelines, Endocr Pract. 2010;16 (Suppl 1) Ultrasound findings that increase the risk of malignancy • • • • • Hypoechoic Microcalcifications Irregular margins Intranodular vascularity Rounded appearance; more tall than wide, shape of the nodule AACE/AME/ETA Thyroid Nodule guidelines, Endocr Pract. 2010;16(Suppl 1) International Journal of Endocrinology and Metabolism. HORMONES 2007, 6(2):101-119 Suspicious for malignancy • • • • • • Growing nodule Fixed nodule Firm or hard consistency Cervical adenopathy History of head and neck irradiation Family history of medullary thyroid carcinoma (MTC), multiple endocrine neoplasia type 2 (MEN 2), or papillary thyroid carcinoma (PTC) • Persistent dysphonia, dysphagia or dyspnea • Age <30 or >60 years • Male sex AACE/AME/ETA Thyroid Nodule guidelines, Endocr Pract. 2010;16(Suppl 1) International Journal of Endocrinology and Metabolism. HORMONES 2007, 6(2):101-119 Thyroid Nodule Work-up • Assess for biochemical abnormality. (TSH, FT4, ?FT3) • If normal Labs – U/S to evaluate: number and echotexture. – Cytopathological Eval. Fine needle aspiration (FNA) with or without U/S guidance. • If abnormal Labs: low TSH and or increased FT4/FT3 – I123 thyroid scan and uptake – Nodule(s) hot or warm – Treat options: I131 RAI, ATD’s, Surgery, refer to endocrinologist for treatment Am. Thyroid Assoc. Thyroid Nodule Guidelines. Accessed 6/4/2011 Basic and Clinical Endocrinology, Lange Series, 7th edition Cold Nodules on I123 Thyroid scan/uptake • TSH and Free T4 normal – Consider thyroid cancer, benign adenoma, or thyroid cyst – Ultrasound to delineate solid vs. cystic lesion – Referral for ultrasound guided FNA biopsy – If biopsy is suspicious for cancer or demonstrates cancer, referral to surgeon with ample experience in thyroid surgery. Thyroid Malignancies • • • • Papillary: Follicular: Medullary: Anaplastic: ~80% ~15% ~3-5% < 2% Basic and Clinical Endocrinology, Lange Series, 7th edition Problem Solving in Endocrinology and Metabolism. Kennedy and Basu, 2007 Closing Comments