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A. Epidemiologynavigator

  1. Thyroid problems are extremely common
  2. ~5% of population has palpable thyroid abnormality [1]
    1. About 5% of thyroid nodules are malignant
    2. Anomalies ~2X more likely to be carcinoma in men than in women
  3. More common in women than men (10:1)
    1. Routine screening of women age >35 years old every 5 years with TSH is recommended
    2. Lower incidence of anomalies in men make routine screening of men less useful
  4. Familial syndromes with TSH (thyrotropin) mutations well described (uncommon)
  5. US Preventive Task Force does not recommend for or against routine TSH screening [6,7]

B. Thyroid Hormone Regulationnavigator

  1. Hypothalamus produces thyrotropin releasing hormone (TRH)
  2. TRH stimulates anterior pituitary to produce TSH (thyrotropin, thyroid stimulating hormone)
  3. TSH stimulates iodination in the thyroid to form T3 and T4
  4. T3 is triiodothyronine and is sole mediator of cell effects of thyroid hormones
  5. T4 is thyroxine and is circulating at highest levels
  6. Thyroid hormones crticial to cardiac, neurological, muscular, hepatic functions [2]
  7. Regulate thermogenesis, metabolism, and vascular tone

C. Disease Entities [24] navigator

  1. Hyperthyroidism
    1. Subtle in elderly, often presents with atrial fibrillation or heart failure [23]
    2. In young persons, often presents as resting tachycardia, weight loss, heat intolerance
    3. Hypertension, mainly systolic with widened pulse pressure [23]
    4. Heat intolerance, weight loss, palpitations common [2]
    5. Most common causes are thyroxine overdose and Graves' Disease
    6. Graves' Disease: autoimmune stimulation of TSH receptor (anti-TSH-R antibodies)
    7. TSH is usually suppressed due to high levels of T4 and/or T3
    8. Elevated TSH with hyperthyroidism suggests pituitary tumor or pituitary resistance to T4
  2. Hypothyroidism [3,4]
    1. Most common hormone deficiency
    2. Multiple causes and levels of severity with somewhat variable end organ dysfunction
    3. Hashimoto's Thyroiditis: autoimmune destruction of thyroid follicles (most common)
    4. Other types of thyroiditis, both autoimmune and non-autoimmune
    5. Common complication of treatment for hyperthyroidism
    6. Follows surgery and/or iodine ablation for hyperthyroidism / thyroid cancers
    7. Commonly caused by drugs: lithium, sulfonylureas, amiodarone
    8. Subclinical hypothyroidism: elevated TSH with normal T4 or FTI
    9. Hypertension, mainly diastolic with narrow pulse pressure
    10. Skeletal and cardiac muscle weakness
    11. Cold intolerance, but not weight gain, is common feature [2]
    12. Hypercholesterolemia, hyperprolactinemia, hyponatremia, anemia, hyperhomocysteinemia
    13. Creatinine phosphokinase (CPK) from muscle may be elevated in moderate, severe disease
  3. Subclinical Thyroid Disease [3]
    1. Increased use of TSH as screening has increased number of cases
    2. Subclinical disease implies normal thyroid hormones (T4, T3) with abnormal TSH
    3. Low TSH (<0.5 mU/L) with normal T4 and T3 is subclinical hyperthyroidism
    4. High TSH (>5.0 mU/L) with normal T4 and T3 is subclinical hypothyroidism
  4. Subclinical Hypothyroidism
    1. Associated with deleterious lipid abnormalities
    2. Associated with >20% increased cardiac event risk [27]
    3. In general, patients with subclinical hypothyroidism should be treated if they have either symptoms, thyroperoxidase antibodies, or serum TSH >10 mU/L [26]
    4. Patients with serum TSH 5-10mU/L should generally not be treated [6,7,16,17]
    5. Subclinical thyroid dysfunction not associated with depression, anxiety, or cognition in elderly (>64 years) [11]
  5. Subclinical Hyperthyroidism [12]
    1. Usually defined as <0.1-0.5 mU/L serum TSH with normal T3 and T4
    2. Subtle signs or symptoms of thyrotoxicosis may be present
    3. Increased risk for atrial fibrillation (AFib) [5] and osteoporosis
    4. Subclinical hyperthyroidism associated with >20% increased cardiac events but studies are conflicting and confidence intervals are large [27]
    5. Subclinical hyperthyroidism with new onset AFib should be treated
    6. Subclinical hyperthyroidism associated with goiter generally requires treatment
    7. Screening for and treatment of osteoporosis in patients with subclinical hyperthyroidism
    8. In absence of symptoms, no treatment recommended for TSH 0.1-0.5mU/L [6,7,16,17]
  6. Drug Induced Thyroid Disease
    1. Decrease TSH Secretion: dopamine, glucocorticoids, octreotide
    2. Decrease T4 Secretion: lithium, iodide, amiodarone
    3. Increase T4 Secretion: iodide, amiodarone
    4. Decrease T4 Adsorption: colestipol, cholestyramine, aluminum, iron, sucralfate
    5. Increase Serum TBG: estrogen, tamoxifen, heroin, methadone, mitotane, fluorouracil
    6. Decrease Serum TBG: androgens, danazol, slow relase niacin, glucocorticoids
    7. Displace T4 from Binding Sites: furosemide, salicylates
    8. Increase Hepatic T4 Metabolism: phenobarbital, rifampin, phenytoin, carbamazepine
    9. Decrease T4 to T3 Conversion: propylthiouracil, amiodarone, ß-blockers, glucocorticoids
    10. Amiodarone causes a multiplicity of effects leading to hypo- or hyperthyroidism
    11. Excess intake of thyroxine (T4) replacement - subclinical or clinical hyperthyroidism
  7. Thyroid Mass (Thyroid Nodule) [1,5]
    1. Common in population, ~95% are benign, particularly in ages 20-70 years
    2. Thyroid nodules are best detected with ultrasonography, not physical exam
    3. Multinodular versus Solitary Nodule
    4. Increasing number of non-palpable, radiographically detected thyroid masses
    5. Definitive diagnosis is usually made by needle biopsy and pathological examination
    6. Galectin-3, a cell adhesion lectin, immunostaining is restricted to neoplatsic thyroid disease and may differentiate benign from malignant thyroid lesions [25]
  8. Autoimmune Endocrinopathies
    1. Three types of autoimmune endocrinopathy are known
    2. Type 2 is thyroiditis or Type 1 DM with Addison Disease (Schmidt Syndrome)
    3. Type 3 is defined as occurrance of thyroiditis with any 2 other autoimmune disorders
    4. DM Type 1, pernicious anemia, or myasthenia gravis are commonly found in Type 3
  9. "Euthyroid-Sick Syndrome" [1]
    [Figure] "Euthyroid Sick Syndrome"
    1. In patients that are critically ill
    2. T4 and T3 are both low (impaired peripheral conversion)
    3. Reverse T3 (rT3) high and free T4 index low
    4. TSH normal or slightly low (as chronicity of illness increases)
    5. Treatment with thyroxine replacement is ineffective
  10. Thyrotropin (TSH) Receptor Abnormalities [8]
    1. The TSH receptor belongs to large family of G-protein coupled receptors
    2. Mutations in TSH-R may cause either hypothyroidism or hyperthyroidism
    3. TSH-R mutations also found in a variety of familial thyroid diseases
    4. Gs-alpha protein mutations have been found in some thyroidcarcinomas and nodules
  11. Iodotyrosine Deiodinase (DEHAL1) Mutations [14]
    1. DEHAL1 gene codes for protein which controls reuse of iodide for thyroid hormone synthesis
    2. Mutations in DEHAL1 associated with severe goitrous hypothyroidism
    3. These patients have normal thyroid function at birth
  12. Cowden Disease [20]
    1. Thyroid adenomas and goiter
    2. Carries a 10% risk of thyroid cancer
    3. Colonic polyposis syndrome
    4. Mutations of the PTEN gene on chromosome 10q
  13. Hemangiomas - large lesions may catabolize L-thyroxine [21]
  14. Exposure to Radioactive Iodine [10]
    1. Following nuclear accident or attack
    2. Radioactive iodine taken up in the thyroid
    3. Main risk is development of thyroid cancer
    4. Potassium iodide (adults, 130mg/d) daily until exposure ceases prevents uptake

D. Diffuse Thyroid Enlargement (Goiter)navigator

  1. Hyperthyroidism
    1. 95% Graves' Disease
    2. 5% Hashimoto's early phase or other type of thyroiditis
  2. Euthyroid: usually preclinical stage of either Graves' or Hashimoto's Disease
  3. Hypothyroid - Usually Hashimoto's Thyroiditis
  4. Evaluation Overview
    1. Consider endemic causes - iodine deficiency or adverse drug effects
    2. History (particularly medications), focused physical
    3. Laboratory: serum, radiologic, tissue
  5. Physical Exam
    1. Overall: complete vital signs, eye findings
    2. Observation of gland size is very important; normal gland rarely visible
    3. Palpation should be performed from behind the patient
    4. Characterize the enlargement: Single Nodule, Multinodular, Diffuse
    5. Prominent glands should be measured with a ruler
  6. Thyroid nodules are best detected with ultrasonography, not physical exam
  7. Laboratory: Thyroid Function Tests (TFTs)
    1. TSH should be obtained on all patients with any symptoms
    2. Full TFTs obtained in patients with abnormal TSH to rule out more serious disease
    3. T4 index (FTI or free thyroxine index), T3 (triiodthyronine)
    4. Thyroid Stimulating Antibodies
    5. Serum calcitonin levels may be used to detect medullary thyroid cancer
  8. Radioiodide Uptake
    1. Functional versus non-functional nodules
    2. Also help determine if condition is transient versus longer term
    3. In Hashimoto Disease, radioidiodine uptake is low normal, normal or elevated
    4. Goiters usually show normal or elevated uptake
    5. In Subacute (De Quervain's) and Silent thyroiditis, uptake is low
    6. Therefore, if patient is hypothyroid, a radionuclide scan is not useful
    7. Uptake is diffusely elevated in Graves' Disease
  9. Fine Needle Aspiration of Thyroid Nodule(s) - see below

E. Multinodular Goiter [1]navigator

  1. Defined as a structurally and functionally heterogeneous thyroid enlargement
  2. Worldwide, most commonly due to iodine deficiency
  3. Hyperthyroidism
    1. Often subclinical (low TSH, normal serum T4, free T4, and T3)
    2. Foci of functional autonomy develop within simple goiter (?)
    3. Ablative Therapy (radioactive iodine)
    4. Plummer's Disease
    5. Toxic multinodular goiter most commonly from activating mutations in thyrotropin receptor or G proteins [4]
  4. Euthyroid
    1. Most patients are women
    2. Autonomously functioning nodules more common
    3. Hormone suppression
  5. Hypothyroid
    1. Unclear etiology (? Hashimoto's disease)
    2. Hormone replacement with T4 therapy is indicated
    3. Triiodothyronine (T3) replacement not required if T4 therapy is used [19]
  6. Evaluation
    1. Serum T4, FT4-index, and TSh should be obtained
    2. Thyroid scan or ultrasound are not usually indicated
    3. Fine needle aspiration should be performed if carcinoma suspected (particularly in men)
    4. Overall, <1% of patients with multinodular goiter in developed countries have carcinoma
  7. Treatment of Multinodular Goiter
    1. Hyperfunctioning goiters should be treated as hyperthyroidism (see below)
    2. Nontoxic multinodular goiters treated mainly for compression, appearance
    3. Venous outflow obstruction may also occur and is an indication for treatment
    4. Euthyroid multinodular goiters may be treated with T4 suppression therapy
    5. Radioidoine therapy (131-I) is effective in many patients as well

F. Causes of Solitary / Dominant Nodules [1,9,13]navigator

  1. Classification
    1. Colloid nodules, cysts, thyroiditis: 80%
    2. Benign follicular neoplasms: 15%
    3. Thyroid carcinoma: 5%
    4. Nodules are either solid or cystic and most will grow over time [13]
    5. Even enlarging nodules have low risk for malignancy over time [13]
  2. Risk Factors for Carcinoma
    1. Family history of medullary thyroid carcinoma or multiple endocrine neoplasm
    2. Rapid growth of mass
    3. Firm or very hard nodule
    4. Fixation of nodule to adjacent structures
    5. Vocal cord paralysis or other symptoms
    6. Regional lymphadenopathy
    7. Previous head and neck irradiation has 5-10% risk of developing nodule over 20 years
    8. Age <20 or >70 years or male sex more likely to be carcinoma
    9. Nodule >4cm in diameter
  3. Benign Lesions
    1. Hashimoto's Thyroiditis is most common
    2. Colloid only may be seen - usually patient is observed
    3. Cystic nodules are common and may enlarge over time
    4. Galectin-3 immunostaining can differentiate benign from malignant thyroid lesions [25]
  4. Follicular Neoplasm
    1. Most are adenomas; size is crucial determinant
    2. Biopsy results "suspicious for follicular neoplasm" yield 15-20% malignancy on surgery [5]
    3. In elderly 25% >4cm present with T3 Thyrotoxicosis
    4. Radionucleotide scanning will help deliniate hot from cold nodules
    5. Carcinoma is major concern here, but hot nodules are usually benign
    6. Full TFTs including T3 levels should be obtained
  5. Frank Malignancy
    1. CT or MRI of neck for more extensive evaluation
    2. Papillary, Follicular, or Medullary (~5%) Carcinomas may be found
    3. Anaplastic thyroid carcinomas or thyroid lymphoma are very uncommon
    4. Malignancy rate in incidently discovered, nonpalpable thyroid glands is <5% overall [9]
    5. Galectin-3 and human bone marrow endothelial cell protein (HBME-1) are expressed only by malignant and not benign thyroid tissue [5,25]
  6. Causes of Solitary Nonfunctional ("Cold") Thyroid Nodules (on Iodine Scanning)
    1. Adenoma (~75-80%)
    2. Carcinoma (~15%)
    3. Cyst (simple and other)
    4. Multinodular goiter
    5. Inflammatory diseases, Abscess, Dermoid, Teratoma (all rare)
  7. Causes of "Hot" Nodules
    1. Hot nodules are far more common in woman than men (F:M 13:1)
    2. Patient may be euthyroid or hyperthyroid ("toxic")

G. Evaluation of Thyroid Nodules [1,5,9]navigator

  1. Overview
    1. Main issue is to rule out presence of carcinoma in the nodule
    2. Risk factors must be considered carefully in evaluation but biopsy often necessary
    3. TSH levels should be obtained in every case of thyroid nodule [1,9]
    4. Abnormal TSH should be followed up with repeat and T3 and T4 levels
    5. ~10% of thyroid nodules have a suppressed TSH indicating nodules are functional
    6. Radionuclide scanning of nodule with suppressed TSH may obviate need for biopsy
    7. Radionuclide scanning with Iodine-123 or Iodine-131 is recommended over Tc-99m
    8. Normal or elevated TSH means increased risk of cancer and needle biopsy is recommended
    9. Elevated TSH level makes thyroiditis likely and autoantibodies should be evaluated
    10. Possible thyroiditis does not obviate need for biopsy because cancer may be present
  2. Radio-Iodine Scan (123-I)
    1. Assesses organification and uptake
    2. Thus, will determine "hot" versus "cold" nodules; diffuse versus local uptake
    3. Generally, these are preferred over technetium (Tc-99m) scans
    4. Scans should be performed prior to FNA on patients with hyperthyroidism (by TFTs)
  3. Technetium Scan
    1. Assesses blood supply and uptake of gland (not organification)
    2. Useful for determining anatomy of gland and in patients allergic to iodine
  4. Fine Needle Aspiration (FNA) [5]
    1. Biopsy is usually an in-office procedure with FNA
    2. Two to 4 passes with needle sufficient in ~80% of cases for diagnosis
    3. False negative ~5%, False positive ~5%; Sensitivity 68-98%; Specificity 72-100%
    4. Ultrasonography should always be added to FNA for evaluation and diagnosis in nodular disease [22]
    5. Nondiagnostic FNAs should be always repeated with ultrasound guidance
    6. FNA with "suspicious for follicular neoplasm" carries ~20% associated frank cancer
    7. If FNAs are nondiagnostic twice, surgical biopsy and/or resection should be considered
    8. FNA has led to reduction in thyroidectomies by ~50%
    9. Yield of non-diagnostic is extremely operator dependent
  5. Ultrasound
    1. Mainly done to ascertain gland size, number and size of nodules
    2. Detection of cysts (>1.9mm) or nodules (>3mm) and calcifications
    3. May delineate extra-thyroid from intra-thyroid masses
    4. Evaluate lymph nodes in patients with thyroid cancer
    5. Useful for aiding FNA
    6. Very useful for following size of nodules (highly reproducible)
  6. MRI and CT Scanning
    1. Mainly for evaluation of complicated cases, particularly with carcinoma
    2. Evaluate massess for regional extension and symptoms due to local effects

H. Treatment of Thyroid Nodules [1,16]navigator

  1. Carcinoma
    1. Fine needle or other tissue diagnosis is required
    2. Therapy depends mainly on tumor type and extent of disease
    3. Papillary and follicular carcinomas should generally be resected
    4. Surgery followed by thyroxine (T4) suppressive/replacement therapy is recommended
    5. Other tumor types with local mass effects should be resected to alleviate symptoms
    6. Anaplastic tumors are highly aggressive with very poor prognosis
    7. Lymphomas may be treated with systemic chemotherapy
  2. Adenomas [1]
    1. Symptomatic disease such as local compression or T4 production should usually be treated definitively with surgical resection
    2. Consider L-thyroxine suppressive therapy but this is not very effective [1,15]
    3. Thyroxine shrinks ~30% of benign nodules by ~50%
    4. Radio-iodine ablation for active nodules is also effective
  3. Cold Nodules
    1. Hormone or iodine suppression therapy is often very effective
    2. Levothyroxine (thyroxine) and/or iodine are both effective in selected cases
    3. Thyroxine therapy is only effective in shrinking 10-30% of benign nodules [15]
    4. Thyroxine therapy is continued for 6-12 months and discontinued if no effect
    5. Thyroxine therapy can reduce bone mass and cause frank osteoporosis
    6. Therefore, postmenopausal female patients should be taking estrogen replacement
    7. Most benign nodules remain stable in size and remain benign [15]
    8. Surgery for compression of trachea or esophagus, growing nodule, recurrent nodules
    9. Surgery also for appearance and/or discomfort
  4. Hot (Hyperfunctioning) Nodules
    1. Ablative therapy with iodine is major option
    2. Surgical resection can also be performed
    3. Antithyroid drug therapy can also be given, but is generally required for life
    4. Multiple direct percutaneous injection of ethanol into nodules has also been used
  5. Patients treated with radioiodine for hyperthyroidism have increased mortality versus matched controls unless they are treated with thyroxine therapy after ablation [18]

References navigator

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