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 1
Q3: The best assay to confirm that a patient s hypothyroidism is autoimmune in nature? 1) Thyroid stimulating immunoglobulins 2) Anti-nuclearnuclear antibody 3) TSH 4) Thyroid peroxidase antibodies Q4: The best assay to confirm that a patient s hyperthyroidism is autoimmune in nature? 1) Thyroid stimulating immunoglobulins 2) Anti-nuclear antibody 3) TSH 4) Thyroid peroxidase antibodies Q5: Which is the best study to confirm the etiology of a patient s thyrotoxicosis? 1) I 123 thyroid scan/uptake 2) Neck CT or MRI 3) Thyroid ultrasound 4) Fine needle aspiration of the thyroid 2
Q6: Which is the best study to make the initial evaluation for thyroid nodules discovered on routine physical exam? 1) I 123 thyroid scan/uptake 2) Neck CT or MRI 3) Thyroid ultrasound 4) 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) Re-check thyroid U/S in 1 year 2) Fine needle aspiration of the thyroid 2) Neck CT or MRI 4) I 123 thyroid scan/uptake Q8: Thyroid S/U shows homogeneous increased radiotracer uptake, the diagnosis is? 1) Metastatic thyroid cancer 2) G di 2) Graves disease 3) Toxic multi-nodular goiter 4) Toxic thyroid nodule 3
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 il or methimazole 3) Levothyroxine sodium 4) I 131 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. 4
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, 7 th edition 5
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, 7 th 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: T3 99% bound to protein, i.e. metabolically ll 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, 7 th edition THYROID TESTING Biochemical 1) TSH - highly sensitive, best test for thyroid function. 2) Free T4 (FT4)- biologically active. ) ( ) g y 3) Free T3 (FT3) - biologically active. - rarely need to check unless, TSH is low or undetectable with a normal FT4. 6
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 y 7
HYPOTHYROIDISM Prevalence: 4-8% general population. Mean age of Dx: 5 th decade of life Female to male ratio: 10:1 Endocrine Secrets. McDermott, 4 rd 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, 4 rd Edition Basic and Clinical Endocrinology, Lange Series, 7 th edition 8
Clinical Symptoms of Hypothyroidism Fatigue Lethargy Cold intolerance Constipation Decreased memory Depression Mental Impairment Arthralgias Hoarseness Heavy menstrual flow Paresthesias Sleepiness Weight gain,edema 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 9
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 THYROID AXIS intact. t Consider TPO-Ab Levothyroxine Sodium (LT 4 ) Exogenously administered LT 4 hormone Indistinguishable from endogenous T 4, both in its physiologic effects and its quantification as measured in blood LT 4 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 10
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 surgery Short bowel syndrome Celiac disease Reduced Absorption Colestipol hydrochloride Sucralfate Ferrous sulfate Food (eg, soybean formula) Aluminum hydroxide Cholestyramine Sodium polystyrene sulfonate Drugs That Increase Clearance Rifampin Carbamazepine Phenytoin Factors That Reduced T 4 to T 3 Clearance Amiodarone Selenium deficiency Other Mechanisms Lovastatin Sertraline Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8 th ed. 2000. Synthroid [package insert]. Abbott Laboratories; 2003. 11
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 LT 4, 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. 12
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, d 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 13
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 i high h (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 y o 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. 14
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 15
Hyperthyroidism HYPERTHYROIDISM ETIOLOGY Graves disease ( autoimmune ). Toxic multi-nodular goiter ( toxic MNG ). Toxic nodule (hot or warm nodule) Common Symptoms and Signs of Thyrotoxicosis Symptoms Nervous / shaky Fatigue Muscle weakness Increased perspiration Heat intolerance Tremor Palpitations Appetite/weight changes Menstrual disturbances Signs 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. 16
GRAVES Dz ~75% of cases of hyperthyroidism. Thyroid Stimulating Immunoglobulins (TSI s) and / or TSH receptor antibodies (TRAb) levels usually increased Incidence 2 nd 4 th decade of life. ~5 times more likely in women. Basic and Clinical Endocrinology, Lange Series, 7 th edition Thyrotoxicosis - work-up Labs- demonstrate thyrotoxicosis. TSH - Low or undetectable Free T4 and/or Free T3 Increased I 123 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. PE 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) 17
Graves Work up Cont. I 123 thyroid S/U 4hr = 28% (5-15%) 24hr = 76% (6-30%) diffuse homogeneous uptake. TREATMENT options Treatment Options for Thyrotoxicosis I 131 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 1 131 RAI Treatment of choice Goal is complete ablation i.e. hypothyroid Hypothyroid about 3-5 months post I 131 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) 18
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 I 123 thyroid scan / uptake 19
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 I 123 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 20
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 I 123 thyroid scan and uptake Nodule(s) hot or warm Treat options: I 131 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, 7 th edition Cold Nodules on I 123 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. 21
Thyroid Malignancies Papillary: ~80% Follicular: ~15% Medullary: ~3-5% Anaplastic: < 2% Basic and Clinical Endocrinology, Lange Series, 7 th edition Problem Solving in Endocrinology and Metabolism. Kennedy and Basu, 2007 Closing Comments 22