THYROID DIAGNOSTIC PROCEDURES, TREATMENT AND PREVENTION

Jassin M. Jouria, MD

Dr. Jassin M. Jouria is a medical doctor, professor of academic medicine, and medical author. He graduated from Ross University School of Medicine and has completed his clinical clerkship training in various teaching hospitals throughout New York, including King’s County Hospital Center and Brookdale Medical Center, among others. Dr. Jouria has passed all USMLE medical board exams, and has served as a test prep tutor and instructor for Kaplan. He has developed several medical courses and curricula for a variety of educational institutions. Dr. Jouria has also served on multiple levels in the academic field including faculty member and Department Chair. Dr. Jouria continues to serves as a Subject Matter Expert for several continuing education organizations covering multiple basic medical sciences. He has also developed several continuing medical education courses covering various topics in clinical medicine. Recently, Dr. Jouria has been contracted by the University of Miami/Jackson Memorial Hospital’s Department of Surgery to develop an e-module training series for trauma patient management. Dr. Jouria is currently authoring an academic textbook on Human Anatomy & Physiology.

Abstract

Management of the common forms of thyroid disease has undergone significant study and development, as evidenced by the latest guidelines to diagnose and treat the thyroid. Because the thyroid gland’s role is so pervasive in the body, it is important for clinicians to understand the symptoms of various thyroid diseases. The diagnosis and treatment of thyroid conditions are discussed.

1 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Policy Statement

This activity has been planned and implemented in accordance with the policies of NurseCe4Less.com and the continuing nursing education requirements of the American Nurses Credentialing Center's Commission on Accreditation for registered nurses. It is the policy of NurseCe4Less.com to ensure objectivity, transparency, and best practice in clinical education for all continuing nursing education (CNE) activities.

Continuing Education Credit Designation

This educational activity is credited for 3.5 hours. Nurses may only claim credit commensurate with the credit awarded for completion of this course activity. Pharmacology content is 0.5 hours (30 minutes).

Statement of Learning Need

The thyroid gland is active in virtually every cell of the body, regulating cellular respiration, energy expenditure, overall metabolism, growth and development of cells and tissues. It is important to understand the symptoms of thyroid diseases, and to know the management and treatment of these conditions.

Course Purpose

To provide advanced learning for clinicians interested in the diagnosis, management and treatment of thyroid diseases.

2 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Target Audience

Advanced Practice Registered Nurses and Registered Nurses (Interdisciplinary Health Team Members, including Vocational Nurses and Medical Assistants may obtain a Certificate of Completion)

Course Author & Planning Team Conflict of Interest Disclosures

Jassin M. Jouria, MD, William S. Cook, PhD, Douglas Lawrence, MA,

Susan DePasquale, MSN, FPMHNP-BC – all have no disclosures

Acknowledgement of Commercial Support

There is no commercial support for this course.

Please take time to complete a self-assessment of knowledge, on page 4, sample questions before reading the article.

Opportunity to complete a self-assessment of knowledge learned will be provided at the end of the course

3 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1. ______or T4 (containing four iodine atoms) is the primary thyroid hormone secreted by the thyroid gland.

a. Thyroid stimulating hormone b. Thyroxine c. Triiodothyronine d. Thyroglobulin

2. True or False: The thyroid stimulating hormone (TSH) test is often the only test ordered by clinicians when thyroid disease is suspected, and this can lead to misdiagnosis.

a. True b. False

3. Thyroid stimulating hormone (TSH) is released by the

a. parathyroid. b. thymus. c. pituitary gland. d. thyroidea ima.

4. What is the consensus regarding the diagnostic limits for thyroid stimulating hormone (TSH) that would indicate thyroid failure and hypothyroidism?

a. TSH >10 mIU/L b. TSH ≥ 4 mIU/L c. TSH ≥ 3 mIU/L d. None of the above

5. Decreased thyroid stimulating hormone (TSH) levels are seen in

a. primary hypothyroidism. b. TSH-producing tumors. c. Hashimoto’s thyroiditis. d. primary hyperthyroidism.

4 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Introduction

Laboratory testing to diagnose thyroid disease makes use of a number of blood test and imaging procedures to hopefully early identify and manage medical treatment. Many tests utilize direct measurement of specific analytes while others are calculated values. Thyroxine or T4 (containing four iodine atoms) is the primary thyroid hormone secreted by the thyroid gland. Thyroid stimulating hormone (TSH) is released by the pituitary gland depending on the level of T4 recognized by the pituitary; the more T4 the less the TSH level and the less the T4 the higher the TSH level. While the TSH level has been the gold standard to diagnose and treat thyroid disease, there are other diagnostic tests that help guide treatment. Often clinicians will rely solely on the TSH, which can lead to misdiagnosis. The varied tests for thyroid disease and treatment recommendations are emphasized in the initial sections of this course.

Thyroid Hormones And Testing: A Review

The major thyroid hormone secreted by the thyroid gland is thyroxine. Thyroxine is called T4 because it contains four iodine atoms. Thyroxine converts to triiodothyronine (T3) by the removal of one iodine atom. It is this conversion process (T4 to T3) that makes thyroxine effective. Thyroxine (T4) circulates in the blood in two forms: bound or free. When T4 is bound to proteins, i.e., thyroglobulin, it cannot enter the various tissues that need thyroid hormone. Free T4 (fT4), on the other hand, does enter the various target tissues to exert its effects. This section identifies and explains the role of varied thyroid hormones and known disease, drug and other chemical interactions affecting thyroid processes and health.1-3,42-47,106,107

5 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Thyroid Stimulating Hormone

The thyroid-stimulating hormone (TSH) is commonly the first — and often only — test ordered when thyroid disease is suspected. In most labs, normal adult values range from 0.4-5mIU/L. By day 3, neonatal ranges are 3-20µIU/L. TSH (thyrotropin) is secreted diurnally. In addition, TSH secretion can be affected by age, gender, ethnic background and overall health. Third generation TSH assays can detect TSH with a coefficient of variation of 20% down to a level of approximately 0.01 mIU/L. It should be noted that TSH levels will begin to increase before fT4 levels begin to decrease.2

There is some disagreement regarding diagnostic limits for TSH. For many years and for many clinicians, TSH >10 mIU/L was indicative of thyroid failure and hypothyroidism. The National Academy of Clinical Biochemistry has, however, recommended 4 mIU/L as an upper limit, while the American Association of Clinical Endocrinologists has set the upper limit at 3 mIU/L. Other professional groups have suggested even lower values such as 2.5 mIU/L.

There is a growing consensus that ‘one size does not fit all’ and that individual patient responses must be taken into account during treatment. In addition, there is currently no accepted reference measurement procedure (RMP) for the TSH assay, meaning there are significant variations from lab to lab and between different assay manufacturers. Increased TSH levels are seen in the table below.

6 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Various Upper Levels of Normal for TSH

Upper Level of Normal National Academy of Clinical 2.5 mIU/L with no evidence of thyroid Biochemists (NACB) disease

National Health and Nutrition 4.5 mIU/L with no evidence of thyroid Examination Survey III, NHANES disease (self-reported) (Disease Free)

National Health and Nutrition 4.12 mIU/L with no evidence of thyroid Examination Survey III, NHANES disease (self-reported), negative for anti- (Reference Population) thyroid antibodies, not pregnant or using estrogen contraceptives, androgens or lithium

Hanford Thyroid Disease Study 4.10 mIU/L with no evidence of thyroid disease, negative for anti-thyroid antibodies, normal US (no nodules or evidence of thyroiditis)

Pregnancy, 1st trimester 2.0-2.5 mIU/L

Pregnancy, 2nd trimester 3.0 mIU/L

Pregnancy, 3rd trimester 3.5 mIU/L

Increased TSH levels may be found in the following conditions:

• Adults, children and neonates with primary hypothyroidism • TSH-producing tumors • Hashimoto’s thyroiditis • Thyrotoxicosis due to a pituitary tumor • TSH antibodies • Hypothyroid patients receiving insufficient replacement hormone or hyperthyroid patients receiving excessive replacement hormone • Hypothermia in infants and children

7 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Decreased TSH levels are seen in:

• Primary hyperthyroidism • Secondary, tertiary hypothyroidism • Euthyroid Sick Syndrome • Hypothyroid patients receiving excessive replacement hormone or insufficient replacement hormone in those treated for hyperthyroidism

Drugs, pregnancy, estrogen levels, liver disease, non-thyroidal diseases and resistance to thyroid hormones can also affect thyroid stimulating hormone levels. The effects of varied drugs on the function of the thyroid gland are highlighted in the table below.

Drug Effects on Thyroid Function

In Euthyroid Individuals Inhibition of T4 Synthesis Propylthiouracil Methimazole Inhibition of T4/T3 secretion which Lithium can be exacerbated by an Iodide underlying lymphocytic thyroiditis Amiodarone Aminoglutethimide Thyroiditis may be induced Interferon Interleukin-2 Amiodarone Sunitinib Hyperthyroidism-induced Iodide Amiodarone TSH suppression Glucocorticoids Dopamine agonists Somatostatin analogs Rexinoids Carbemazepine/Oxcarbemazepine Metformin TSH elevation Metyrapone Displacement from thyroxine Furosemide binding globulin causing laboratory Phenytoin artifacts Probenecid Heparin Nonsteroidal anti-inflammatory medications (NSAIDs)

8 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Free T4

The T4 is normally bound to thyroglobulin with only a small fraction unbound, or free (fT4). The normal range of fT4 is generally considered to be 10-26pmol/L. (0.7-2.0ng/dL). The fT4 test — as opposed to the total T4 test, is believed to more accurately represent thyroid hormone functional levels. The assay is an RIA and may be corrected for medications via a resin T3 uptake test.1-3,20

Elevated fT4 levels are seen in:

• Graves’ disease • Hypothyroidism treated with replacement hormone • Euthyroid sick syndrome • High altitude

Depressed fT4 levels are seen in:

• Primary, secondary or tertiary hypothyroidism • Hypothyroidism treated with T3

Free T3

The free T3 (fT3) test is commonly used to aid in the diagnosis of hyperthyroidism and to monitor treatment. Most T3 is intracellular and therefore only a very small portion is found in the serum. Normal levels are generally between 260-480pg/dL (4.0-7.4pmol/L; 0.26-0.48 ng/dL).

Elevated fT3 levels are seen in:

• Hyperthyroidism • T3 toxicosis

9 nursece4less.com nursece4less.com nursece4less.com nursece4less.com • High altitudes

Depressed fT3 levels are seen in:

• Primary or secondary hypothyroidism • 3rd trimester of pregnancy • Deiodinase deficiency or insufficiency

TSH, fT4 and fT3 Levels in Thyroid Disease

TSH fT4 fT3 Interpretation -- Normal Normal Subclinical hypothyroidism -- â Normal or â Hypothyroidism ââ Normal Normal Subclinical hyperthyroidism ââ Normal or - Normal or - Hyperthyroidism ââ Normal or â Normal or â Rarely, 2o hypothyroidism. More commonly, non-thyroidal chronic disease Normal -- -- Thyroid hormone resistance

Assessing Thyroid Hormone in Pregnancy

FT4I (calculated) Usually normal values in pregnancy Direct assay of fT4 Usually decreased in pregnancy. May be normal with alterations in TBG binding assays.

Other Laboratory Tests To Diagnose Thyroid Disease

Clinicians often do not rely on a full thyroid blood screen to diagnose a thyroid condition. This section reviews thyroid tests that can help clinicians develop a clear and more accurate diagnosis of an existing thyroid disease.57,72,83,107

The human body depends on thyroid hormones to function at an optimal healthy state. Because no test can fully measure how thyroid

10 nursece4less.com nursece4less.com nursece4less.com nursece4less.com hormone is utilized once it enters the bloodstream, it is important for clinicians to understand the varied tests and measures that inform how each unique individual responds to thyroid hormone imbalances.

Thyroglobulin Test

Thyroglobulin (Tg) binds T4 in the thyroid. The thyroglobulin test is used primarily as a tumor marker to follow the effectiveness of thyroid cancer treatment, primarily the well-differentiated thyroid cancers, and to monitor disease-free progression. Other reasons for testing for thyroglobulin are to monitor the treatment of Graves’ disease. Rarely, it may be used to try and determine the underlying cause of congenital hypothyroidism or to help differentiate between subacute thyroiditis and thyrotoxicosis factitia.

Thyroglobulin is normally primarily found in the thyroid within thyroid follicles. Normal levels for adults are 3-42 ng/mL(3-42µg/L) and for newborns (at 48 hours), 36-48 ng/mL(36-48µg/L).

Increased thyroglobulin levels are seen with:

• Untreated or metastatic well-differentiated thyroid cancer (Thyroglobulin levels are not diagnostic of thyroid cancer) • Subacute thyroiditis, thyrotoxicosis • Hyperthyroidism

Depressed levels of thyroglobulin may be seen with:

• Thyrotoxicosis factitia • Newborns and infants with goiter and hypothyroidism

11 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Thyroxine-Binding Globulin

Often confused with thyroglobulin, thyroxine binding globulin (TBG) is the main serum carrier protein for T4. Serum levels of TBG can have significant effect on the T4 levels. TBG measurement is most useful to distinguish between hyperthyroidism and euthyroidism with increased binding, increased versus functionally normal T4 levels, and to identify hereditary deficiency of TBG.

Normal levels of TBG in infants are 3-6 mg/dL (30-60mg/L). In adult males, the normal range is 1.2-2.5 mg/dL (12-25mg/L) while in adult females, the normal range is 1.4-3.0 mg/dL (14-30mg/L). Women on oral contraceptives and in the 3rd trimester of pregnancy may have elevated TBG values.

Elevated TBG levels are seen in:

• Genetic hyperexpression of TBG • Some cases of hypothyroidism • Infectious hepatitis • Acute intermittent porphyria • Estrogen-producing tumors • Late-stage HIV • Heroin, methadone use

Depressed TBG levels are seen in:

• Genetic defect in TBG gene • Nephrotic syndrome • Trauma, stress, major illness, chronic liver disease • Ovarian hypofunction

12 nursece4less.com nursece4less.com nursece4less.com nursece4less.com • Acromegaly • Anabolic steroid use • Hypoproteinemia • Malnutrition

Triiodothyrodine Uptake Test

The triiodothyrodine uptake (T3U) test is an indirect measurement of the amount of unsaturated TBG available and is inversely proportional to the TBG levels. This test is usually done along with the T4 test (resulting in the calculated “T7” test). Normal levels (as compared to controls) should be 0.9-1.0 and 25-35%.

The T3U test can be done to correct for drugs that may interfere with the T4 assay. T7 is also known as the Free Thyroxine Index (FTI) and is a calculated result —the product of the T5 value and the T3U. The FTI can give a clearer picture of the totality of thyroid function in both suspected hypothyroidism and hyperthyroidism as well in patients who are pregnant or with suspected abnormalities in TBG levels.

Decreased T3U levels occur in a normal pregnancy, with a variety of drugs such as estrogens, methadone and heparin. Increased T3U levels can occur with heparin, salicylates and anabolic steroids.

Thyroid Antibodies Testing

One of the primary ways of diagnosing autoimmune thyroid disease is by testing for antibodies. The most commonly found antibody is thyroid peroxidase (TPO antibodies/TPOAb). These have been referred to in the past as anti-microsomal antibodies. Other antibodies include anti-thyroglobulin (Tg antibodies/TgAb), and TSH receptor (TSH-R

13 nursece4less.com nursece4less.com nursece4less.com nursece4less.com antibodies/TSH-RAb) antibodies. These antibodies are persistent, even with treatment.

In the NHANES III survey, approximately 10% of participants were TgAb positive while approximately 11% of participants were TPOAb positive, though only those positive with TPOAb were associated with progression to hypothyroidism. These antibodies should be assessed for anyone with a goiter who may be at risk for autoimmune thyroiditis as well as any patients with signs and symptoms of hypothyroidism and in screening patients for thyroid disease.

These antibodies can variously act as either agonists or antagonists, particularly TSH-RAb. Stimulating antibodies (TSI) promote thyroid hormone production leading to hyperthyroidism while inhibiting antibodies (TBII) inhibit production and lead to hypothyroidism, though this is not routinely tested.

Antibodies to TSH should be assessed particularly in euthyroid and thyroid hormone treated pregnant women or those with a history of hyperthyroidism, as these antibodies are predictors of fetal and neonatal thyrotoxicosis. TPO-Ab can be positive in both Hashimoto’s thyroiditis and in Graves’ disease.

Radioactive Iodine Uptake Test

The Radioactive Iodine Uptake test (RAIU) is a direct measurement of the ability of the thyroid gland to concentrate inorganic iodine. The test measures the rate of accumulation, incorporation and release of iodine. In order to minimize exposure to the patient, this test is often

14 nursece4less.com nursece4less.com nursece4less.com nursece4less.com done in conjunction with thyroid imaging such as scintigraphy (thyroid scan).

The patient may be asked to use a low-iodine diet for 7-10 days before the test and may be asked to fast. The first scan is usually done at two hours, then 4-6 hours after ingesting the radiotracer (either 123I or 131I) with a second scan within 24 hours. Normal values are 1-13% after 2 hours, 5-30% after 6 hours, and 15-40% after 24 hours.

Increased uptake is associated with hyperthyroidism. Decreased uptake is associated with hypothyroidism. Neither is diagnostic and may be affected by malabsorption, diarrhea, rapid diuresis and renal insufficiency.

Calcitonin Testing

Calcitonin, produced by the parafollicular or C cells of the parathyroid gland may be used to diagnose medullary thyroid cancer. Stimulation tests, using intravenous calcium or pentagastrin are more sensitive than direct measurement in the blood.

Agents Affecting Thyroid Laboratory Tests And Treatment

There are a large number of substances that can significantly affect all aspects of thyroid function, metabolism, laboratory tests, treatment outcomes and other clinical parameters.5,34-49,107

15 nursece4less.com nursece4less.com nursece4less.com nursece4less.com – – – Agents that • Monovalent anions (SCN , Cl04 , N03 ) block iodide transport into • Dietary the thyroid − Minerals (Bromine, Chloride) gland − Exogenous iodine supplements including kelp

• Minerals: Lithium, fluoride

• Drugs: ethionamide

Agents that • Drugs: impair TG iodination and − Thionamides and thiourylenes, iodotyrosine (PTU,methimazole, carbimazole) coupling − Sulfonamides (acetazolamide, sulfadiazine, sulfisoxazole)

− Sulfonylureas (carbutamide, tolbutamide, metahexamide, chloropropamide)

− Salicylamides (p-aminosalicylic acid, p- aminobenzoic acid)

− Others: Resorcinol, amphenone, aminoglutethimide, Antipyrine (phenazone), amphenidone, ketoconazole

• Dietary thiocyanates

Agents that • Drugs: amiodarone, iodide (as topical antiseptics inhibit thyroid as well), lithium hormone secretion

Agents that • Drugs: amiodarone, IL-2, γ-IFN, Sunitinab, can induce sarafenib. Ipilmumab, pembrolizumab, nivolumab, thyroiditis tyrosine kinase inhibitors

Agents that • Drugs: α-IFN, HAART (highly active antiretroviral can induce therapy) Graves’ disease

Agents that • Drugs: p-bromdylamine maleate, phenylbutazone, can affect thalidomide thyroid function via • Minerals: calcium, rubidium, cobalt unknown mechanisms

Agents that • Drugs: Estrogen, opiates, clofibrate, 5-fluorouracil,

16 nursece4less.com nursece4less.com nursece4less.com nursece4less.com increase TBG perpneazine levels

Agents that • Drugs: Androgens, metabolic steroids, decrease TBG glucocorticoids, l-asparaginase, nicotinic acid levels

Agents that • Drugs: salicylates, diphenylhydantoin, furosemide, interfere with sulfonylureas, heparin, dinitrophenol, free fatty TBG-binding acids, phenylbutazone, halofenate, orphenadrine, thyroid hormone analogs

Agents that • Drugs: Propylthiouracil (PTU), glucocorticoids, inhibit propranolol, iodinated contrast agents, deiodinases amiodarone, clomipramine

Agents that • Drugs: Diphenylhydantoin, carbamazepine, stimulate phenobarbital. Cholestyramine, colestipol, degradation or rifampin, sucralfate, imatinib, bexarotene, excretion sevelemer. Colesevelam

• Diet: soy, caffeine

• Mineral salts: aluminum hydroxide, ferrous sulfate

Agents that • Drugs: iodine-containing drugs, lithium, dopamine increase TSH blocking agents, decarboxylase inhibitors, L-dopa secretion or inhibitors, cimetidine, dlomifene, spironolactone, response to amphetamines TRH

Agents that • Drugs: Thyroid hormone replacement therapy, decrease TSH Thyroid hormone analogs, Dopaminergic agents, secretion or Dopamine, L-Dopa, serotonin agonists, dopamine response to antagonists, serotonin anatagonists, TRH glucocorticoids, acetylsalicylic acid, growth hormone, somatastatin, opiates, fenclofenac, clofibrate, bexarotene, metformin, ipilmumab, pembrlizumab, nivolumab

• Vitamins: Pyridoxine

Agents that • Drugs: interfere with absorption of − Bile acid sequestrants levothyroxine − Cation exchange resins (Kayexelate)

− Oral bisphosphonates

− Proton pump inhibitors

− Raloxifene

17 nursece4less.com nursece4less.com nursece4less.com nursece4less.com − Orlistat

− Ciprofloxacin

− H2 receptor antagonists

• Multivitamins (containing ferrous sulfate or calcium carbonate)

• Minerals: Ferrous sulfate, Chromium picolinate, Calcium salts (carbonate, citrate, acetate)

• Phosphate binders (sevelamer, aluminum hydroxide)

• Charcoal

• Dietary

− Ingestion with a meal

− Grapefruit juice

− Espresso coffee

− High fiber diet

− Soybean formula (infants)

− Soy

Medical Malabsorption syndromes conditions • Celiac disease that interfere with • Jejunoileal bypass surgery absorption of • Cirrhosis (biliary) levothyroxine • Achlorhydria

Neonatal Testing for Thyroid Disease

Neonatal screening for congenital hypothyroidism that, in the U.S., occurs at a rate of between 1 of 3600 and 1 of 5000, has been a success story to a very large degree. TSH screening is more specific,

18 nursece4less.com nursece4less.com nursece4less.com nursece4less.com but T4 screening is more sensitive, though with a high rate of false positives, particularly for low birth weight and premature infants. In general, these should be done after the first 24 hours to minimize the falsely positive TSH that is due to the physiological increase in TSH, T4 and T3 immediately after birth.82,103

By the third day, neonatal TSH should be < 20µU/mL (20mU/L). Neonatal T4 peaks during the first 24 hours and then decreases to 12- 22µg/dL (152-292mmol/L) within 1-3 days, dropping further to 10- 17µg/dL (126-214mmol/L) within two weeks.

Low T4 with a normal TSH, hypothyroxinemia is found in 50% of babies born less than 30 weeks gestation — these will be missed if only TSH is screened in this population. Premature babies have hypothalamo-pituitary immaturity, low TBG levels and decreased conversion rate of T4 to T3. In addition, hypothyroxinemia may be seen in euthyroid sick syndrome in newborns.

Isolated hyperthyrotropinemia with normal T4 and elevated TSH levels can also occur, indicating the inadequate production of T4. It is most common in premature babies. The hyperthyrotropinemia can be a transient finding due to goitrogens, iodine deficiency, or certain medications, genetic defects of hormone biosynthesis and also dysgenesis, especially ectopia, could be the causes.

Elevated TSH levels with normal T4 levels can persist for years. Iodine excess, particularly from the use of iodine-containing antiseptics may also cause transient hypothyroxinemia in preterm babies.

19 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Screening Recommendations

Different organizations have recommended somewhat different screening plans, as listed below, while the U.S. Preventive Services Task Force and the Royal College of Physicians (London) find there is insufficient evidence for screening any specific population. The screening recommendations for pregnant women and newborns have been covered above.62-64,88,104 • The American Thyroid Association recommend that both women and men over the age of 35 should be screened every 5 years • The American Association of Clinical Endocrinologists recommends that older patients, particularly older women, should be screened. • The American Academy of Family Physicians recommends that all patients over the age of 60 should be screened. • American College of Physicians recommends that women over the age of 50 years with an incidental finding suggestive of symptomatic thyroid disease should be evaluated.

Thyroid Scans

Thyroid imaging utilizes I-123 or I-131 (and sometimes Technetium pertechnetate-99m) to visualize and evaluate the size, position, function and the presence of “hot” or “cold” spots in the thyroid. The radioactive iodine uptake test (RAIU), also known as a thyroid uptake test, is a measurement of thyroid function, and does not involve imaging. “Hot” spots, indicating increased uptake of iodine are generally nonmalignant while “cold” spots generally need further evaluation, with a greater possibility that these represent malignancies.

20 nursece4less.com nursece4less.com nursece4less.com nursece4less.com The 123I or 131I (tracer) can be given as an IV, a pill, or as a liquid. A waiting period of 24 hours is needed before the actual scan with a probe positioned over the thyroid gland. If there is a suspicion of the ectopic presence of thyroid tissue, the probe can be moved, for example, to the mediastinum. The actual scan is likely to take less than 10 minutes. Inorganic iodine is also concentrated in fetal iodine and in breast milk, so pregnant and lactating women should not ordinarily be tested with radioactive iodine.

As mentioned, thyroid cancer commonly appears as “cold” areas. Areas of diffuse “hotness” or increased uptake represent hyperthyroid disease such as Graves’ disease, while areas of diffuse “coldness” represent hypothyroid disease. Hashimoto’s thyroiditis is often characterized by a “mottled” appearance. A Computerized Rectilinear Thyroid (CRT) scanner in some areas is replacing the gamma camera scan. More commonly, nuclear labs use a scintillation camera. The CRT scanner uses computer technologies to enhance the clarity of the scans and can provide information on the size and function of the thyroid. Indications for a thyroid scan are highlighted below.

• Hyperthyroid patients with or without a goiter (diffuse or nodular): These can be used to determine the functionality of a palpable nodule, to detect unsuspected or nonpalpable nodules, to differentiate between Graves’ disease, toxic nodular goiter and other causes of thyrotoxicosis. The scan can also be used to estimate the volume of the thyroid before 131I therapy. • Euthyroid patients with a solitary nodule or multiple nodules: These can be used to determine if the nodule(s) are hyperfunctioning, to identify nodules for fine needle aspiration

21 nursece4less.com nursece4less.com nursece4less.com nursece4less.com biopsies, and to estimate the volume of functional tissue for future surgery. • Patients with suspected ectopic thyroid tissue. • Patients who has had thyroid cancer to follow remaining thyroid tissue.

The I-131 has a half-life of 8 days and can be used for whole body scintigraphy, post cancer treatment. I-123 has a shorter half-life of 13 hours and is commonly used for thyroid scintigraphy. Tc-99m pertechnetate and Tc-99m sestamibi each have half-lives of 6 hours with the former being useful for thyroid scans and the latter useful in the localization of thyroid metastases. TI-210-Cl- has a much longer t1/2 (77hours) and can be used to localize metastases. Finally, F-18 fluorodeoxyglucose, a positron emitter with a t1/2 of 110 minutes can be used in PET scans.

Patients do not need to fast before thyroid scintigraphy, but should be on low iodine diet for 7-10 days preceding the scan.

Non-isotopic imaging comprises ultrasonography (US), CT and MRIs. US is commonly used to clarify results from puzzling physical finding, for guiding fine needle aspiration (FNA) biopsies, detect small nodules, identify individual nodules that may be at greater risk of neoplastic transformation and to evaluate the recurrence of thyroid cancer after surgery, particularly in the cervical lymph nodes. In US, a normal thyroid has a relatively homogenous appearance, sometimes compared to “ground glass”. In goiter, US may be able to locate a specific region where the echo pattern is distinct from the rest of the thyroid, though US cannot identify specific disorders.

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Focal lesions are often surrounded by a distinctive halo or rim, but the greatest use of US may be to guide FNA biopsies. Hypothyroid patterns often have low echogenicity, particularly in Hashimoto’s thyroiditis. In pediatric patients, an additional sign, with 98% sensitivity and 100% specificity appears to be in the lymph nodes adjacent to the lower part of the thyroid lobes. A sonographic classification system has been proposed based on real-time sonography that may be a useful tool for the differentiation of asymptomatic diffuse thyroid disease. Diffuse thyroid disease versus normal thyroid has been differentiated in the literature based on differences in echogenicity, echotexture, AP (anterior posterior) diameter, vascularity, a glandular margin, and the presence of scattered microcalcifications. Micronodulation has been described as a sonographic sign of Hashimoto’s thyroiditis and a “thyroid inferno” has been described as a sonographic sign of Graves’ disease.

Ultrasonography can be somewhat correlated with an increased or decreased risk of thyroid cancer.

Increased risk of thyroid cancer is associated with the following features: hypoechoic, microcalcifications, central vascularity, irregular margins, incomplete haloes, a nodule that is taller than it is wide, documented enlargement and associated rounded adenopathy, particularly when associated with cystic spaces. Decreased risk of thyroid cancer is associated with the following features: hyperechoic, large and coarse calcifications (with the exception of medullary cancer), peripheral vascularity, a lesion that looks like a “puff pastry” (wider than taller) and “comet-tail shadowing”.

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Sonography is often used in conjunction with a FNA biopsy, though it may be reserved for very deep or very small nodules, for nonpalpable nodules, nodules suspicious for cancer and in nonpalpable adenopathy. The success rate is low for nodules smaller than 8 mm.

Computed tomography and MRIs are sometimes used, but because of the cost, these are generally thought not to be cost-effective and usually not required. PET scans are sensitive and specific for monitoring recurrent or persistent thyroid cancer post-surgically when using a biochemical indicator such as thyroglobulin. Multimodality scanning (using PET, CT and MRI scans simultaneously) can superimpose function and anatomy and are currently in development. Thyroid scans utilizing radioactive tracers are commonly done along with the RAIU tests.

Fine Needle Aspiration Biopsy

The fine needle aspiration biopsy (FNAB) of the thyroid is commonly performed with US guidance. The basic procedure itself dates from the mid-1800s. The medical literature reported the first needle aspiration in the diagnosis of infectious disease during 1904 (study by Grieg and Gray), where needle aspiration of the lymph nodes on patients with sleeping sickness revealed motile trypanosomes. In their report, the authors suggested FNA might be more effective at diagnosing cases of sleeping sickness than blood testing. In the 1930s, at the Memorial Sloan Kettering Cancer Center in New York and later during World War II refinement of the FNA procedure developed.104 Since those early years, FNAB has become a very well accepted, cost-effective safe and efficient method to evaluate the histology of the aspirated cells.

24 nursece4less.com nursece4less.com nursece4less.com nursece4less.com However, it should be noted that false-positives and false-negatives are common and reliance on FNAB solely is not advisable.

Advantages of the FNAB include cost, convenience, outpatient status and that it is a relatively painless procedure not leaving any scar. On the other hand, the number of false positives and false negatives, likely due to sampling errors, limits FNAB. The procedure requires specialized training, though it can be done in an office setting. Currently, the best evidence suggests that US or CT guidance provides the best and most reliable results. In adults, research has indicated a 97% positive predictive value with a 92% negative predictive value for malignancy. It does not appear that there are significant differences in nodules based on size. Further, studies have shown that the reliability of FNAB as a diagnostic tool is not affected by the size of the nodules and size alone should not be used as the primary independent factor for determining candidacy for surgery.

Papillary thyroid carcinoma can commonly be diagnosed by FNAB, but the same is not true for follicular adenomas, which can be difficult to differentiate from follicular carcinomas in most samples. The presence of a follicular neoplasm in the FNAB sample is considered an indication for thyroid surgery.

In the pediatric population, there are fewer studies. Pediatric patients are more likely than adult patients to have reactive lymphadenopathy, limiting the utility of the biopsy. Research on the use of FNAB in pediatric patients has shown that FNAB is a sensitive test in this population, particularly for excluding the possibility of a thyroid tumor. Similarly, smaller studies of pediatric patients have shown that FNAB

25 nursece4less.com nursece4less.com nursece4less.com nursece4less.com had a diagnostic sensitivity of 100%, positive-predictive value of 93.3%, and accuracy of 94.5% for diagnosing pediatric cervical lymphadenopathy.

Genetic markers and gene panels are becoming more widely used in assessing the potential for malignant thyroid tumors. A number of different alterations in gene expression, the expression of micro RNA (miRNA) and in the methylation of gene promotors has been described. In papillary thyroid cancer, the best-described are point mutations of the BRAF and the RAS genes. In addition, RET/PTC and TRK rearrangements have been detected in papillary thyroid cancers — these activate the mitogen-activated protein kinase (MAPK) pathway and are found in over 70% of papillary thyroid tumors. The BRAF mutation is the most common mutation found in papillary tumors. Follicular thyroid cancer has been studied for genetic markers as well; these tumors have been shown to contain RAS mutations or a PAX8/PPARγ rearrangement. These markers are mutually exclusive as are those described for papillary tumors, and are also found in more than 70% of follicular thyroid tumors. In both familial and in sporadic medullary thyroid tumors, point mutations are commonly found in the RAS or the RET genes. In poorly differentiated and anaplastic carcinomas, markers involve the TP53 and CTNNB1.

Treatment Of Hypothyroidism And Hyperthyroidism

The pillar of the treatment of hypothyroidism has long been L- thyroxine (Levothyroxine). The dosage should be titrated, leaving a minimum of 6-8 weeks between changes in dosage, to allow TSH to fall within the normal range. High doses of levothyroxine will likely result in significant changes in TSH within 4 weeks, but subsequent

26 nursece4less.com nursece4less.com nursece4less.com nursece4less.com changes in dosage generally take longer to be effective. However, since the normal range varies among different labs and because there is still a lack of consensus regarding the value above which to assign the label hypothyroid, patient feedback regarding their symptoms and energy levels can be an important part of assessing the overall ideal dosage. In this context, it is important to remember that some symptoms will respond more slowly (i.e., skin or hair changes) than will others (i.e. energy level, change in weight, menstrual symptoms). Women have been shown to require higher doses, on average, but age does not appear to be an independent predictor of dosage. The medical and surgical treatment of hypo- and hyperthyroidism is discussed in this section.9,57,88,105-107

Medical Treatment of Thyroid Disease

Starting dosage in those with little thyroid function can be estimated based on weight (1.6µg/kg body mass daily). Those patients who have undergone a total thyroidectomy may require a higher dose while those with subclinical hypothyroidism or those who have undergone treatment for Graves’ disease may require less replacement hormone. It is not clear which dosing schedule is better, i.e., within 2 hours of the last meal of the day versus 20 minutes before breakfast. This may also be “titrated” though ease of compliance should be considered a factor. Central hypothyroidism measurement of T4 is considered a better measure of effectiveness than the measurement of TSH.

Once a euthyroid state has been achieved, generally the recommendation is for follow-up every 6 months for 2-3 years unless otherwise clinically indicated. After 2-3 years, most recommend yearly follow-ups. It should be noted that major life changes may be an

27 nursece4less.com nursece4less.com nursece4less.com nursece4less.com indication for follow-up. These changes can include trauma, injury, perimenopause, the diagnosis of an autoimmune disorder or the appearance or re-appearance of symptoms.

It is possible that while the TSH levels (and therefore the T4 levels) are in the normal range, the T3 levels may be subnormal if the patient is not converting T4 to T3 efficiently, i.e., in the case of the aforementioned D2 polymorphisms. The latest trends in personalized medicine would support this concept — that once the TSH (and, by extension, the T4 levels) have reached normal ranges — and remembering that ranges are just that (some patients report feeling improvement in hypothyroid symptoms with low-end normal TSH levels) at that point, it may be useful if selected patients undergo trials of additional T3. The dose of T3 can be problematic given its short half-life of one day, and many clinicians recommend 3 daily doses to achieve approximately physiologic levels of T3.

Several studies have been undertaken in an effort to establish more physiologic levels of both T4 and T3 by using combination therapy. Brain function may benefit the most from T3 therapy; functional PET and MRIs indicate that the hippocampus and amygdala are particularly sensitive to fluctuations in T3, as is the frontal lobe and executive function. Treatment with T4 only may not allow for sufficient recovery of T3 levels and may therefore be most critical for those patients with cognitive difficulties, mood swings, depression and other symptoms of neuropsychological function.

A recent review of studies combining T4 with T3 therapy suggested that certain patients might benefit from combined therapy. These

28 nursece4less.com nursece4less.com nursece4less.com nursece4less.com patients include those in whom normal TSH/T4 levels have been achieved yet who still experience cognitive difficulties, depression, mood swings, patients with autoimmune thyroiditis, some thyroidectomized patients, those patients with known or suspected deiodinase deficiencies and those for whom hypothyroid symptoms appear to be resistant to T3 therapy. Three meta-analyses of combination therapy have been done, with somewhat variable results: two found no significant differences between combined and monotherapy. A third study found improvements in both physical and psychological wellbeing. Each study had methodological limitations including small sample size, a lack of homogeneity in the patient populations, large variations in the dosages of T4/T3 and lack of clarity in outcomes measured. More recent investigations have identified that substitution of l-T3 for l-T4 at equivalent doses (relative to the pituitary) reduced body weight and resulted in greater thyroid hormone action on the lipid metabolism, without detected differences in cardiovascular function or insulin sensitivity. On the other hand, a recent systematic review of clinical practice guidelines did not support the use of combination therapy. There may be increased risk of cardiovascular effects, particularly in the elderly and those with pre-existing cardiovascular conditions.

Combinations of T4 and T3 exist that attempt to mimic the purported physiological ratio of 80/20%. These include Thyrolar (Liotrix), which is a 4:1 combination of synthetic T4/T3. Combination therapeutic dosing can also be supplied by compounding pharmacies that can provide at 4:1 combination of levothyroxine and triiodothyronine.

29 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Glandular preparations are generally eschewed by mainstream medicine due to the lack of standardization and substantiation, though these were the mainstay of hypothyroidism treatment for over a century. Many patients, however, are looking for more natural approaches to treating hypothyroidism and may request information regarding these products, which can include Armour (Erfa in Canada) and other dessicated thyroid products. These are generally derived from porcine thyroid glands. Three dosage forms are usually available: 30mg (1/2 grain), 60mg (1 grain) and 125mg (2 grains); 1 grain of Armour contains 30µg of T4 and 9 µg of T3 and is roughly equivalent to 74 µg of levothyroxine. Patients are usually started at ¼ to ½ grain daily and titrated as done with levothyroxine.

Anecdotally, it has been noted by some that certain patients do better with glandular preparations than others. Recently, it was reported that in those patients with persistant subjective complaints while on T4 monotherapy, 78% reported a preference for Armour thyroid treatment when switched. Other reports suggested while there were no significant differences in symptoms or in neurocognitive measurements, patients switched from synthetic T4 therapy realized modest weight loss and 48.6% reported preference for the Armour thyroid treatment.

The most common treatment for hyperthyroidism in the U.S. is treatment with I-131. Antithyroid medications are also commonly used, which include methimazole and propylthiouracil. In general, the antithryoid medications are used in the pediatric population while in adults, the antithyroid medications are used prior to therapy with I-

30 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 131. Medications should be titrated until indications of thyroid normalization.

Both methimazole and propylthiouracil (PTU) are thiomides and interfere with the production of T4. PTU prevents thyroid hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions, blocking iodine organification, blocking the coupling of iodotyrosinases and inhibition of D2. PTU may take up to 3-4 weeks before stores of T4 are depleted. Adverse effects include rash, rare agranulocytosis, hepatitis and cholestatic jaundice. PTU is pregnancy risk category D. However, since more PTU is protein-bound, it is preferred to methimazole in the first trimester. Very low amounts of PTU are secreted into breast milk. PTU is also used to treat thyroid storm, often along with potassium iodide and propranolol. Methimazole shares the mechanism of action with PTU but is considered significantly more potent. Methimazole does not inhibit the D2 deiodinase. In non-pregnant adults, methimazole is the primary drug used to treat Graves’ disease. Methimazole has a longer duration of action and its use can result in a euthyroid state more rapidly. Methimazole is also pregnancy risk category D and is contraindicated in pregnancy and during lactation. Adverse effects include a maculopapular rash, rare agranulocytosis, hepatitis and cholestatic jaundice.

Potassium iodide inhibits thyroxine release by the thyroid as well as inhibiting thyroid peroxidase-catalyzed reactions. Indications include thyroid storm, Graves’ disease, toxic adenoma, goiter and thyroiditis, but it is rarely used alone.

31 nursece4less.com nursece4less.com nursece4less.com nursece4less.com The I-131 is a beta emitter with an effective half-life of about 56 days in the thyroid. It is contraindicated in pregnancy or lactation with a potential adverse effect of delayed hyperthyroidism. Its effects are much less rapid than treatment with antithyroid drugs or with a thyroidectomy, but it is safe, effective and does not require a stay in the hospital. In addition, it has been suggested that treatment with radioactive iodine has a higher cure rate for Graves’ disease and is associated with a lower recurrence rate. However, it should be noted that treatment with radioactive iodine is also associated with an increased risk of development or worsening of ophthalmologic symptoms and disorders as well as an increased risk of hypothyroidism.

The American Thyroid Association recently provided recommendations for I-131 therapy in compliance with the Nuclear Regulatory Commission regulations. Contraindications include pregnancy and breastfeeding. In general, the dose of 131I is between 75-200 µCi/g of the estimated mass of thyroid tissue divided by the percent uptake of I-123 in 24 hours previously determined by RAI testing. For doses over 200 µCi/g, hospitalization along with proper radiation safety measures should be considered.

The I-131 should be administered as a single dose. The iodine is selective for thyroid tissue and the treatment is therefore associated with few adverse effects. There is no credible evidence that I-131 therapy is associated with increased risk of thyroid carcinoma, increased mortality or any other form of cancer, including leukemias. I-131 treatment is not recommended for children under the age of 5. In those children between the ages of 5 to 10 years, I-131 therapy can

32 nursece4less.com nursece4less.com nursece4less.com nursece4less.com be used if the calculated activity of administered I-131 is less than 10 mCi. In any child older than 10, I-131 can be undertaken as long as the activity is greater than 150 µCi/g of thyroid tissue.

Surgical Treatment of Thyroid Disease

Thyroidectomy

Thyroidectomy, while once the most common treatment for hyperthyroidism, is now generally reserved for specific cases including: • In children with severe hyperthyroidism • In pregnant women who are noncompliant with or intolerant of antithyroid pharmacotherapy • In those patients with very large goiters or severe ophthalmopathy • In those patients who refuse radioactive iodine therapy • In those patients with refractory amiodarone-induced hyperthyroidism • In those patients who require rapid normalization of thyroid functions. This can include pregnant women, women who desire pregnancy in the next 6 months, or patients with unstable or otherwise dangerous cardiac conditions.

Pre-thyroidectomy treatment generally involves antithyroid medication, treatment with iodine salts (SSKI: 2 drops bid for 10-14 days) and beta blockers until euthyroid biochemical status and pulse <80bpm is achieved. Excess iodine in the diet or as supplements should be avoided. Thyroid storm can generally be avoided with this procedure, but adverse effects include hypoparathyroidism and damage to the recurrent laryngeal nerve.

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Ophthalmopathy

Up to half of Graves’ disease patients have signs and symptoms of thyroid eye disease, but approximately 5% can develop severe ophthalmopathy including diplopia, visual-field deficits, or blurred vision. The less serious eye symptoms, which can include photophobia, tearing and irritation are often treated with sunglasses and saline drops as needed. If more serious ophthalmopathy is suspected, an ophthalmologist should monitor patients regularly. Emergency symptoms that the patient should be made aware of included loss of color vision or orbital pain.

Dermopathy

Graves’ disease can result in an infiltrative dermopathy over the lower legs. The dermopathy includes a non-pitting and erythematous edema on the shins. The dermopathy commonly accompanies ophthalmopathy and is characterized by an accumulation of glycosaminoglycans and inflammatory cells in the skin. There is no effective treatment; topical steroid creams are often used for symptomatic relief.

Neurological and Cardiovascular Symptoms

Symptomatic relief for neurologic and cardiovascular symptoms may be necessary. Beta-blockers are the drug of choice unless contraindicated in which case calcium channel blockers may be used. These medications can usually be stopped once a euthyroid state has been attained.

34 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Thyroid Nodules

Fine needle aspiration biopsy (FNAB) is most commonly used to evaluate thyroid nodules. The Bethesda System for Reporting Thyroid Cytopathology is used to classify thyroid nodules into a number of categories: benign, atypia of undetermined significance (AUS), follicular neoplasm, suspicious for malignancy, malignancy, and nondiagnostic. The benign category has a less than 1% risk of malignancy. AUS has a 5-10% risk, follicular neoplasm has a 20-30% risk, suspicious for malignancy has a 50-75% risk, and malignant has 100% risk. Hypocellular aspirates are a significant problem and may either be related to poor technique or the presence of cystic nodules.

Benign nodules should be observed and re-evaluated at 6-18 month intervals. If the patient is experiencing significant distress, such as dysphagia or discomfort a surgical consult should be obtained. Indeterminate samples should be repeated at regular intervals. For AUS, the FNAB can be repeated in 3-6 months, with surgical consult as needed. If there are atypical findings on US such as hypoechogenicity, irregular borders, calcifications, or hypervascularity, a surgical consult should also be sought. Bethesda categories of follicular neoplasm, suspicious for malignancy, and malignant classifications each warrant surgical consultation.

Prevention Of Thyroid Disease

Screening and prevention of thyroid disease is an evolving field of research and medical management. This section covers considerations of family and personal history, and prevention, including supplementation and diet. More could be said on this topic, however a

35 nursece4less.com nursece4less.com nursece4less.com nursece4less.com brief highlight of its significance in the treatment plan is offered here.93-102

Individuals who are at risk for thyroid disease include those with family members with a history of thyroid disease, a family history of autoimmune disease, a personal history of thyroid or autoimmune disease, live in a region with either an excess or deficiency of iodine or take a variety of multi-mineral, herbal or nutraceutical supplements which contain iodine, are taking medications such as Interferon Beta- 1b, Interleukin-4, immunosuppressants, antiretrovirals, some monoclonal antibodies, Lithium, and amiodarone, have been exposed to radiation in the region of the thyroid or have been exposed to radioactive contrast agents that contain iodine. The only currently accepted prevention of thyroid disease is avoiding as much as possible the risk factors such as those listed above. Some of these risk factors are obviously unavoidable. Others, such as the intake of excess amounts of goitrogenic foods (including cabbage, Brussels sprouts, broccoli, turnips, rutabagas, kohlrabi, radishes, cauliflower, African cassava, millet, kale and soy products) should be avoided. However, it should be noted that an individual would likely need to ingest very large quantities of these foods before any significant risk is incurred and these are generally very healthy foods and should overall be encouraged.

On the other hand, the intake of iodine in amounts significantly exceeding recommended daily limits is likely to be quite common, particularly in individuals who are interested in health and wellness. Many websites and social media sites tout the benefit of iodine and selenium. While adequate amounts of these minerals are crucial to a

36 nursece4less.com nursece4less.com nursece4less.com nursece4less.com healthy and functioning thyroid, the levels of iodine for example often far exceed the Recommended Daily Allowance (RDA) of 150µg for adults over the age of 19. A quick survey of supplements shows that iodine is available in amounts many-fold more than the recommended daily allowance, i.e., at 225 µg, 1000 µg and even 12.5 mg doses.

Kelp products often contain large amounts of iodine as well. With selenium, the situation is similar; multimineral supplements or selenium supplements often exceed the recommended daily allowance of 55 µg. While there are differences in how much selenium is bioavailable (sodium selenite is completely absorbed but is excreted rapidly while sodium selenite is more poorly absorbed but more efficiently incorporated into selenoproteins), the tolerable upper limit (UL) for selenium is 400 µg and in areas of China where selenium deficiencies are common, evidence of selenium toxicity (selenosis) such as gastrointestinal disturbances, skin rashes, a garlic breath odor, fatigue, irritability, and neurologic disorders begin to occur when blood selenium levels correspond to intakes of 850 µg/day.

Supplements with 200 µg of selenium representing 286% of the daily value (DV) are common. Selenium is required for deiodinase activity and in individuals with Hashimoto’s thyroiditis as well as in pregnant women with anti-TPO antibodies, selenium supplementation has been shown to decrease antibody levels and improves the normalcy of US. In pregnant women supplementation with selenium significantly decreases the percentage of those suffering postpartum thyroiditis and definitive hypothyroidism. In Graves’ disease, selenium supplementation results in a more rapid return to euthyroidism and a beneficial effect on mild instances of inflammatory orbitopathy.

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Vitamin D deficiency is a risk factor for Graves’ disease and other autoimmune diseases, though there are some contradictory results. Sufficient Vitamin D levels, particularly in those individuals at higher latitudes, those patients who practice sun-safety measures, those patients who for cultural or religious reasons get little sun-exposure, those with a darker complexion, older individuals or any patient at risk for Vitamin D deficiency may benefit from Vitamin D supplementation. Supplementations with either Vitamin D2 (ergocalciferol) or D3 (cholecalciferol) appear to be of equal effectiveness.

The Arthritis Foundation recommends the anti-inflammatory diet for symptoms relief. A recent review of the role of the “Western diet” consisting of high-fat and cholesterol, high-protein, high-sugar, and excess salt intake, as well as frequent consumption of processed and ‘fast foods’, otherwise known as too much, too fatty, too salty and too sugary is known to promote cardiovascular disease, obesity, prediabetes and diabetes, metabolic syndrome and worsen those conditions where they exist.

These same dietary trends increase the risk of autoimmune diseases. It has been suggested that the body of studies so far addressing nutrition as an etiological factor in inflammatory autoimmune diseases has not firmly verified functional links between dietary macronutrients and a risk for developing disease. However, the inconclusive results of epidemiologic studies do not justify omitting nutrients as influential factors, but rather illustrate the challenge to detect these on the level of otherwise heterogeneous populations.

38 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Subjects prone to autoimmunity have complex individual risk profiles comprised of genetic and environmental determinants that make their response to nutritional cues diverse. The Western diet or the Standard American Diet (SAD) has been associated with the increase in chronic diseases in developed and developing nations.

The anti-inflammatory diet is similar in many ways to the better- known Mediterranean diet and emphasizes whole grains, vegetables, fruit, lean meats, nuts, seeds and oily fish while de-emphasizing processed or prepared foods, foods with added salt and sugar, fatty meats and dairy products. While final confirmation that either the anti- inflammatory diet or the Mediterranean diet can prevent autoimmune disease or more specifically thyroid disease awaits further studies, the nutritional value of these diets and the benefit in preventing disease make these nutritional approaches viable clinical recommendations.

Summary

The human body depends on thyroid hormones to function at an optimal healthy state. Because no test can fully measure how thyroid hormone is utilized once it enters the bloodstream, it is important for clinicians to understand the varied tests and measures that inform how each unique individual responds to thyroid hormone imbalances. While the TSH has been the gold standard to diagnose and treat thyroid disease, there are other diagnostic tests that help guide treatment. Often clinicians will rely solely on the TSH test, which can lead to misdiagnosis. Therefore, lab diagnosis of thyroid diseases makes use of a number of tests and imaging procedures to diagnose and manage treatment.

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Please take time to help NurseCe4Less.com course planners evaluate the nursing knowledge needs met by completing the self-assessment of Knowledge Questions after reading the article, and providing feedback in the online course evaluation.

Completing the study questions is optional and is NOT a course requirement.

1. ______or T4 (containing four iodine atoms) is the primary thyroid hormone secreted by the thyroid gland.

a. Thyroid stimulating hormone b. *Thyroxine c. Triiodothyronine d. Thyroglobulin

2. True or False: The thyroid stimulating hormone (TSH) test is often the only test ordered by clinicians when thyroid disease is suspected, and this can lead to misdiagnosis.

a. *True b. False

3. Thyroid stimulating hormone (TSH) is released by the

a. parathyroid. b. thymus. c. *pituitary gland. d. thyroidea ima.

40 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 4. What is the consensus regarding the diagnostic limits for thyroid stimulating hormone (TSH) that would indicate thyroid failure and hypothyroidism?

a. TSH >10 mIU/L b. TSH ≥ 4 mIU/L c. TSH ≥ 3 mIU/L d. *None of the above

5. Decreased thyroid stimulating hormone (TSH) levels are seen in

a. primary hypothyroidism. b. TSH-producing tumors. c. Hashimoto’s thyroiditis. d. *primary hyperthyroidism.

6. One of the consequences of a hypothyroid patient receiving excessive replacement hormone may be

a. *decreased TSH levels. b. increased TSH levels. c. TSH-producing tumors. d. TSH antibodies.

7. True or False: The T4 test—as opposed to the total fT4 test, is believed to more accurately represent thyroid hormone functional levels.

a. True b. *False

8. The free T3 (fT3) test is commonly used to aid in the diagnosis of ______and to monitor treatment.

a. hypothyroidism b. myxedema c. Hashimoto’s thyroiditis d. *hyperthyroidism

41 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 9. Elevated free T3 (fT3) levels are seen in

a. primary hypothyroidism. b. secondary hypothyroidism. c. *T3 toxicosis. d. deiodinase deficiency or insufficiency.

10. Depressed free T3 (fT3) levels are seen in

a. hyperthyroidism. b. high altitudes. c. *3rd trimester of pregnancy. d. T3 toxicosis.

11. The thyroglobulin test is used primarily

a. *as a tumor marker to monitor thyroid cancer treatment. b. to monitor T3 toxicosis. c. to determine the underlying cause of congenital hypothyroidism. d. to help differentiate between subacute thyroiditis and thyrotoxicosis factitia.

12. True or False: Clinicians often do not rely on a full thyroid blood screen to diagnose a thyroid condition.

a. *True b. False

13. Tests that measure thyroid function are important because they inform clinicians

a. about thyroid hormone utilization in the bloodstream. b. if a patient has thyroid cancer. c. *how each person responds to thyroid hormone imbalances. d. All of the above

42 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 14. Depressed levels of thyroglobulin may be seen with

a. subacute thyroiditis. b. *thyrotoxicosis factitia. c. thyrotoxicosis. d. hyperthyroidism.

15. Thyroglobulin levels are NOT used to

a. *diagnose thyroid cancer. b. monitor untreated, well-differentiated thyroid cancer. c. monitor metastatic, well-differentiated thyroid cancer. d. to monitor the treatment of Graves’ disease.

16. ______binding globulin is the main serum carrier protein for T4.

a. *Thyroxine b. Triiodothyrodine c. T7 d. Thyroglobulin 17. True or False: The thyroglobulin test may be used to monitor the treatment of Graves’ disease.

a. *True b. False

18. Triiodothyrodine Uptake (T3U) is an indirect measurement of the amount of unsaturated ______available.

a. Fatty Acids b. *Thyroxine-Binding Globulin (TBG) c. Linolenic acid d. Natural food ingested is

19. The ______test is usually done along with the T4 test, resulting in the calculated “T7” test.

a. *triiodothyrodine uptake (T3U) b. thyroglobulin c. free T3 (fT3) d. free thyroxine

43 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 20. Free Thyroxine Index (FTI) is also known as

a. *T7. b. T3U. c. free T3 (fT3). d. a full thyroid blood screen.

21. The Free Thyroxine Index (FTI) can give a clearer picture of thyroid function in

a. suspected hypothyroidism and hyperthyroidism. b. in patients who are pregnant. c. in patients with suspected abnormalities in TBG levels. d. *All of the above

22. True or False: The measurement of Triiodothyrodine Uptake (T3U) is inversely proportional to the Thyroxine- Binding Globulin (TBG) levels.

a. *True b. False 23. Decreased T3U levels occur

a. with inorganic iodine. b. with salicylates. c. with anabolic steroids. d. *in a normal pregnancy.

24. One of the primary ways of diagnosing autoimmune thyroid disease is by testing for

a. inorganic iodine. b. Thyroxine-Binding Globulin (TBG) levels. c. *antibodies. d. free thyroxine.

25. Stimulating antibodies (TSI) promotes thyroid hormone production leading to

a. *hyperthyroidism. b. Hashimoto's thyroiditis. c. hypothyroidism. d. TBII production.

44 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 26. Elevated levels of antibodies, such as TSH-RAb, are predictors of

a. suspected hypothyroidism. b. Hashimoto's thyroiditis. c. *fetal and neonatal thyrotoxicosis. d. abnormalities in TBG levels.

27. True or False: Inhibiting antibodies (TBII) inhibit production of thyroid hormones and lead to hypothyroidism, and this is routinely tested for.

a. True b. *False

28. The first thyroid imaging thyroid scan done with a Radioactive Iodine Uptake test (RAIU) is performed ______after ingesting the radiotracer.

a. *two hours b. 8 hours c. within 24 hours d. within 12 hours

29. With the Radioactive Iodine Uptake test (RAIU), which of the following is diagnostic of thyroid disease?

a. Increased uptake b. Decreased uptake c. Inorganic iodine concentrations d. *None of the above

30. Testing calcitonin, which is produced by the parafollicular or C cells of the parathyroid gland, may be used to diagnose

a. hyperthyroidism. b. Hashimoto's thyroiditis. c. hypothyroidism. d. *medullary thyroid cancer.

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31. The American Academy of Family Physicians recommends that all patients over the age of ___ should be screened for thyroid disease.

a. *60 b. 35 c. 50 d. 45

32. True or False: The Radioactive Iodine Uptake test (RAIU) is a direct measurement of the ability of the thyroid gland to concentrate inorganic iodine.

a. *True b. False

33. Thyroid imaging utilizes I-123 or I-131 (and sometimes Technetium pertechnetate-99m) to visualize and evaluate the size, position, function and the presence of

a. inorganic iodine. b. *“hot” or “cold” spots in the thyroid. c. thyroid tumors. d. medullary thyroid cancer.

34. Thyroid imaging “hot” spots, indicating increased uptake of iodine, are generally a sign of

a. malabsorption syndrome. b. celiac disease. c. *non-malignancy. d. medullary thyroid cancer.

35. Genetic markers and gene panels are becoming more widely used in assessing the potential for

a. *malignant thyroid tumors. b. celiac disease. c. neonatal thyrotoxicosis. d. abnormalities in TBG levels.

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CORRECT ANSWERS:

1. ______or T4 (containing four iodine atoms) is the primary thyroid hormone secreted by the thyroid gland.

b. Thyroxine

“Thyroxine or T4 (containing four iodine atoms) is the primary thyroid hormone secreted by the thyroid gland.”

2. True or False: The thyroid stimulating hormone (TSH) test is often the only test ordered by clinicians when thyroid disease is suspected, and this can lead to misdiagnosis.

a. True

“Thyroid stimulating hormone (TSH) is released by the pituitary gland depending on the level of T4 recognized by the pituitary; the more T4 the less the TSH value and the less the T4 the higher the TSH value. While the TSH has been the gold standard to diagnose and treat thyroid disease, there are other diagnostic tests that help guide treatment. Often clinicians will rely solely on the TSH test, which can lead to misdiagnosis.”

3. Thyroid stimulating hormone (TSH) is released by the

47 nursece4less.com nursece4less.com nursece4less.com nursece4less.com

c. pituitary gland.

“Thyroid stimulating hormone (TSH) is released by the pituitary gland depending on the level of T4 recognized by the pituitary;…”

4. What is the consensus regarding the diagnostic limits for thyroid stimulating hormone (TSH) that would indicate thyroid failure and hypothyroidism?

d. None of the above

“There is some disagreement regarding diagnostic limits for TSH. For many years and for many clinicians, TSH >10 mIU/L was indicative of thyroid failure and hypothyroidism. The National Academy of Clinical Biochemistry has, however, recommended 4 mIU/L as an upper limit, while the American Association of Clinical Endocrinologists has set the upper limit at 3 mIU/L. Other professional groups have suggested even lower values such as 2.5 mIU/L. There is a growing consensus that “one size does not fit all” and that individual patient responses must be taken into account during treatment. In addition, there is currently no accepted reference measurement procedure (RMP) for the TSH assay, meaning there are significant variations from lab to lab and between different assay manufacturers.”

5. Decreased thyroid stimulating hormone (TSH) levels are seen in

d. primary hyperthyroidism.

“Decreased TSH levels are seen in: Primary hyperthyroidism; Secondary, tertiary hypothyroidism; Euthyroid Sick Syndrome; Hypothyroid patients receiving excessive replacement hormone

48 nursece4less.com nursece4less.com nursece4less.com nursece4less.com or insufficient replacement hormone in those treated for hyperthyroidism.”

6. One of the consequences of a hypothyroid patient receiving excessive replacement hormone may be

a. decreased TSH levels.

“Decreased TSH levels are seen in: Primary hyperthyroidism; Secondary, tertiary hypothyroidism; Euthyroid Sick Syndrome; Hypothyroid patients receiving excessive replacement hormone or insufficient replacement hormone in those treated for hyperthyroidism.”

7. True or False: The T4 test—as opposed to the total fT4 test, is believed to more accurately represent thyroid hormone functional levels.

b. False

“The fT4 test—as opposed to the total T4 test, is believed to more accurately represent thyroid hormone functional levels.”

8. The free T3 (fT3) test is commonly used to aid in the diagnosis of ______and to monitor treatment.

d. hyperthyroidism

“The free T3 (fT3) test is commonly used to aid in the diagnosis of hyperthyroidism and to monitor treatment.”

9. Elevated free T3 (fT3) levels are seen in

c. T3 toxicosis.

“Elevated fT3 levels are seen in: Hyperthyroidism; T3 toxicosis; High altitudes.”

10. Depressed free T3 (fT3) levels are seen in

c. 3rd trimester of pregnancy.

49 nursece4less.com nursece4less.com nursece4less.com nursece4less.com “Depressed fT3 levels are seen in: Primary or secondary hypothyroidism; 3rd trimester of pregnancy; Deiodinase deficiency or insufficiency.”

11. The thyroglobulin test is used primarily

a. as a tumor marker to monitor thyroid cancer treatment.

“The thyroglobulin test is used primarily as a tumor marker to follow the effectiveness of thyroid cancer treatment, primarily the well-differentiated thyroid cancers, and to monitor disease- free progression.”

12. True or False: Clinicians often do not rely on a full thyroid blood screen to diagnose a thyroid condition.

a. True

“Clinicians often do not rely on a full thyroid blood screen to diagnose a thyroid condition.”

13. Tests that measure thyroid function are important because they inform clinicians

c. how each person responds to thyroid hormone imbalances.

“The human body depends on thyroid hormones to function at an optimal healthy state. Because no test can fully measure how thyroid hormone is utilized once it enters the bloodstream, it is important for clinicians to understand the varied tests and measures that inform how each unique individual responds to thyroid hormone imbalances.”

14. Depressed levels of thyroglobulin may be seen with

b. thyrotoxicosis factitia.

“Depressed levels of thyroglobulin may be seen with: Thyrotoxicosis factitia; Newborns and infants with goiter and hypothyroidism.”

15. Thyroglobulin levels are NOT used to

50 nursece4less.com nursece4less.com nursece4less.com nursece4less.com

a. diagnose thyroid cancer.

“The thyroglobulin test is used primarily as a tumor marker to follow the effectiveness of thyroid cancer treatment, primarily the well-differentiated thyroid cancers, and to monitor disease- free progression. Other reasons for testing for thyroglobulin are to monitor the treatment of Graves’ disease. Rarely, it may be used to try and determine the underlying cause of congenital hypothyroidism or to help differentiate between subacute thyroiditis and thyrotoxicosis factitia.”

16. ______binding globulin is the main serum carrier protein for T4.

a. Thyroxine

“Often confused with thyroglobulin, thyroxine binding globulin is the main serum carrier protein for T4.”

17. True or False: The thyroglobulin test may be used to monitor the treatment of Graves’ disease.

a. True

“The thyroglobulin test is used … for testing for thyroglobulin are to monitor the treatment of Graves’ disease.”

18. Triiodothyrodine Uptake (T3U) is an indirect measurement of the amount of unsaturated ______available.

b. Thyroxine-Binding Globulin (TBG)

“Triiodothyrodine Uptake (T3U): This test is an indirect measurement of the amount of unsaturated TBG available and is inversely proportional to the TBG levels.”

19. The ______test is usually done along with the T4 test, resulting in the calculated “T7” test.

a. triiodothyrodine uptake (T3U)

51 nursece4less.com nursece4less.com nursece4less.com nursece4less.com

“[Triiodothyrodine Uptake (T3U)] test is usually done along with the T4 test (resulting in the calculated “T7” test).”

20. Free Thyroxine Index (FTI) is also known as

a. T7.

“T7 is also known as the Free Thyroxine Index (FTI)….”

21. The Free Thyroxine Index (FTI) can give a clearer picture of thyroid function in

a. suspected hypothyroidism and hyperthyroidism. b. in patients who are pregnant. c. in patients with suspected abnormalities in TBG levels. d. All of the above [correct answer]

“The FTI can give a clearer picture of the totality of thyroid function in both suspected hypothyroidism and hyperthyroidism as well in patients who are pregnant or with suspected abnormalities in TBG levels.”

22. True or False: The measurement of Triiodothyrodine Uptake (T3U) is inversely proportional to the Thyroxine- Binding Globulin (TBG) levels.

a. True

“Triiodothyrodine Uptake (T3U): This test is an indirect measurement of the amount of unsaturated TBG available and is inversely proportional to the TBG levels.”

23. Decreased T3U levels occur

d. in a normal pregnancy.

“Decreased T3U levels occur in a normal pregnancy, with a variety of drugs such as estrogens, methadone and heparin. Increased T3U levels can occur with heparin, salicylates and anabolic steroids.”

52 nursece4less.com nursece4less.com nursece4less.com nursece4less.com

24. One of the primary ways of diagnosing autoimmune thyroid disease is by testing for

c. antibodies.

“One of the primary ways of diagnosing autoimmune thyroid disease is by testing for antibodies.”

25. Stimulating antibodies (TSI) promotes thyroid hormone production leading to

a. hyperthyroidism.

“Stimulating antibodies (TSI) promote thyroid hormone production leading to hyperthyroidism while inhibiting antibodies (TBII) inhibit production and lead to hypothyroidism, though this is not routinely tested for.”

26. Elevated levels of antibodies, such as TSH-RAb, are predictors of

c. fetal and neonatal thyrotoxicosis.

“Antibodies to TSH should be assessed particularly in euthyroid and thyroid hormone treated pregnant women or those with a history of hyperthyroidism as these antibodies are predictors of fetal and neonatal thyrotoxicosis.”

27. True or False: Inhibiting antibodies (TBII) inhibit production of thyroid hormones and lead to hypothyroidism, and this is routinely tested for.

b. False

“Stimulating antibodies (TSI) promote thyroid hormone production leading to hyperthyroidism while inhibiting antibodies (TBII) inhibit production and lead to hypothyroidism, though this is not routinely tested for.”

53 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 28. The first thyroid imaging thyroid scan done with a Radioactive Iodine Uptake test (RAIU) is performed ______after ingesting the radiotracer.

a. two hours

“The Radioactive Iodine Uptake test (RAIU) is a direct measurement of the ability of the thyroid gland to concentrate inorganic iodine. The test measures the rate of accumulation, incorporation and release of iodine. In order to minimize exposure to the patient, this test is often done in conjunction with thyroid imaging such as scintigraphy (thyroid scan). The patient may be asked to use a low-iodine diet for 7-10 days before the test and may be asked to fast. The first scan is usually done at two hours, then 4-6 hours after ingesting the radiotracer (either 123I or 131I), with a second scan within 24 hours.”

29. With the Radioactive Iodine Uptake test (RAIU), which of the following is diagnostic of thyroid disease?

a. Increased uptake b. Decreased uptake c. Increased uptake with thyroid imaging d. None of the above [correct answer]

“Increased uptake is associated with hyperthyroidism. Decreased uptake is associated with hypothyroidism. Neither is diagnostic and may be affected by malabsorption, diarrhea, rapid diuresis and renal insufficiency…. The radioactive iodine uptake test (RAIU), also known as a thyroid uptake test, is a measurement of thyroid function, and does not involve imaging.”

30. Testing calcitonin, which is produced by the parafollicular or C cells of the parathyroid gland, may be used to diagnose

d. medullary thyroid cancer.

“Calcitonin, produced by the parafollicular or C cells of the parathyroid gland may be used to diagnose medullary thyroid cancer.”

54 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 31. The American Academy of Family Physicians recommends that all patients over the age of ___ should be screened for thyroid disease.

a. 60

“The American Academy of Family Physicians recommends that all patients over the age of 60 should be screened [for thyroid disease].”

32. True or False: The Radioactive Iodine Uptake test (RAIU) is a direct measurement of the ability of the thyroid gland to concentrate inorganic iodine.

a. True

“The Radioactive Iodine Uptake test (RAIU) is a direct measurement of the ability of the thyroid gland to concentrate inorganic iodine.”

33. Thyroid imaging utilizes I-123 or I-131 (and sometimes Technetium pertechnetate-99m) to visualize and evaluate the size, position, function and the presence of

b. “hot” or “cold” spots in the thyroid.

“Thyroid imaging utilizes I-123 or I-131 (and sometimes Technetium pertechnetate-99m) to visualize and evaluate the size, position, function and the presence of “hot” or “cold” spots in the thyroid. The radioactive iodine uptake test (RAIU), also known as a thyroid uptake test, is a measurement of thyroid function, and does not involve imaging.”

34. Thyroid imaging “hot” spots, indicating increased uptake of iodine, are generally a sign of

c. non-malignancy.

“‘Hot’ spots, indicating increased uptake of iodine are generally non-malignant while “cold” spots generally need further evaluation, with a greater possibility that these represent malignancies.”

55 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 35. Genetic markers and gene panels are becoming more widely used in assessing the potential for

a. malignant thyroid tumors.

“Genetic markers and gene panels are becoming more widely used in assessing the potential for malignant thyroid tumors.”

References Section

The References below include published works and in-text citations of published works that are intended as helpful material for your further reading.

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