Gland Designs: Options for Managing Thyroid Disease

Educational Objectives

The goal of this program is to improve the management of Graves disease and thyroid nodules. After hearing and assimilat­ing this program, the clinician will be better able to:

1.   Identify common clinical manifestations of Graves disease.

2.   Compare treatment regimens for Graves disease.

3.   Select patients for thyroidectomy or radioiodine treatment.

4.   List characteristics of benign thyroid nodules.

5.   Recognize signs and characteristics of thyroidcancer.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Woeber spoke in San Francisco, CA, at Diabetes Update and Advances in Endocrinology and Metabolism, presented March 12-14, 2009, by the University of California, San Francisco, School of Medicine. Dr. Haber was recorded on October 23, 2009, in New York, NY, at An Update on Diabetes and Endocrine Disorders for the Practicing Physician, presented by the Mount Sinai School of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors for their coopera­tion in the production of this program.

Graves Disease

Kenneth A. Woeber, MD, Harris M. Fishbon Professor of Clinical Medicine, University of California, San Francisco, School of Medicine, and Chief, Department of Endocrinology and Metabolism, UCSF Medical Cen­ter at Mount Zion

Causes of hyperthyroidism: excess exogenous thyroid hormone; »20% of patients receiving levothyroxine for hypothy­roidism have suppressed thyrotropin (TSH) levels; excess iodine; gestational transient thyrotoxicosis (occurs in »20% of pregnancies); ratio of triiodothyronine (T3) to thyroxine (T4) increases in patients with endogenous hyperthyroidism due to Graves disease or toxic multinodular goiter (ratio not increased in patients with thyroiditis or excess levothyroxine)

Graves disease: most common cause of hyperthyroidism; more common in women than in men; incidence peaks at 40 to 60 yr of age; concordance rate in monozygotic twins, 35% (lower in dizygotic twins, and significantly lower in human leukocyte antigen [HLA]-identical twins [indicates gene loci other than HLA play important role]); pre­disposition to Graves disease »80% genetic; female siblings and daughters have 5% to 8% risk for Graves disease

Susceptibility genes: HLA-DRB1 gene variant  —  excess in patients with Graves disease results in altered peptide presentation to T cells; present in many patients negative for HLA-DR3 antigen; cytotoxic T lymphocyte-associated molecule-4  —  normally suppresses T cell activation; single nucleotide polymorphism leads to T cell activation; CD40 gene  —  expressed by B cells and antigen-processing cells; various polymorphisms may result in enhanced B cell activation; single nucleotide polymorphisms  —  may lead to alterations in TSH receptor domain

Clinical manifestations: diffuse goiter in >90%; overt ophthalmopathy in »50% (>90% of patients have orbital signs on magnetic resonance imaging [MRI], computed tomography [CT], or ultrasonography [US]); TSH receptor anti­bodies in »80% (false-negative rate high); thyroid peroxidase antibodies in »75%; overlap with other autoimmune diseases; disproportionate increase in T3 secretion; ocular disease  —  proptosis; periocular swelling; swelling of medial recti muscles classic finding on orbital imaging; stages 2 to 6 represent infiltrative ophthalmopathy of Graves disease; many patients with excess thyroid hormone due to conditions other than Graves disease have non­specific finding of lid retraction or lid lag; thiazolidinediones (eg, rosiglitazone) reported to cause aggravation of thyroid eye disease due to peroxisome proliferator-activated receptor gamma (PPAR-g) agonism; thyroid achropachy  —  clubbing of fingers; infiltrative dermopathy  —  can involve face or hands; occurs in <5% of patients; caused by expression of TSH receptors on extrathyroidal connective tissues; cytokines released with binding of TSH receptor antibodies; results in production of mucoglycosaminoglycans, which cause edema and fibrosis

Cardiac disease in hyperthyroidism: »33% of patients with hyperthyroidism have cardiac involvement (50% with no pre­existing cardiac disease); atrial fibrillation (AF) occurs in 12% to 15% of patients; arterial thromboembolism in thyro­toxic AF  —  incidence nearly as high as that in pneumatic heart disease, significantly higher than in nonvalvular AF, and comparable to that in mitral stenosis; patients should be anticoagulated with warfarin; warfarin requirements decrease in patients with hyperthyroidism and increase as patients approach euthyroid state (and further increase as patients become hypothyroid; in thyrotoxicosis, metabolic clearance rate of vitamin K-dependent clotting factors II, VII, IX, and X accel­erated [less warfarin required to maintain anticoagulation]); cardioversion  —  avoid until patient euthyroid for ³3 mo; men less likely to spontaneously revert to sinus rhythm; patients with longer duration of symptoms, AF, and associated preex­isting heart disease less likely to revert

Treatment: in most countries, antithyroid drugs most common approach to treatment (in United States, radioiodine more commonly used than methimazole); carbimazole converted in vivo to methimazole; b-blockers (eg, propranolol); iodine

Methimazole or carbimazole vs propylthiouracil (PTU): 15 mg of methimazole given once daily as effective as PTU 100 mg tid; half-time of disappearance from thyroid tissue of methimazole, »36 hr (more rapid with PTU); incidence of minor adverse effects of methimazole lower than that of PTU (14% vs 52%); methimazole used in mild to moderate cases; in patients with severe hyperthyroidism, 15 mg of methimazole bid more effective than once daily, but associ­ated with higher incidence of adverse effects (30% vs 14%); serious adverse effects rare with methimazole and PTU, but tend to occur within first 3 mo; when initiating therapy, perform baseline white blood cell count and liver function testing; instruct patient to notify physician immediately with development of fever and sore throat (order complete blood cell [CBC] count) or of pruritus or worsening pruritus (perform alanine aminotransferase [ALT] and alkaline phosphatase testing); adverse effects  —  hepatitis associated with methimazole or carbimazole usually cholestatic and reversible when agent withdrawn; PTU produces necroinflammatory (hepatocellular) hepatitis (often does not reverse and may require liver transplantation, or may lead to death); myeloperoxidase antineutrophil cytoplasmic autoanti­body (MPO-ANCA) vasculitis (lupus-like syndrome) more common with PTU than methimazole; pregnancy  —  teratogenic complications and congenital malformations rarely reported with methimazole, but never reported with PTU; when available, PTU agent of choice in women planning conception; methimazole and carbimazole can reduce efficacy of radioiodine (131I) treatment; duration of treatment  —  French study saw higher relapse rates with 6 mo of treatment with carbimazole, compared to 18 mo (not confirmed by subsequent studies); treatment with methimazole for 12 to 18 mo recommended (remission rate, »50%); block-replace regimen  —  patients given high doses of methim­azole followed by levothyroxine to avoid hypothyroidism; slightly higher remission rates reported with combined reg­imen vs methimazole (in titrated doses) alone not supported by meta-analysis of 12 randomized trials

Predictors of relapse: younger age; male sex; tobacco smoking; large goiter; severe ophthalmopathy; undetectable TSH

Radioiodine treatment: indications  —  severe thyrocardiac disease; toxic nodular goiter (does not go into remission [ie, patients permanently hyperthyroid]; patients must be on lifelong methimazole therapy); adverse reaction to an­tithyroid drugs; relapse after 12 to 18 mo of antithyroid drug treatment; efficacy  —  study showed 86% of patients treated with 173 μCi/g at 24 hr became hypothyroid or euthyroid at 1 yr (80% on PTU or methimazole before treat­ment); all nonresponders also on PTU or methimazole before treatment (suggests agents can reduce single-dose re­sponse rate); inverse asymptotic relationship between radioiodine at 24 hr and persistent hyperthyroidism (90% responded to dose >138 μCi/g, but no improvement in response rate with 400 μCi/g); dose calculation  —  target dose, »150 μCi/g; multiply 0.15 mCi by estimated gland weight in grams, and divide by fractional uptake of 131I at 24 hr

Adverse effects of radioiodine therapy: hypothyroidism  —occurs at rate of »2% per year after first year; provoca­tion or aggravation of eye disease  —  study showed patients without new or worsening ophthalmopathy experienced worsening after radioiodine therapy with methimazole or prednisone (progression occurred in 23% of tobacco smokers and 6% of nonsmokers); options for patients with active Graves ophthalmopathy who smoke include glu­cocorticoid therapy (40 mg tapered over 2 mo), or surgery; outcomes of 10-yr methimazole vs 131I treatment  —  100% of methimazole group became euthyroid (50% had goiter); 61% of 131I group became hypothyroid (25% had goiter); quality of life, dual energy x-ray absorptiometry (DEXA), and echocardiographic findings similar, but total cholesterol and low-density lipoprotein (LDL) cholesterol higher in 131I group; no significant adverse effects

Indications for thyroidectomy: large goiter with compressive manifestations; pregnancy with adverse reaction to anti­thyroid drug (surgery should be undertaken during second trimester to reduce risk for miscarriage or preterm deliv­ery); severe infiltrative eye disease (studies show surgery with radioiodine therapy more beneficial than surgery alone)

Pharmacologic utility of radioiodine: saturated solution of potassium iodide (SSKI) has 6 times more iodine per drop than Lugol’s solution; roles  —  abrupt decrease in thyroid hormone secretion due to transient (»10 days) inhibition of thyroglobulin proteolysis (useful for thyroid storm); transient reduction of thyroid vascularity in Graves disease (indi­cated for 10 days before thyroidectomy); occasionally used after treatment with 131I while patient approaches euthy­roid state (eg, after adverse reaction to methimazole or PTU)

Management of Graves ophthalmopathy: acute active phase  —  dark lenses; elevate head of bed by 15º; artificial tears; diuretics (eg, chlorthalidone); prisms; glucocorticoids or orbital radiotherapy for severe disease (studies sug­gest intravenous [IV] methylprednisolone more effective than oral prednisone and less likely to cause adverse ef­fects); large doses associated with hepatotoxicity (4.5-6.0 g of IV methylprednisolone acceptable); chronic inactive phase  —  eye muscle and eyelid surgery

Questions and answers: thyroid-stimulating immunoglobulin (TSI) levels and severity of ophthalmopathy  —  roughly correlated; most patients with active or severe ophthalmopathy have elevated TSI; monitor patients; postsurgical hypoparathyroidism  —  patients who recover generally do so within first 6 mo after surgery; calcium and vitamin D supplementation required; young woman planning conception  —  PTU or radioiodine acceptable; must wait ³6 mo after radioiodine therapy to conceive; course of hyperthyroidism associated with Graves dis­ease attenuates during pregnancy (after parturition, Graves disease worsens or appears for first time due to im­mune resurgence); speaker prefers PTU; Graves ophthalmopathy in euthyroid patient  —  patients have high TSI levels; treat eye disease rather than addressing thyroid disease; avoid hypothyroidism after radioiodine therapy (TSH stimulates TSH receptors expressed on extrathyroidal tissue)

Thyroid Nodules

Richard S. Haber, MD, Professor of Medicine, Division of Endocrinology, Diabetes, and Bone Disease, Mount Sinai School of Medicine, New York, NY

Introduction: 4% to 7% of adults in United States have palpable thyroid nodules; more common in women than in men (4:1 ratio); malignancy rare (<5%); most thyroid cancers indolent (mortality rate <10%); nonpalpable (eg, <1 cm) nodules more common than palpable nodules; palpable nodules appear at age »20 yr, and prevalence increases with age; >50% of population ³60 yr of age has thyroid nodules (statistically normal); thyroid cancer  —  37,000 new cases per year (incidence rising; not known whether due to better detection or actual increase); 1400 deaths per year

Benign thyroid nodules: colloid nodules  —  also referred to as nodular goiter or hyperplastic nodules; >50% of thy­roid nodules; often multiple; imaging studies show areas of eosinophilic pink stain due to colloid (secretory product of thyroid); cellularity low; thyroid cells bland and uniform; follicular adenoma  —  neoplastic nodule; often soli­tary; diagnosed by presence of capsule; lesions appear cellular, with less colloid; others  —  Hashimoto’s thyroiditis; subacute thyroiditis (less common; associated with epidemic viral upper respiratory infection; painful swelling of thyroid occurs during winter)

Thyroid cancers: 85% papillary carcinoma (usually indolent); 8% follicular carcinoma; anaplastic carcinoma rare (1%-2%) and aggressive (mean survival, 6 mo); medullary carcinoma (10-yr mortality rate, 50%); thyroid lym­phoma (rare; typically occurs in patients with lymphocytic Hashimoto’s thyroiditis); metastasis to thyroid ex­tremely rare (renal cell carcinoma in 50% of reported cases)

Hyperfunctioning (“hot”) nodule: radioiodine imaging  —intense uptake of radioiodine over nodule; faint or no io­dine uptake in contralateral lobe; 5% of nodules hot; likelihood of malignancy <1% (100% predictive value for be­nign nodule); 95% of nodules “cold” (ie, radioiodine uptake decreased compared to surrounding tissue) or “warm” (ie, radioiodine uptake similar or slightly increased, but not suppressed, on other side); cold or warm findings have little predictive value for malignancy; radioiodine imaging and work-up of hot nodules useful only in patients with low levels of TSH

Neck irradiation and thyroid cancer: during 1930s to 1970s, »1 million children in United States treated with low doses of radiation therapy for benign disease (eg, enlarged thymus glands or tonsils, acne, tinea capitis); study of >4000 patients found 39% developed thyroid nodules; 11% developed thyroid cancer; cancers typically occurred decades after irradiation; patients often present with hyperparathyroidism and parotid tumors

Other risk factors for thyroid cancers: exposure to radioactive iodine in Chernobyl fallout; Graves disease; positive family history of thyroid cancer

Evaluation of thyroid nodules: patient history  —  »33% of nodules in children malignant; risk for malignancy higher in old age than in midlife; risk for malignancy higher in men than in women; hypothyroidism suggests nodule due to Hashimoto’s thyroiditis; hyperthyroidism suggests hot nodule or Graves disease; positive family history of Hashimoto’s disease, multinodular goiter, medullary carcinoma (mostly sporadic, but approximately one-third fa­milial), or familial colonic polyposis (associated with papillary carcinoma); evaluation  —  red flags include hard, fixed nodules or enlarged lymph nodes; routine serum TSH; consider antithyroid antibody testing in suspected Hashimoto’s disease; check calcitonin if medullary cancer suspected; thyroglobulin (marker for recurrence of thy­roid cancer) not helpful in patients with intact thyroid; US  —best imaging method; less costly and better than CT and MRI; advantages include echogenicity of thyroid tissue, high resolution for superficial structures, convenience, low cost and in-office availablility; detects nonpalpable nodules; characterizes nodules (cystic vs solid); detects cer­vical node metastases; accurately measures size of nodule; can be used to guide fine needle aspiration; sonographic features of thyroid cancer  —  hypoechoicity; irregular margins; punctate calcifications; anterior-posterior diameter greater than transverse diameter (“tall greater than wide”); extrathyroidal extension; presence of ³3 features has high predictive value; fine needle aspiration  —best test; helps determine need for surgery

Suggested Reading

Abraham P et al: A systematic review of drug therapy for Graves' hyperthyroidism. Eur J Endocrinol 153:489, 2005; Alex­ander EK et al: High dose of (131)I therapy for the treatment of hyperthyroidism caused by Graves disease. J Clin Endocrinol Metab 87:1073, 2002; Nakamura H et al: Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves disease. J Clin Endocrinol Metab 92:2157, 2007; Nakazawa HK et al: Management of atrial fibrillation in the post-thyrotoxic state. Am J Med 72:903, 1982; Neto AM et al: Extremely high doses of radioiodine required for treatment of Graves' hyperthyroidism: a case report. Cases J 2:8479, 2009; Puxeddu E et al: The 2009 American Thyroid Association Guidelines for management of thyroid nodules and differentiated thyroid cancer: progress on the road from consensus- to evi­dence-based practice. Thyroid 19:1145, 2009; Reiners C et al: Thyroid cancer in infants and adolescents after Chernobyl. Mi­nerva Endocrinol 33:381, 2008; Sadetzki S et al: Risk of thyroid cancer after childhood exposure to ionizing radiation for tinea capitis. J Clinical Endocrinol Metab 91:4798, 2006; Tysome JR et al: Improving prediction of malignancy of cytologi­cally indeterminate thyroid nodules. Br J Surg 96:1400, 2009; Walter MA et al: Effects of antithyroid drugs on radioiodine treatment: systematic review and meta-analysis of randomised controlled trials. BMJ 334:514, 2007; Woeber KA: Triiodothy­ronine production in Graves' hyperthyroidism. Thyroid 16:687, 2006.