Common Thyroid Disorders Louie Riesch MSN, MPH, RN, ACNS-BC, CDE Texas Diabetes and Endocrinology Anatomy of the Thyroid Gland Hypothalamic-Pituitary-Thyroid Axis Physiology Hypothalamus TRH Pituitary TSH reflects tissue thyroid hormone actions TSH as an index of therapeutic success and potential toxicity T4 TSH Target Tissues T3 Thyroid Gland Heart Liver T4 T3 TR Bone T4 è T3 Liver CNS 1
Production of T 4 and T 3 Ê T 4 is the primary secretory product of the thyroid gland, which is the only source of T 4 Ê The thyroid secretes approximately 100 nmol of T 4 per day Ê T 3 is derived from 2 processes Ê The total daily production rate of T 3 is about 15-30 µg Ê About 80% of circulating T 3 comes from deiodination of T 4 in peripheral tissues Ê Largely liver and kidneys Ê About 20% comes from direct thyroid secretion Free Hormone Concept Ê Only unbound (free) hormone has metabolic activity and physiologic effects Ê Total hormone concentration Ê Normally is kept proportional to the concentration of carrier proteins Ê Is kept appropriate to maintain a constant free hormone level 2
Drugs and Conditions That Increase Serum T 4 and T 3 Levels by Increasing TBG Drugs that increase TBG Ê Oral contraceptives and other sources of estrogen Ê Methadone Ê Clofibrate Ê 5-Fluorouracil Ê Heroin Ê Tamoxifen Conditions that increase TBG Ê Pregnancy Ê Infectious/chronic active hepatitis Ê HIV infection Ê Biliary cirrhosis Ê Acute intermittent porphyria Ê Genetic factors Evaluate for thyroid disease Ê All >35 years of age, every 5 years Ê Patients >60 Ê Women >50 with incidental finding suggestive of thyroid disease Ê USPSTF: insufficient evidence for across-theboard screening Symptoms Ê Hypothyroidism Ê Fatigue Ê Depression Ê Weight gain Ê Loss of body hair Ê Dry skin Ê Elevated lipids Ê Slower heartbeat Ê Constipation Ê Muscle weakness Ê Heavy periods Ê Hyperthyroidism Ê Fatigue Ê Insomnia Ê Weight loss or gain Ê Heat intolerance Ê Light periods Ê Visual changes Ê Diarrhea Ê Tremor Ê Tachycardia Ê Irritability 3
Exam Ê TSH Ê Look Ê Palpate Ê Imaging? Thyroid-Stimulating Hormone (TSH) Assays Ê Key test for diagnosis of hypothyroidism and hyperthyroidism Ê TSH assay sensitivity has improved with subsequent test generations Ê First generation: RIA Sensitivity: 1.0 µiu/ml Ê Second generation: IRMA Sensitivity: 0.1 µiu/ml Ê Third generation: ELISA Sensitivity: 0.03 µiu/ml Ladenson PW, et al. Arch Intern Med. 2000;160:1573-1575. Braverman LE, et al. Werner & Ingbar s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. Zophel K, et al. Nuklearmedizin. 1999;38:150-155. 4
Interpretation FT4 FT3 TSH Comments Hypothyroid Low Low High Subclinical Hypothyroid Hyperthyroid Noncompliance with LT4 Normal Normal High High or highnormal High Low TSHRAbsensitive and specific for Graves High Low High Influencing Medications FT4 FT3 TSH Glucocorticoids Dopamine Normal Normal Low Lithium, iodine Low Low High Amiodarone Normal to high Low High or low Phenobarbitol Carbamezapine Phenytoin Rifampicin Low Low Normal Hyperthyroid Ê Mr. Smith is a 49 year-old, smoker, hx of HTN. C/O insomnia. Wife says she thinks he s lost weight. Ê Labs show: TSH <0.1, FT4 2.3; CMP and CBC wnl. Ê Exam: Lid lag, HR 110, tremor, warm/sweaty, thyroid = diffusely enlarged Ê Imaging 5
Graves Disease (Toxic Diffuse Goiter) Ê The most common cause of hyperthyroidism Ê Accounts for 60% to 90% of cases Ê Incidence in the United States estimated at 0.02% to 0.4% of the population Ê Affects more females than males, especially in the reproductive age range Ê Graves disease is an autoimmune disorder possibly related to a defect in immune tolerance Treatment of Hyperthyroidism Ê Antithyroid drugs Ê Inhibit the synthesis of T4 and T3 Ê Surgical resection Ê Remove hyperplastic and adenomatous tissues Ê Restore normal thyroid function and, consequently, pituitary function Ê Radioactive iodine therapy Ê Iodine 131 taken up by functioning thyroid tissue can decrease thyroid hormone production Braverman LE, et al. Werner & Ingbar s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. Anti-thyroid Drugs Ê Methimazole Ê Inhibits organification of iodide Ê Decreases production of T4 and T3 Ê Dose is 2.5 40 mg/day Ê Side effects Ê Rash Ê Agranulocytosis Ê Aplasia Cutis Ê Hepatotoxicity Ê Used preferentially over PTU less incidence of side effects 6
Anti-thyroid Drugs Ê Propylthiouracil Ê Inhibits organification of iodide Ê Decreases production of T4 and T3 and conversion of T4 to T3 Ê Dose is 100-600 mg/day Ê Side ffects Ê Rash Ê Agranulocytosis Ê Hepatotoxicity Ê Boxed Warning Ê Used preferentially in 1 st trimester of pregnancy Thyroid Storm Which ATD? Ê Methimazole Ê All except first trimester Ê Start 10-30 mg qd; maintenance 2.5 mg - 10mg Ê PTU Ê Start 50-150 tid; maintenance 50mg tid 7
Monitoring in ATD Ê CBC Ê TFTs: FT4 & TSH 4 weeks after starting med Ê Liver Ê Allergy Ê Relapse Ê Pregnancy Hypothyroid Ê Ms. Smith is a 49 year-old, smoker, hx of HTN. Seeing you for weight gain, fatigue, and cold intolerance. Ê Labs show: TSH 26, FT4 0.2; CMP and CBC wnl. Ê Exam: thyroid diffusely enlarged, HR 62, +1 pedal edema. Hypothyroidism: Types Ê Primary hypothyroidism Ê From thyroid destruction Ê Central or secondary hypothyroidism Ê From deficient TSH secretion, generally due to sellar lesions such as pituitary tumor or craniopharyngioma Ê Infrequently is congenital Ê Central or tertiary hypothyroidism Ê From deficient TSH stimulation above level of pituitary ie, lesions of pituitary stalk or hypothalamus Ê Is much less common than secondary hypothyroidism Bravernan LE, Utiger RE, eds. Werner & Ingbar's The Thyroid. 8th ed. Philadelphia, Pa: Lippincott Williams & Wilkins 2000. Persani L, et al. J Clin Endocrinol Metab. 2000; 85:3631-3635. 8
Chronic Autoimmune Thyroiditis (Hashimoto s Thyroiditis) Ê Occurs when there is a severe defect in thyroid hormone synthesis Ê Patients present with hypothyroidism, painless goiter, and other overt signs Ê Persons with autoimmune thyroid disease may have other concomitant autoimmune disorders Treatment of Hypothyroidism Thyroid Hormone Replacement Ê Treatment of choice: levothyroxine (synthetic levothyroxine, LT 4 ) Ê ½ life of 1 week Ê Chemically stable Ê T 4 converted to T 3 in periphery Ê Other therapies (T 3 or T 3 and T 4 mixtures) Ê Thyroid USP, liothyronine, liotrix, thyroglobulin Ê Some disadvantages Singer PA, et al. JAMA. 1995;273:808-812. Endocr Pract. 2002;8:457-469. Braverman LE, et al. Werner & Ingbar s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. Hypothyroidism Treatment Ê Levothyroxine sodium is the treatment of choice for the routine management of hypothyroidism Ê Ê Ê Adults: about 1.7 µg/kg of body weight/day Children up to 4.0 µg/kg of body weight/day Elderly <1.0 µg/kg of body weight/day Ê Clinical and biochemical evaluations at 6- to 8-week intervals until the serum TSH concentration is normalized Ê Given the narrow and precise treatment range for levothyroxine therapy, it is preferable to maintain the patient on the same brand throughout treatment Singer PA, et al. JAMA. 1995;273:808-812. Endocr Pract. 2002;8:457-469. 9
Primary Hypothyroidism Treatment Algorithm Initial Levothyroxine Dose 6-8 Weeks TSH >4 µiu/ml Repeat TSH Test TSH <0.3 µiu/ml TSH 0.5-2.0 µiu/ml Symptoms Resolved Increase Levothyroxine Dose by 12.5 to 25 µg/d Continue Dose Measure TSH at 6 Months, Then Annually or When Symptomatic Decrease Levothyroxine Dose by 12.5 to 25 µg/d Singer PA, et al. JAMA. 1995;273:808-812. Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed Aug. 2007 Percentage of Euthyroid, Subclinical and Hypothyroid Patients Reporting Symptoms 60% euthyroid have 1 symptom 15% 4 symptoms Canaris et al. Thyroid hormone impact on weight in euthyroid patients Not effective weight loss drug May increase metabolism but increases appetite Kaptein JCEM 2009 Fig 2b 10
Hazards of Overtreatment Heart, Bone, Psychiatric Ê High risk subclinical hyperthyroid in patients on thyroid medication Ê Colorado Prevalence Study, 2000 Ê 20.7% (316) of patients on thyroid medication had subclinical hyperthyroidism Ê 0.9% (13) Overt hyperthyroidism Ê More adverse effects with poor monitoring Ê Only 56% received standard monitoring Ê Atrial fibrillation, unstable angina with poor monitoring Factors That May Reduce Levothyroxine Effectiveness Ê Malabsorption Syndromes Ê Postjejunoileal bypass surgery Ê Short bowel syndrome Ê Celiac disease Ê Reduced Absorption Ê Colestipol hydrochloride Ê Sucralfate Ê Ferrous sulfate Ê Food (e.g. soybean formula) Ê Aluminum hydroxide Ê Cholestyramine Ê Calcium carbonate Ê Drugs That Increase Clearance Ê Rifampin Ê Carbamazepine Ê Phenytoin Ê Factors That Reduced T 4 to T 3 Clearance Ê Amiodarone Ê Selenium deficiency Ê Other Mechanisms Ê Lovastatin Ê Sertraline Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8 th ed. 2000. Synthroid [package insert]. Abbott Laboratories; 2003. When is T3 given? Ê Not recommended by American Thyroid Association Ê Experimental use ok by European Thyroid Association Ê Genetic condition Ê 10 15% of patients feel unwell on LT4 monotherapy, as they still have complaints in spite of TSH normalization. Ê The thyroid gland secretes both T4 and T3, suggesting a physiological role for the amount of T3 directly secreted by the thyroid, and not originated by peripheral conversion of T4. 11
Has a Role in the Treatment of Hypothyroidism Been Demonstrated with T3? Ê Endpoints have been mostly affective ones Ê Trials have been relatively short Ê Studies to date mixed and meta-analyses negative, but not completely Ê Combination therapy still not yet completely understood in the setting of patient preferences Liothyroinine Ê LT3 or Cytomel Ê Short-acting Ê About 4 times as potent Ê Watch for hyperthyroid symptoms Ê Take bid, avoid evening dosing Ê May need to reduce LT4 Desiccated thyroid Ê Combination of T4/T3 Ê 1 grain = about 100mcg Synthroid Ê No RTCs of desiccated thyroid until 2013. 12
Counsel Patients Taking Alternative Therapies About Potential Side Effects and Hazards Ê Supraphysiologic amounts of iodine may alter thyroid status, particularly in those with disease Ê Many thyroid-enhancing products have sympathomimetic amines and iodine Ê Many thyroid support products have significant amount of thyroid hormone Thyroid hormone conversions Case #1 Ê Ms. A has been hypothyroid since age 35. Ê She takes Synthroid 0.088mg qd and an MVI Ê TSH 7.5 Ê She is now 52 and in menopause Ê Complains of hot flashes and trying to treat with soy products Ê What could be happening? 13
Case #1 Ê Soy milk Ê Calcium supplements Ê Iron Ê Coffee Ê Separate food, supplements, other medications by at least 2 hours Ê Coffee by 1 hour Case #2 Ê Mr. B has had hypothyroidism for 5 years. Ê He takes Armour 1gr qd. TSH was 0.3 at lov. Ê Recently started on Lithium to treat bipolar Ê He complains of weight gain, increased fatigue and is worried the psych regimen is not working. Ê TSH is now 28 Again Ê Take LT4 at the same time of day Ê No food, no coffee, no milk Ê ½ hour prior to eating or 2 hours after eating Ê Make sure to ask about any new medications Ê May not be able to change the other meds Ê MONITOR 14
Case #3 Ê Mr. B takes Synthroid 0.1mg qd. Ê TSH <0.1, FT4 4.7 Ê Complains of fatigue and says he takes an extra Synthroid when tired. Ê Remind patients of the problems with over-replacement. Ê AF, bone loss Ê Can t assess dose properly Consequences of Mild Thyrotoxicosis Atrial Fibrillation 30 Incidence of Atrial Fibrillation (%) 25 20 15 10 5 TSH 0.1 mu/l TSH >0.1 0.4 mu/l 0 0 1 2 3 4 5 6 7 8 9 10 Years N=2007 pts > 60 Normal TSH (>0.4 5.0 mu/l) Adapted from: Sawin CT, et al. N Engl J Med. 1994;331:1249-1252. Case #4 Ê TSH is 12, FT4 is 5 Ê Pt presents with these labs. Exam is normal. Pt states she was on a cruise and gained about 5 pounds. Otherwise feels well, energetic, and attributes the weight gain to overeating. Ê What can explain the labs? 15
Case #4 Ê She forgot her meds on vacation Ê Tried to catch up by taking 2 0.05mg Levothyroxine qd for the past week when she returned home. Questions? 16