Thyroid Part II Lecture Notes PDF

THYROID PART II Brad Case, ND, DC Endocrine System NM7356-CA Bastyr University—San Diego  2 HYPERTHYROIDISM Graves’ Disease (Diffuse toxic goiter) Non-Graves’ Hyperthyroidism  3 Thyrotoxicosi...

THYROID PART II Brad Case, ND, DC Endocrine System NM7356-CA Bastyr University—San Diego  2 HYPERTHYROIDISM Graves’ Disease (Diffuse toxic goiter) Non-Graves’ Hyperthyroidism  3 Thyrotoxicosis The clinical syndrome that results when tissues are exposed to high levels of thyroid hormone—results in accelerated metabolism Usually due to hyperthyroidism, with causes including: Graves’ disease (Diffuse toxic goiter) Toxic thyroid adenoma Plummer’s Disease (Toxic multinodular goiter) TSH-secreting pituitary tumor (secondary hyperthyroid) May also be due to an excessive amount of exogenous thyroid hormone or iodine In rare cases, an ovarian tumor (teratoma) secretes high amounts of thyroid hormone, called “struma ovarii”  4 GRAVES’ DISEASE AKA: Diffuse Toxic Goiter  5 Graves’ Disease Dr. Robert Graves Diffuse Toxic Goiter: 1796-1853 The most common form of thyrotoxicosis/hyperthyroidism Five times more common in women than men Peak incidence 20—40 yrs old (but can occur at any age) Strong familial predisposition—15% have close relative with the disease; 50% of relatives have circulating antibodies Environmental triggers include: stress, tobacco, infection, iodine exposure, and postpartum state  6 Graves’ Disease Diffuse Toxic Goiter: The syndrome consists of one or more of the following: Thyrotoxicosis—high serum levels of T3 and T4 Diffuse (i.e., bilateral and non-nodular) goiter Ophthalmopathy—exophthalmos/proptosis Thyroid Dermopathy/pre-tibial myxedema  7 Diffuse Goiter  8 Physical Exam The thyroid in Graves’ disease will palpate as symmetrically enlarged, smooth, and rubbery in consistency Bruits may be heard or a thrill may be palpable over the gland  9 Graves’ Disease—Pathogenesis Autoantibodies: T-lymphocytes become sensitized to antigens in the thyroid gland and stimulate B-lymphocytes to create antibodies (Abs) to these antigens The main Ab in Graves’ is called Thyroid Stimulating Ab (TSAb) or Thyroid Stimulating Immunoglobulin (TSI) These autoantibodies bind to the TSH receptor and mimic the action of TSH → persistent stimulation of the thyroid and elevated levels of thyroid hormones, as well as thyroid growth, i.e., goiter Other factors in the pathogenesis include interferon alfa, viral or bacterial infections, psychological stress  10 Graves’ Disease—Pathogenesis Thyroid-Related Ophthalmopathy/Exophthalmus: There is a common antigen that is found in the TSH receptor, thyroid tissue, orbital fibroblasts, and extraocular muscles Cytokines from cytotoxic T-lymphocytes and cytotoxic antibodies cause activation and proliferation of orbital fibroblasts and pre-adipocytes This results in more retro-orbital fat and glycosaminoglycans and also swollen extraocular muscles The result is, proptosis (protrusion of the eyes), diplopia, redness, congestion, and conjunctival and periorbital edema Cigarette smoking is a potent risk factor for this aspect of the syndrome 11  12 Graves’ Disease—Ophthalmopathy 13 14  15 Graves’ Disease—Pathogenesis Thyroid hormones cause an increase in the number of membrane-bound β-adrenergic receptors in various tissues; thyrotoxicosis increases this number further So, many of the symptoms of hyperthyroidism are those suggestive of an increased catecholamine response, namely: Tachycardia Tremor Sweating Stare—excessive eyelid retraction Lid lag—the upper eyelid is higher than normal when the globe is in downgaze  16 Graves’ Disease—Clinical Features Signs and Symptoms: Children—rapid growth with accelerated bone maturation Young adults—palpitations, nervousness, easy fatiguability, hyperkinesia, diarrhea, excessive sweating, intolerance to heat/preference for cold, marked weight loss without loss of appetite, thyroid enlargement, thyrotoxic eye signs, mild tachycardia, muscle weakness, and loss of muscle mass Over 60—palpitations, dyspnea on exertion, tremor, nervousness, and weight loss  17 Graves’ Disease—Clinical Features Other Signs and Symptoms: Thyroid dermopathy aka pre-tibial myxedema— thickening of the skin, especially over the lower tibia d/t accumulation of glycosaminoglycans; has a peau d’orange surface and cannot be picked up between the fingers; may extend to the feet Thyroid acropachy (thick extremity)—subperiosteal bone formation and swelling, especially in the metacarpals, and clubbing of the digits Onycholysis—separation of the fingernails from their beds, likely d/t rapid growth of the nails  18 Pre-tibial Myxedema/Dermopathy 19 20  21 Graves’ Disease—Labs fT4—high fT3—high TSH—low TSAb/TSI—high (fairly specific to Graves’) Anti-TPO—may be high (also high in Hashimoto’s) Anti-TG—may be high (also high in Hashimoto’s) CBC may show: Anemia—IDA, pernicious, autoimmune hemolytic, normocytic/normochromic… Low-normal or slightly depressed WBCs Relative lymphocytosis and monocytosis—d/t autoimmune factors Low-normal or slightly depressed platelets SHBG may be high → low free testosterone Diabetic pts may see increased HbA1c Lipid panel may show low cholesterol and triglyceride levels  22 Differential Diagnoses Differentials and Variations: T3 Thyrotoxicosis—5% of Graves’ pts have normal fT4 but high T3 Subclinical hyperthyroidism (very mild/early Graves’)—the TSH is low, but the fT4 and T3 levels remain barely in the normal range Secondary hyperthyroidism, i.e., TSH-secreting pituitary tumor— pts have high TSH, high T3, high fT4, and elevated RAIU Sick Euthyroid Syndrome—pts are severely, systemically ill (non- thyroid); cytokines affect the hypothalamus and pituitary, thus decreasing TRH and TSH production; pts have low TSH, but also low fT4 and T3  23 Graves' Disease—Imaging CT or MRI—extraocular muscle enlargement is seen in most pts with Graves’ Radioactive Iodine Uptake (RAIU)—diffuse, increased uptake https://radiopaedia.org/cases/thyroid- associated-orbitopathy-5?lang=us  24 Radioactive Iodine Uptake (RAIU) Diffuse Toxic Goiter  25 Graves’—Complications Thyrotoxic Crisis (aka Thyroid Storm): Most commonly occurs after surgery, radioactive iodine therapy, or parturition in a pt with hyperthyroidism; or during severe, stressful illness, e.g., uncontrolled diabetes, trauma, acute infections, severe drug reaction, or MI Marked hypermetabolism and excessive adrenergic responses are the hallmarks Recent detailed studies show that total T3 and T4 levels are usually not elevated more than before the storm (no increased synthesis/release), though there may be more free T3 and T4 due to decreased binding to TBG In pts with thyrotoxicosis, there are more β-adrenergic binding sites for catecholamines, so the response to stress is greatly exaggerated So, we have more adrenergic binding sites, increased catecholamines, and increased fT3 and fT4 with very low TSH  26 Graves’—Complications Thyrotoxic Crisis (aka Thyroid Storm) Signs and Symptoms: Fever of 100.4º—105.8º F with flushing and sweating; hyperpyrexia is out of proportion to other findings CV—Marked tachycardia, atrial fibrillation, and high pulse pressure; heart failure can also occur Heart failure and shock can lead to death CNS—Marked agitation, restlessness, delirium, coma GI—Nausea, vomiting, diarrhea, jaundice Clinical diagnosis; labs are usually not run  27 Graves’—Complications Thyrotoxic Crisis (aka Thyroid Storm) Treatment of thyroid storm includes the following: Supportive measures Antiadrenergic drugs—e.g., beta blockers, etc. Thionamides—methimazol and propylthiouracil (PTU) Iodine preparations Glucocorticoids Bile acid sequestrants—e.g., cholestyramine Treatment of the underlying condition Rarely plasmapheresis Blood is removed and circulated through a machine that separates it into red cells, white cells, platelets, and plasma. The plasma is then discarded and replaced with an albumin solution.  28 Graves’—Treatment Conventional: Antithyroid Drugs: (Have Immunosuppressive Effects) Methimazole (Tapazole) Inhibits TPO-mediated iodination of TG to form T4 and T3 Most useful in young pts with small glands and mild disease Start with 10—20 mg/d (in the a.m.) for 1—2 months Then, reduce the dose to 5—10 mg/d for maintenance The pt takes for 1—2 yrs, then it is tapered or discontinued 20—50% of pts go into remission (may not be lifelong) Methimazole has fewer adverse reactions and a longer duration of action than PTU, so it is usually the drug of choice; however, it may be teratogenic, so PTU is used in pregnancy and for lactating mothers  29 Graves’—Treatment Conventional: Antithyroid Drugs: Propylthiouracil (PTU) Has the potential for severe or fatal hepatotoxicity Can also cause vasculitis However, it may be preferred for pregnant women in their first trimester d/t the potential teratogenicity of methimazole Also preferred in the case of methimazole allergy Initial dose: 100 mg every 8 hours; taken for 4—8 weeks Then, reduce the dosage to 50—200 mg once or twice per day Typically, the pt is on the drug for 1—2 yrs, then it is tapered or discontinued  30 Graves’—Treatment Conventional: Antithyroid Drugs: Response to treatment & titration of drugs: Serum fT4 and T3 should be used to monitor pt response/adjust doses TSH often remains suppressed for weeks or months after beginning care, so it should not be used as an index of thyroid function early in the course of treatment TSAbs—ideally, these will no longer be detectable at the end of the course of therapy The thyroid gland may also return to normal size All pts should be monitored for life  31 Graves’—Treatment Conventional: Antithyroid Drugs: Adverse Reactions: Pruritic rash (5% of pts)—can be managed with antihistamines Agranulocytosis (0.5%)— requires discontinuation of drug and antibiotics; presents as severe sore throat and fever https://www.cureus.com/articles/84653- Cholestatic jaundice and acute propylthiouracil-induced-skin-vasculitis arthritis are rare side effects  32 Graves’—Treatment Conventional: Radioactive Iodine I is the preferred treatment in the US for most pts >21 y.o. 131 (unless the pt has severe eye symptoms) 1 dose, taken orally (capsule) Gland shrinks and pt becomes euthyroid in 2—6 months >80% go on to become hypothyroid w/in 6—12 months Monitor fT4 and TSH every 6—8 weeks When hypothyroidism develops, pt should be prescribed levothyroxine (or DTE); pts remain on this drug for life Start with 50—200 mcg/d Long-term follow up studies indicate that radioactive iodine does not appear to cause infertility, birth defects, or cancer later in life  33 Graves’—Treatment Conventional: Radioactive Iodine Elderly pts, those with underlying heart conditions, or other medical problems including severe thyrotoxicosis or very large glands should be treated with methimazole first to make them euthyroid prior to administration of radioactive iodine Radioactive iodine is contraindicated in those with severe eye disease Pts with mild to moderate eye disease are given prednisone (0.4 mg/kg/d) for 1—2 months following the radio-iodine treatment to prevent worsening of the eye symptoms  34 Graves’—Treatment Conventional: Surgical Treatment: Thyroidectomy (total or near total) 1st choice for those with very large glands, pts who are non- compliant, those who are pregnant, or who have allergies or other contraindications to iodine or drug therapy Also used for multinodular goiters or malignant nodules Causes pt to become hypothyroid → levothyroxine (or DTE) for life Causes hypoparathyroidism in ~1% May damage recurrent laryngeal nerve → hoarseness Pt is prepared with antithyroid drugs until euthyroid (~6 weeks); to prevent thyroid storm For the 2 weeks prior to Sx, pt is given potassium iodide (5 drops bid) to diminish vascularity of the gland, which decreases intraoperative blood loss  35 Graves’—Treatment Conventional: Other Medical Measures: β-adrenergic-blocking agents E.g., Propranolol (10—40 mg every 6 hours), Inderal LA, nadolol, atenolol, metoprolol Used in acute phase of thyrotoxicosis to control adrenergic symptoms such as tachycardia, hypertension, and atrial fibrillation Gradually withdrawn as other therapies lower thyroid hormone levels to normal Cholestyramine (4 g orally tid) binds to T4 in the gut and may be used in severe cases  36 Graves’—Treatment Naturopathic: Reduce risk factors like stress and smoking; increase rest Diet—frequent meals high in calories and protein Anti-thyroid foods: Raw Brassicas and other goitrogens—turnips, cabbage, rutabagas, mustard, rapeseeds, cassava root, peanuts, pine nuts, millet, and soy Must also restrict iodine intake, e.g., iodized salt, kelp, seafood Indole-3-carbinol (200—600 mg/d)—constituent of Brassicas L-Carnitine (2—4 g/d)—antagonist of thyroid hormone in peripheral tissues—prevents its entry into nuclei; good choice for pregnant or lactating pts, as well as pts with liver damage or those who can’t use anti-thyroid medications Contraindicated in hypothyroidism  37 Graves’—Treatment Naturopathic: 4 Ls + L-Carnitine Botanicals: Lycopus spp.—blocks TSH receptors and blocks peripheral conversion of T4 to T3—5 mL tid (100 mL max/week) Leonurus cardiaca—inhibits TSH; reduces thyroid hormone production; cardiac tonic; hypotensive, nervine Lithospermum officinale—blocks TSH receptors Lemonbalm (Melissa officinalis)—blocks TSH receptors—2—6 mL tid Nervines: Valariana officinalis, Scutellaria lateriflora Cactus grandiflorus—heart tonic for rapid pulse Iris versicolor—reduces swelling (goiter) Eleutherococcus senticosus—5 mL/d Vitex agnus-castus—3 mL/d  38 Graves’—Treatment Iodine: In large doses, iodine temporarily reduces thyrotoxicosis symptoms by stopping hormone synthesis (called the Wolff-Chaikoff effect) The thyroid may remain suppressed or it may resume hormone synthesis at a reduced or increased rate (escape from Wolff- Chaikoff) In a euthyroid pt., it can cause hyperthyroidism (Jod-Basedow phenomenon) In other words, other than the initial suppression of thyroid function, its effects are unpredictable Fucus spp. is high in iodine; use with caution  39 Graves’—Prognosis If treated with anti-thyroid drugs—expect a course of remissions and exacerbations; 25% eventually become hypothyroid due to autoimmune thyroid destruction, termed “burned out Graves’ disease” If the gland is destroyed through surgery or radioactive iodine, the pt will remain hypothyroid for life, which is easier and safer to manage than hyperthyroidism All pts require monitoring of TSH & thyroid hormones for life  40 NON-GRAVES’ HYPERTHYROIDISM Toxic Adenoma Toxic Multinodular Goiter (Plummer’s Disease) Amiodarone-Induced Thyrotoxicosis  41 Toxic Adenoma A functioning thyroid adenoma that hypersecretes T3 and T4; causes hyperthyroidism Usually benign follicular adenomas; almost never malignant Nodules start small and grow slowly Autonomously functioning, i.e., the adenoma does not need TSH stimulation The excess T3 and T4 suppresses TSH secretion; results in reduced function and atrophy of the contralateral (normal) lobe  42 Toxic Adenoma Signs & Symptoms: Similar to that of Graves’, but there is no ophthalmopathy Physical Exam: A large nodule is noted on one side and almost no thyroid tissue is found on the other side  43 Toxic Adenoma Labs/Imaging: TSH—low T3—high fT4—borderline elevation RAIU Scan—hot nodule on one side; diminished or absent function of the other side Treatment: Radioactive iodine—generally effective; spares the contralateral lobe; pt remains euthyroid Surgery—if the nodule is very large and causing obstructive symptoms such as dysphagia or difficulty breathing Medications are only used prior to Sx or radiotherapy because, unlike w/Graves’, remissions do not occur  44 Toxic Multinodular Goiter (Plummer’s Disease) Usually begins with a euthyroid multinodular goiter— Dr. Henry Plummer in older pts with longstanding disease, the goiter 1874-1936 becomes toxic Nodules may become active following treatment with iodine or iodine-containing drugs (Jod-Basedow phenomenon) Signs/Symptoms: Presents with tachycardia, arrhythmia, heart failure, wt loss, nervousness, weakness, tremors, sweats Physical exam: Multinodular goiter—may be small or large—may extend substernally  45 Toxic Multinodular Goiter (Plummer’s Disease) Labs/Imaging: TSH—low T3—high T4—moderately high RAIU Scan—high uptake in nodules/irregular patchy distribution Treatment: Treated with anti-thyroid drugs and/or radioiodine therapy; surgery is considered if pt is a good candidate  46 Radioactive Iodine Uptake (RAIU)  47 Amiodarone-Induced Thyrotoxicosis Amiodarone—an antiarrhythmic drug that contains iodine It is stored in the fat, myocardium, liver, and lung 2% of pts treated with the drug develop amiodarone-induced thyrotoxicosis Type 1—due to the excess iodine—usually occurs within 6—12 months of starting the drug; blood flow is increased on Doppler ultrasound; treated with methimazole and beta blockers Type 2—the result of thyroiditis—usually results after taking the drug for 2—3 years; blood flow is decreased on Doppler ultrasound; treated with prednisone 48  49 Thyroid and Labs Subclinical Primary Primary Hypothyroidism Hyperthyroidism Hypothyroidism TSH    T4 N   T3 N   50 References Greenspan's Basic & Clinical Endocrinology Textbook of Natural Medicine, 4th edition, by Pizzorno and Murray Fundamentals of Naturopathic Endocrinology by Michael Friedman, ND The 5-Minute Clinical Consult 2017, 25th Edition, by Frank Domino Nutritional Medicine, by Alan Gaby, MD Lippincott’s Pharmacology, 5th Edition, by Richard Harvey Endocrine Handbook, by Henry Harrower, MD Practice guidelines and classifications GARD - NIH Databases UpToDate DynaMed Plus BMJ Best Practice