Tips For Taming Thyroid Disorders in Primary Care

Tips For Taming Thyroid Disorders in Primary Care Christine Kessler MN, ANP-BC, CNS, BC-ADM, CDTC, FAANP Metabolic Medicine Associates King George, Virginia Co-chair: Metabolic & Endocrine Disease Summit (MEDS) Objectives: At the conclusion of this session, the participant will be able to: 1. Discuss pertinent physical assessment and laboratory diagnostic studies to aid in diagnosis of clinical and subclinical hyperthyroidism and hypothyroidism 2. Develop strategies to safely initiate, titrate, monitor and maintain ATD & THR therapy in adults. 3. Address controversies surrounding medical management of subclinical (and overt) hyperthyroidism and hypothyroidism in adults My Disclosure Reminder: What Can Go Wrong With Thyroid Hypothyroidism Hyperthyroidism Thyroid nodules/cancer TSH Free T4 T3 TRAb Levothyroxine dosing Desiccated thyroid use Anti-thyroid drug dosing The problem can be Intrinsic (PRIMARY): thyroid TPO Abs Beta blocker use When to refer Extrinsic (SECONDARY): H-P (brain) disorders Or dietary/ medication/ acute illness problems 1

When to Should Check Thyroid Function Over the age of 60 Personal or family hx of autoimmune disease Type 1 DM, psoriasis, lupus, RA, pernicious anemia, Celiac Dz, Addisons s, Sarcoidosis, Scleroderma, etc New onset atrial fibrillation or CHF Difficult to treat dyslipidemia New onset anxiety or depression Fertility issues In presence of notable S&S of thyroid disease Amiodarone use Pre-pregnancy or pregnancy in higher risk patients Case 1: Louise 43 y/o seen for annual physical. No complaints or untoward symptoms except for heavy menstrual periods. EXAM: benign LABS: Mild Microcytic anemia, normal Chem & lipids TSH: 0.09 mu/l (0.4-4.5) FT4: 2.1 ng/dl (0.8-1.8) FT3: 192 (60-180) Subsequent TRAb is slightly positive Differential Diagnosis for Louise Graves Thyroiditis Something else? REVIEW: Hypothalamic-Pituitary-Thyroid Axis Hypothalamus TRH FT4 & T3 What messes this up? Hypothalamus TRH FT4 & T3 Pituitary Pituitary 9-10x more T4 than T3 produced T4 is highly protein bound (>90%) (TBG, SBG, albumin etc) Unbound T4 is FT4 Most T3 from FT4 60% T4 converts to T3, 20% to reverse T3, Rest to gut T4 TSH Thyroid Gland FT4 T3 Liver T3 is 4-5x more metabolically active: Heart Liver Bone CNS Adapted from Merck Manual of Medical Information. ed. R Berkow. 704:1997. 9-10x more T4 than T3 produced T4 is highly protein bound (>90%) (TBG, SBG, albumin etc) Unbound T4 is FT4 Most T3 from FT4 60% T4 converts to T3, 20% to reverse T3, Rest to gut T4 TSH Thyroid Gland FT4 T3 Liver T3 is 4-5x more metabolically active: Heart Liver Bone CNS Adapted from Merck Manual of Medical Information. ed. R Berkow. 704:1997. 2

Primary Tests of Thyroid Function TSH Free T4 Total T3 or Free T3 Thyroid antibodies Thyroid scanning/ultrasound Thyroid Testing Pointers TSH (0.4-4.5 or 0.3-3.0 uu/ml or?) Higher normal in elderly (uncertain level 6.5+?) LOWER normal in black population? (1.2 vs 1.8 ave) Best test for screening for thyroid dysfunction Inverse to T4 Log/linear response w/ FT4 A 2-fold change in FT4 produces a 100-fold change in TSH Don t use TSH alone for diagnosis! Changes slowly in response to Rx; (6-8 weeks, may take up to 12 weeks in elderly) TSH Accuracy Affected By: Age-dependent increase in women >45 (not as much in men).antibody connection? Less reliable during first 2 months of thyroid replacement therapy Pregnancy: 1 st trimester decreases; then increases (inverse HCG) Critical illness Numerous drugs: Dopamine, steroids, amiodarone decreased Amiodarone, heroin, lithium increased Thyroid Testing FT4 (0.7-1.9 ng/dl) Indications: In conjunction w/ TSH for DX hyperthyroidism or hypothyroidism. Monitoring response to therapy changes faster than TSH. FT3 /T3 FT3 less accurate than T3 in detecting T3 levels in the low range use T3 USED primarily in hyperthyroid states (T3 thyrotoxicosis Used if abnormal TSH + normal FT4 in hyperthyroidism (not hypothyroidism) Clinical Practice Guidelines for Hypothyroidism in Adults: AACE and ATA 2012 Thyroid Testing FT4 (0.7-1.9 ng/dl) Indications: In conjunction w/ TSH for DX hyperthyroidism or hypothyroidism. Monitoring response to therapy changes faster than TSH. FT3 /T3 FT3 less accurate than T3 in detecting T3 levels in the low range use T3 USED primarily in hyperthyroid states (T3 thyrotoxicosis Used if abnormal TSH + normal FT4 in hyperthyroidism (not hypothyroidism) Clinical Practice Guidelines for Hypothyroidism in Adults: AACE and ATA 2012 3

Therapy Monitoring Clinical and laboratory evaluations should be performed At 6- to 8-week intervals while titrating Every 2 to 3 weeks in severely hyper-/hypothyroid states (the FT4 is most helpful here) Annually once a euthyroid state is established ENDOCRINE PRACTICE Vol 17 No. 3 May/June 2011 Typical Thyroid Hormone Levels in Thyroid Disease TSH FT 4 T 3 Hypothyroidism High Low Low Subclinical High Normal Normal Hyperthyroidism Low High High Subclinical Low Normal Normal When FT4 and TSH Seem Discordant Usually means early or subclinical disease Often occurs soon after initiating a therapy that changes thyroid function (e.g. starting L-thyroxine or starting anti-thyroid meds); or patient not taking meds correctly FT4 will change before TSH I presents with this a sign of Pituitary or Hypothalamic dysfunction (central hypo or hyperthyroidism) -Refer Common Adjunctive Tests Antibodies: (Anti -TPO): For diagnosis of autoimmune hypothyroidism (Hashimoto s thyroiditis) Thyroid Receptor Antibodies (TRAb): For diagnosis of autoimmune hyperthryoidism (Graves dz) TSI- Thyrotropin stimulating immunoglobulin TBII- Thyrotropin binding inhibitory immunoglobulin Thyroglobulin (Tg): cancer marker post thyroidectomy REMBEMBER that she Is asymptomatic Has: Low TSH High FT4 Positive TRAbs Thoughts? Questions? So what about Louise? 4

More Thyroid Tests Thyroid Uptake/Scan Thyroid Ultrasound: assess thyroid nodules, goiter Thyroid Uptake/scanning How rapidly labeled iodine is gets into thyroid travels to functioning parts of thyroid Assesses for Thyroiditis (low uptake) Graves (increased uptake, when other signs lacking) Looking for hot/cold nodules Percent uptake to prepare for I-131 (Rx for hyperthyroidism) Graves Dz Toxic nodules Clinicalgate.com Associated With Elevated Radioiodine Uptake Graves disease Toxic Adenoma/Nodule Toxic MNG Thyroid Uptake Associated With Depressed Radioiodine Uptake Thyroiditis acute subacute Painless Post-partum Hashitoxicosis Iodine ingestion CASE 2: Agitated Angie 38 y/o Angie comes to see you after an ER visit for palpitations, vague neuralgias and a panic attack. She was given a anxiolytic, told to stop drinking caffeine and see her doctor She is still symptomatic & you learn she has been amenorrhic for 5 months, and has troubling insomnia EXAM: HR 110 reg; BP 146/82 Appears anxious; has mild tremor Symmetrically enlarged thyroid gland, non-tender What do you suspect? Fisher, J South Med J 2002 5

Hyperthyroidism Excess synthesis and secretion of thyroid hormones resulting in accelerated metabolism in peripheral tissues Subclinical cases up to 6%, more in >65 yrs Incidence ranges from 1.9% to 2.7% in women (0.2% pregnancies) 0.16% to 0.23% in men Bahn Chair RS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011;21:593 646 LABS: CBC; Chem normal TSH: 0.01 (0.4-4.5) Free T4: 2.9 (0.8-1.80 T3: 199 (60-180) TRAB positive CASE 2: Here are Angie s Labs Clinical Signs & Symptoms of Hyperthyroidism A Word About Graves Disease (Toxic Diffuse Goiter) Tremor Palpitations Proximal (pelvic girdle) weakness Menstrual/fertility disturbances Irritability & anxiety Insomnia Fatigue Increased BP & resting HR Hyperreflexia Increased perspiration Increased defecation Exertional shortness of breath Headache Unintentional weight loss Heat intolerance Hyperactivity Moist, smooth, warm skin Appetite change The most common cause of hyperthyroidism Accounts for 60% to 90% of cases Affects females >males Affects Blacks more than other ethnic groups Also higher in Asians Graves disease is an autoimmune disorder Labs: TRAb positive (TSI or TBII) up to 95% anti-tpo is positive in 45-85% Thyroid 2016; 7:980-986 More Signs of Grave s Disease Exophthalmos Smooth symmetrical goiter Proximal muscle weakness Orbitopathy Pretibial myxedema Lifting of nailbeds Yellowish skin (autoimmune finding) Braverman LE, Utiger RD. In: Werner and Ingbar s The Thyroid, 7th ed. 1996:522. EOM--Cranial nerve palsy 6

Onycholysis Signs & Symptoms of Hyperthyroidism in Elderly Subtle symptoms (apathetic thyrotoxicosis) Depression Tremor SVT, Atrial fibrillation Proximal muscle weakness Increased osteopenia & Hip fracture risk? Aggarwal N, Razvi S. Thyroid and aging or the aging thyroid? An evidence-based analysis of the literature. J Thyroid Res. 2013. DOI.org/10.1155/2013/481287 Priorities in Treatment Non selective beta blockers: (1 st thing to do if symptomatic/ HR> 90): atenolol or metoprolol (in pregnancy propranolol, metoprolol, sotolol, labetatol ok) Blocks T4-T3 conversion! Then ATD Decrease synthesis of thyroid hormones, PTU decreases conversion of T4 to T3, however methimazole preferred over PTU due to rare hepatotoxicity Permanent remission in 40-50% of treated Graves dz patients (12-18 months) Prolonged ATD use in toxic nodular goiter Or RAI or Thyroidectomy endocrine referral Antithyroid Drugs Thionamides Methimazole (Tapazole) preferred except in the first trimester of pregnacy 5-15 mg bid typical dose (max 30 mg bid) Propylthiouracil (PTU) avoid use except in 1 st trimester of pregnancy secondary to rare but serious hepatotoxicity 100-150 mg q 8 hrs typical dose (max 900 mg/day) ~30-40% achieve long lasting remission off meds 86% of Grave s disease patients relapsed within 4 years if the TRAb was still elevated (> 2.0mU/L) at the end of thionamide therapy. Nyo Nyo Tun, et al. Predicting Risk of Recurrent Thyrotoxicosis Following Thionamide Withdrawal in Graves Disease. ENDO 2016, OR33-6, Boston, MA Treatment of Graves and Toxic Nodular Disease Antithyroid Drugs Advantages Nonablative Hypothyroidism Low Frequency Other Problems Not definitive, Side-effects Radioiodine Definitive 100% Fear, thyroiditis ++ Surgery Definitive 100% Complications Discomfort Fisher, J South Med J 2002 Cost + +++ Angie was started on methimazole 3 wks ago Current labs: TSH: 0.09 (low); FT4: 0.6 (low); T3: 55 (low) so TSH still low; FT4 and T3 are lower What is the most appropriate medication adjustment? 1. Increase Methimazole 2. Decrease Methimazole 3. Keep current dose 4. Change to PTU 7

When to worry & what to do Resting tachycardia >100 (older/frail; >/= 120 (younger) Profound diaphoresis Hyper-defecation Beta blocker.if HR elevated--get them to ER!! What About Subclinical Hyperthyroidism? Usually asymptomatic 1 Low or undetectable serum TSH 1 Normal or borderline high serum FT 4 and FT 3 1 Variable prevalence (0.7% to 6.0%) 2 More common in women 3 More common in older people (>65) than overt hyperthyroidism 4 Most common cause is overtreatment with L-thyroxine 1. Ross DS. Mayo Clin Proc. 1988;63:1223. 2. Ross DS. In: Werner and Ingbar s The Thyroid, 7th ed. 1996:1016. 3. Sawin CT. Adv Intern Med. 1991;37:223. 4. Sawin CT et al. N Engl J Med. 1994;331:1249. Subclinical Hyperthyroidism Do you treat? Treatment of subclinical hyperthyroidism Yes, maybe, and no Monitor first as substantial number of pts normalize spontaneously Increased risk of CHF, Afib, CHD and mortality & osteopenia if TSH is <0.1 mu/l Consider CV risk factors & co-morbidities Subclinical Hyperthyroidism Do you treat? Treatment of subclinical hyperthyroidism Yes, maybe, and no Monitor first as substantial number of pts normalize spontaneously Increased risk of CHF, Afib, CHD and mortality & osteopenia if TSH is <0.1 mu/l Consider CV risk factors & co-morbidities Gesing A. The thyroid gland and the process of aging; what is new? Thyroid Research 2012, 5:16 doi:10.1186/1756-6614-5-16 GesingA. The thyroid gland and the process of aging; what is new? Thyroid Research 2012, 5:16 doi:10.1186/1756-6614-5-16 Subclinical Hyperthyroidism--When to Treat FACTOR TSH < 0.1 mul/l TSH 0.1 0.5mUL/L Now let s change directions.. Age > 65 YES Consider treating Age < 65 with co-morbidities Heart disease YES Consider treating Osteoporosis YES NO Menopausal Consider treating Consider treating Hyperthyroidism symptoms YES Consider treating Age < 65 asymptomatic Consider treating NO Thyroid Research 2012, 5:16 doi:10.1186/1756-6614-5-16 8

Case 3: Tired Tina A 59 yo Tina c/o fatigue & forgetfulness, thinning hair, constipation, weight gain. Hx obesity, HTN, HLD, stable angina, psoriasis, sleep apnea, and pernicious anemia VS: BP 156/88; HR 58 reg; T 97; LAB: TSH 6.9 (0.4-4.5 mu/l) FT4 1.1 (0.8-1.8 ng/dl), normal chemistry, mild macrocytosis, lipids not controlled Based on the above: What s the thyroid problem? Incidence of Hypothyroidism Woman 10x > men 6-9% woman develop overt dz 15-21% with subclinical dz Subclinical hypothyroidism affects 2-3% of women in pregnancy. 1:4000 neonates MORE FREQUENT? Primary Hypothyroidism in Adults Found in women 10> men 6-9% overt disease: 15-21% subclinical Dz Thyroid tissue destruction as a result of Chronic autoimmune (Hashimoto) thyroiditis Radiation (like radioactive iodine treatment for thyrotoxicosis) Thyroidectomy Non-toxic multinodular goiter Drugs with antithyroid actions: (List in reference section) Many (of interest estrogen in BCP and HRT ) Increases binding proteins so less FT4 and higher TSH Primary Hypothyroidism: Other Causes Congenital hypothyroidism Agenesis of thyroid Defective thyroid hormone synthesis 1:4000 births (recent data suggest it may be more common than we think!!) Diagnostic Studies of Hypothyroidism MoreTina Talk High TSH, low FT4, low T3 (usually not checked in hypothyroidism) Elevated Anti-TPO in Hashimotos thyroiditis US (normal or goiter or nodules); Scan +/- Lipids (increased), electrolytes, EKG, LFTs (increased) Remember: if LOW TSH & LOW FT4 (pituitary/hypothalamic issue) Do you think her hypothyroidism is likely autoimmune? WHY or WHY NOT? 9

Case 1: Tired Tina Common Features of Hypothyroidism A 59 yo Tina c/o fatigue & forgetfulness, thinning hair, constipation, weight gain. Hx of obesity, HTN, HLD, stable angina, psoriasis, sleep apnea, and pernicious anemia VS: BP 156/88; HR 58 reg; T 97; rest of exam nml LAB: TSH 6.9 (0.4-4.5 mu/l) FT4 1.1 (0.8-1.8 ng/dl), normal chemistry, mild macrocytosis, lipids not controlled Hypothermia Hypoventilation Bradycardia Clinical Features of Hypothyroidism Tiredness/fatigue Forgetfulness/Slower Thinking Moodiness/ Irritability Depression Inability to Concentrate Thinning Hair/Hair Loss Loss of Body Hair Dry, Patchy Skin Weight Gain Cold Intolerance Elevated Cholesterol Family History of Thyroid Disease or Diabetes Puffy Eyes/ thin eyebrow Enlarged Thyroid (Goiter) Hoarseness/ Deepening of Voice Persistent Dry or Sore Throat Difficulty Swallowing Slower Heartbeat Menstrual Irregularities/ Heavy Period Infertility Constipation Muscle Weakness/ Cramps Slow or Absent Ankle Reflex Signs & Symptoms of Hypothyroidism in the Elderly Vague symptoms 50% c/o fatigue and weakness Increase average of 10-20 lbs Often CV or Neuropsych symptoms No mentation problems in elderly with subclinical hypothyroidism with TSH<10 10

Hypothyroidism and the Heart Treating Overt Hypothyroidism Dyslipidemia Hypertension Diastolic Dysfunction Elevated Cholesterol* Long Q-T Syndrome (V-Tach less V-fib) Serum CK Elevation (*Statin Hazard?) Coagulopathy Average start at 50 to 100 (daily dose average 1.6 mcg/kg lean weight) increase every 6 weeks as needed to targeted TSH goal Begin low dose levothyroxine in elderly? 25-50 mcg (what s the evidence?) Elderly TSH goal: 4-to-6.5 Considerations: Higher TSH in elderly associated prolonged life span? Levothyroxine (T4) has half-life of 6-7 days Do You Treat Subclinical Hypothyroidism? Most 40-65 yrs old treated with levothyroxine, (TSH 4.5-10) have cardiac risks reduced (ESP in Black Pts!) If not treated with levothyroxine have higher all-cause mortality.? BUT LOOK at CV risks (dyslipidemia, CV etc) Treatment should be considered in presence of hypothyroidism symptoms, positive TPO antibodies or evidence of CVD, CHF or high risk of these Less likely to be prompt to treat those >70 Initial levothyroxine dosing is generally lower than the treatment of overt hypothyroidism. How would you treat Tired Tina? Consider Age and risk Compliance Dose choices Razi S et al. 2010 JCEM 95:1734-40 Am J Med. 2016; 129 (4):423-30. What are your T4 replacement options Thyroid dose choices Hypothyroidism (Treatment) Synthroid (LT4) MANY DOSE CHOICES!!! T-1/2 LT4 is 7 days Food & drugs can LT4 absorption up to 40-50%. Should be taken with water consistently 30 to 60 minutes before breakfast or at bedtime 4 hours after the last meal MORE PARITY among generic levothyroxine drugs now within 5% variance. Or are they?!! Make sure the pill color hasn t changed without change in dose!!!. 11

Those with Celiac Disease should use Tirosint Factors That May Reduce Levothyroxine Effectiveness Tirosint-SOL (levothyroxine sodium oral solution) and in gel pack Malabsorption Syndromes Postjejunoileal bypass surgery Short bowel syndrome Celiac disease Reduced Absorption Colestipol hydrochloride Sucralfate Ferrous sulfate Food (e.g., soybean formula) Aluminum hydroxide Cholestyramine Sodium polystyrene sulfonate PPI Drugs That Increase Clearance Rifampin Carbamazepine Phenytoin Factors That Reduced T 4 to T 3 Clearance Amiodarone Selenium deficiency Other Mechanisms Lovastatin Sertraline Factors That May Reduce Levothyroxine Effectiveness Malabsorption Syndromes Postjejunoileal bypass surgery Short bowel syndrome Celiac disease Reduced Absorption Colestipol hydrochloride Sucralfate Ferrous sulfate Food (e.g., soybean formula) Aluminum hydroxide Cholestyramine Sodium polystyrene sulfonate PPI Drugs That Increase Clearance Rifampin Carbamazepine Phenytoin Factors That Reduced T 4 to T 3 Clearance Amiodarone Selenium deficiency Other Mechanisms Lovastatin Sertraline Creative THR If miss a dose what do you do? Double up tomorrow (long half life) Can be given weekly in non compliant pts (WORKS) If TSH too low or too high? Can cut out a pill or double a pill per week vs change the dose order until know if working Caution with elderly Cardiac risk (angina/ atrial fibrillation) Malabsorption Tina Again She was originally put on 50 mcg without symptom relief and gradually increased to 100 mcg of levothyroxine. She is a little better, lipids improved but still symptomatic. Her labs are 12 weeks on 100 mcg: TSH: 5.8 FT4: 0.6 What would you do? Keep same dose, recheck in 6 weeks? Increase her daily dose? If increase dose...how much--to 112, 125, 137 mcg?!! 12

Example of how to help calculate new dose Case # 4: Anita ( Grams ) Tina is on 100 mcg of levothyroxine/day Has TSH of 5.8 Have pt take extra 100 mcg once a week Recheck TSH in 6 weeks Next TSH is 2.9 Add up total levothyroxine (700 mcg weekly plus extra 100 mcg= 800 mcg) 800 mcg / 7 (days) = 113 So order 112 mcg daily dose 81 year old WW with long standing hypothyroidism --well controlled on 200 mcg of Synthroid had a sudden drop in TSH from 2.01 to 0.7 with increasing angina Hx: CAD (CABG, Stents), Hashimoto s, pre-diabetes, asthma, GERD, osteoarthritis, MD Meds: carvedilol, norvasc, isosorbide, nitro spray, lipitor, calcium, Vit D, occuvites Case # 4: Anita What could have caused her TSH to drop? Is she taking the medication? Taking at a different time or with other meds/minerals? Is it a new vendor? Changed color of pills? Did she start metformin? Did she start biotin? Clue: her granddaughter (a nurse) visited her recently Here is the REST of the story; Does T3 Replacement Have a Role Hypothyroid Tx? Studies mixed meta-analysis negative but Perhaps up to 16% may have genetic polymorphisms/snps may do better or feel better with combo T4/T3 Wiersinga WM, Duntas L, Fadeyev V, et al: 2012 ETA Guidelines: the use of L-T 4 + L-T 3 in the treatment of hypothyroidism. Eur Thyroid J 2012; 1: 55 71. Should you give T3 Replacement? Best if endocrinology prescribes this esp if ADDING to levothyroxine!!! Triiodothyronine (Cytomel) 5-25 mcg slow/gradual; best bid with with daily T4 T3 is 4-5 x stronger than T4 So cut back the dose of T4 accordingly when adding T3. (FYI if on 100 mcg levothyroxine cut to 25-50 mcg with a bid T3 dose) OR Liotrix (Thyrolar) combo 1 unit 12.5 mcg T3/ 50 mcg T4 13

What About Natural Thyroid (porcine thyroid) Desicated thyroid (porcine based) Has T4 and T3 Most common: Armour Thyroid Nature-thyroid NP-thyroid Less well known: Westhroid Biotech Above FDA regulated vs OTC thyroid granules OTC-Thyroid Supplements The basic "rule of thumb" in converting levothyroxine to desicated thyroid doses: 100 mcg of T4 is roughly equivalent to 25 mcg of T3, or 1 grain (60 mg) of desiccated thyroid NP-Thyroid Acella Pharmaceuticals ckessler@maranatha.net 14

References Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012 Dec. 22(12):1200-35. McDermott MT. Does combination T4 and T3 therapy make sense?. Endocr Pract. 2012 Sep-Oct. 18(5):750-7. [Guideline] J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 2014 Dec. 24(12):1670-751. Smith TJ, Hegedüs L. Graves' Disease. N. Engl. J. Med.2017 Jan 12;376(2):185. Devereaux D, Tewelde SZ. Hyperthyroidism and thyrotoxicosis. Emerg. Med. Clin. North Am. 2014 May;32(2):277-92. De Leo S, Lee SY, Braverman LE. Hyperthyroidism. Lancet. 2016 Aug 27;388(10047):906-918. Yamada M, Mori M. Mechanisms related to the pathophysiology and management of central hypothyroidism. Nat Clin Pract Endocrinol Metab. 2008 Dec. 4(12):683-94. Abreu I, Lau E, Sousa-Pinto B, Carvalho D. Subclinical hypothyroidism: to treat or not to treat! A systematic review with meta-analysis on lipid profile. Endocr Connect. 2017 Mar 1. Wartofsky L. Myxedema coma. Endocrinol Metab Clin North Am. 2006 Dec. 35(4):687-98, vii-viii. Shields BM, Knight BA, Hill AV, Hattersley AT, Vaidya B. Five-year follow-up for women with subclinical hypothyroidism in pregnancy. J Clin Endocrinol Metab. 2013 Dec. 98(12):E1941-5. Sato Y, Yoshihisa A, Kimishima Y, et al. Subclinical Hypothyroidism Is Associated With Adverse Prognosis in Heart Failure Patients. Can J Cardiol. 2018 Jan. 34 (1):80-7. Added resources American Thyroid Association (ATA): thyroid.org American Association of Clinical Endocrinologists (aace.org) Endocrine Society (endocrine.org) Why FT4 and not Total T4 (factors increasing total T4) High estrogen states gravidarum Lab error Autoimmunity Acute illness Acute psychiatric problems Familial thyroid binding abnormalities Generalized resistance to thyroid hormone Drugs Drugs with antithyroid actions Inhibition of T4/T3 synthesis Propylthiouracil Methimazole Inhibition of T4/T3 secretion* Lithium Iodide Amiodarone Interferon Interleukin-2 Sunitinib** TSH suppression Glucocorticoids Dopamine agonists Somatostatin analogs Rexinoids Carbemazepine/Oxcarbemazepine Displacement from thyroxine binding globulin (laboratory artifact) Furosemide Phenytoin Probenecid Heparin 15