Thyroid Disease. Scott D. Isaacs, MD, FACP, FACE HRT Symposium Savannah GA July 14 16, All Rights Reserved. 1

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2 Disclosure Scott D. Isaacs, MD, FACP, FACE, is the Medical Director at Atlanta Center for Endocrinology, Diabetes, Metabolism and Weight Loss. Conflict of interest was resolved through peer review of slide content. Professional Education Services Group staff have no financial interest or relationships to disclose All Rights Reserved. 2

3 Disclosure This continuing education activity is managed and accredited by Professional Education Services Group. Neither PESG nor any accrediting organization supports or endorses any product or service mentioned in this activity All Rights Reserved. 3

5 Learning Objectives At the conclusion of this activity, the participant will be able to: Discuss the endocrinology of thyroid hormones and the relationship to the hypothalamus, pituitary and peripheral organs. Discuss the laboratory evaluation of thyroid disorders. Explain the management of thyroid disease in a case based approach All Rights Reserved. 5

Hypothalamic Pituitary Thyroid Axis TRH TSH T4 and T3 Negative feedback

7 Is it a thyroid problem? A 72 year old woman has been experiencing fatigue, depression and difficulty losing weight for 2 years. Thyroid tests ordered online have been normal except a moderately low reverse T3. She has read that thyroid tests don t accurately evaluate thyroid function and requests thorough thyroid testing and treatment All Rights Reserved. 7

8 Is it a thyroid problem? PMH: Negative Meds: Multiple supplements PE: BP 122/84 P 80 Ht 5 6 Wt 172 lb. Complete exam normal Lab Report: TSH 3.2 mu/l (nl: ) Free T4 1.3 ng/dl (nl: ) Free T3 3.1 pg/ml (nl: ) Reverse T3 9 ng/dl (nl: 10 24) All Rights Reserved. 8

9 Symptoms of Hypothyroidism Weight gain Fatigue Aging Menopausal symptoms Neck or tongue swelling Joint and muscle aches Feeling cold Constipation Memory loss Infertility Slow reflexes Snoring or sleep Apnea Hair loss/eyebrow Loss Brittle nails Fluid retention Decreased sweating Allergies or hives Depression Menstrual cycle problems Galactorrhea All Rights Reserved. 9

11 Possible Interpretations: Symptoms are not related to the thyroid Hypothalamic Pituitary disease is the problem TSH level is not in the optimal range There is a coexisting autoimmune disease Hashimoto s Disease itself causes symptoms Maybe we should consider other possibilities All Rights Reserved. 11

12 Considerations: There are many potential problems that could occur along the entire hypothalamic pituitary thyroid axis. Current tests are not able to evaluate this axis completely All Rights Reserved. 12

13 Epidemiology of Primary Hypothyroidism Up to 5% of adult population has primary thyroid gland failure Hypothyroidism with clinical features and abnormal labs in 0.8% 1.1% (Wickham, England) Elevated TSH (>6 mu/l) was found in an additional asymptomatic 7.5% of females and 2.8% of males Colorado Health Study found 9.5% prevalence of elevated TSH 40% of individuals > 80 years old have TSH > 2.5 mu/l 1 Vanderpump MPJ et al. The Thyroid. 1996; Tunbridge WMG et al. Clin Endocrinol. 1977;7(6); Canaris GJ et al. Arch Intern Med. 2000; 160(4): Surks MI et al. JCEM. 2007;92(12) All Rights Reserved. 13

Hashimoto s Thyroiditis Most common cause of hypothyroidism Immune system mistakenly attacks key machinery in the thyroid gland (TPO & Tg) May have hyperthyroid phase followed by brief

15 Hashimoto s Thyroiditis Most common cause of hypothyroidism Immune system mistakenly attacks key machinery in the thyroid gland (TPO & Tg) May have hyperthyroid phase followed by brief euthyroid phase Variable degrees of thyroid dysfunction Family History Hashimoto s or Graves Other autoimmune problems Eye symptoms (Dysthyroid ophthalmopathy) All Rights Reserved. 15

17 Normal TSH Reference Primary hypothyroidism is diagnosed with a TSH above the upper limit of normal Reference range for upper limit of normal is under discussion 1 20 year follow up Wickham cohort 2 TSH > 2.0 mu/l increases risk of progression to overt hypothyroidism Increased progression to hypothyroidism if thyroid antibodies positive 1 Baloch Z et al. Thyroid (1): Vanderpump MPJ et al. The Thyroid. 1996; All Rights Reserved. 17

20 Thyroid+ laboratory Selenium Iodine CK LDL cholesterol Iron, Ferritin Cortisol ACTH Leptin Celiac antibodies Anti tissue transglutaminase (ttg) antibodies Endomysial antibodies (EMA) Deamidated gliadin peptide (DGP) antibodies All Rights Reserved. 20

24 Trends in Diagnosis More narrow TSH reference range for primary hypothyroidism 95% of screened healthy euthyroid subjects have serum TSH between 0.4 and 2.5 mu/l Treat all patients with TSH > 10 mu/l Treat most patients with TSH between mu/l (especially those with low T4) Use clinical judgment to treat symptomatic individuals with TSH > 2 mu/l Gharib, et al. Subclinical thyroid dysfunction. JCEM. 2005; 90 (1): All Rights Reserved. 24

25 NHANES III Normal TSH Range by Decade The lower TSH limit stays relatively constant with age. The MEAN TSH rises with age. The upper limit of normal rises with age. A natural rise of TSH with age? (survival benefit?) Is there a progression to hypothyroidism with age that is included in normal? All Rights Reserved. 25

Cross sectional Population Study Age related Changes in TSH Hollowell JCME

27 Natural History Mild Hypothyroidism 107 patients followed for 72 months with subclinical hypothyroidism (elevated TSH, normal Free T4). Mean age 62 years from outpatient Endo clinic 26% required T4 RX Overt hypothyroidism associated if baseline: + TPO Ab Free T4 < 1 Extent of TSH elevation > 10 (~40%) > 15 (~90%) Low risk of overt hypothyroidism if TSH 5 10 Recommend biochemical monitoring Diez & Iglesias JCEM 2004;89: All Rights Reserved. 27

28 Progression to Overt Hypothyroidism in CV Study Large population cohort followed for 4 years 3992 >65 years 12.8% subclinical hypothyroid 0.61% overt hypothyroidism Overt hypothyroidism associated if baseline: TSH >10 Not associated with age or TPO ab status Low risk of overt hypothyroidism if TSH 5 10 Recommend biochemical monitoring Somwaru JCEM 2012;97: All Rights Reserved. 28

29 Subclinical Hypothyroidism and Cognitive Impairment Systematic review and meta analysis 1,190 subjects >60 years in 15 studies No association with: Mini mental state exam (MMSE) Executive function Memory (random effects model) Akintola et al. Front. Aging Neurosci., 11 August All Rights Reserved. 29

30 Lower Mortality in Oldest Old with High TSH The oldest old, elderly individuals high TSH do not experience adverse effects and may have a prolonged life span. Risk of mortality of high TSH 0.76 (p 0.005) vs normal TSH. Gussekloo et al. AMA. 2004;292(21): doi: /jama All Rights Reserved. 30

Subclinical Hypothyroidism Progression in the Elderly

32 Recommendation for Evaluation and Treatment of Elevated TSH in the Elderly TSH found on screening Repeat with FT4 and TPO ab Progression to overt disease Most likely if TSH >10 Free T4 < 1.0 Positive TPO antibody Subclinical disease is associated with subclinical hypothyroidism LT4 therapy will reduce total and LDL cholesterol in subclinical hypothyroidism but rarely achieves goal levels All Rights Reserved. 32

Hypothyroidism and Thyrotoxicosis Colorado Health Study 24,337 subjects TSH normal

34 Risk of Subclinical Hyperthyroidism Prevalence 1.5 2% in > 65 years Etiology usually nodular goiter Progression to overt disease 20 70% normalize without treatment 1 3% progresses to hyperthyroidism More likely with very low TSH More likely with nodular thyroid disease Risk of death conflicting data but yes Risk of atrial fibrillation yes 2 3 x risk Risk of osteoporosis Hyperthyroidism associated with increased risk of hip and other fractures especially TSH < All Rights Reserved. 34

35 Evaluation and Treatment of Suppressed TSH in the Elderly If low TSH, repeat with FT4, total T3, TPOab (TSI) and thyroid US in 3 months If TSH miu/l Observation if TSH , normal US, negative thyroid Ab, normal HR, normal BMD, no CV or skeletal risk factors Check TSH, FT4, total T3 every 6 12 mo Graves disease: Treat with anti thyroidal drug (methimazole 5 10 mg/d) if cardiovascular disease or risk factors Nodular goiter: Treat with radioactive iodine if cardiovascular disease or risk factors (consider normalize TSH first with anti thyroidal drug ) If cannot comply with radiation restrictions long term antithyroidal drug All Rights Reserved. 35

36 Evaluation and Treatment of Suppressed TSH in the Elderly If TSH < 0.1 miu/l Graves disease Treat with anti thyroidal drug, radioactive iodine or surgery Toxic nodular goiter radioactive iodine or surgery Surgery if large goiter or compressive symptoms All Rights Reserved. 36

37 Back to our case: A 72 year old woman has been experiencing fatigue, depression and difficulty losing weight for 2 years. TSH 3.2 mu/l (nl: ) Free T4 1.3 ng/dl (nl: ) Free T3 3.1 pg/ml (nl: ) Reverse T3 9 ng/dl (nl: 10 24) Symptoms are not related to the thyroid Hypothalamic Pituitary disease is the problem TSH level is not in the optimal range There is a coexisting autoimmune disease Hashimoto s Disease itself causes symptoms Maybe we should consider other possibilities All Rights Reserved. 37

38 Euthyroid Hashimoto s Coexisting Autoimmune Disease Rheumatoid arthritis Lupus Inflammatory bowel disease Autoimmune hepatitis Celiac disease Vasculitis syndromes Multiple sclerosis, pattern II Type 1 diabetes Addison s Disease Lymphocytic hypophysitis Alopecia Vitiligo Psoriasis All Rights Reserved. 38

39 Autoimmune polyendocrine syndrome type 1 Whitaker syndrome Hashimoto s disease Mucosal and cutaneous candidiasis Hyposplenism Hypoparathyroidism Addison s disease Vitiligo Alopecia Malabsorption Pernicious anemia Autoimmune hepatitis All Rights Reserved. 39

40 Autoimmune polyendocrine syndrome type 2 Schmidt's syndrome Hashimoto's disease Graves' disease Addison's disease Pernicious anemia Type 1 diabetes Celiac disease Myasthenia gravis Primary hypogonadism (less common) Vitiligo (less common) All Rights Reserved. 40

41 7.7% of euthyroid patients have symptoms of hypothyroidism. Mrs. Johnson, we ve done every possible test and your thyroid checks out completely normal, let s look for other causes for your symptoms All Rights Reserved. 41

42 Follow up thyroid testing Free hormone levels Equilibrium dialysis method Thyroid antibodies (TPO, Tg, TSI, TBII) Alpha subunit TRH Stimulation Test 24 Hr Urine Iodine Thyroid Ultrasound Thyroid Scan and Uptake Pituitary MRI Scan Full Endocrine Evaluation Reverse T3 Basal Body Temperature (not recommended) Saliva Testing (not recommended) All Rights Reserved. 42

43 Hypothalamic pituitary thyroid axis physiology is highly complex Hypothyroidism most often develops as a result of thyroid disease (primary hypothyroidism). Can also occur from disorders of the pituitary gland or hypothalamus (central hypothyroidism) All Rights Reserved. 43

Hypothalamic Pituitary Axis Hypothalamus TRH Paraventricular nucleus Thyrotrophs Median eminence

45 Central Hypothyroidism 45.5 cases of CH occur annually per 100,000 of the general population. Pituitary adenomas are the most frequent cause. Mechanical compression of portal vessels and the pituitary stalk. Ischemic necrosis of portions of the anterior pituitary. May have other pituitary hormone deficiencies All Rights Reserved. 45

46 Central Hypothyroidism Pituitary adenoma Congenital Craniopharyngioma Rathke cleft cysts Empty sella syndrome Sheehan syndrome Lymphocytic hypophysitis Head trauma Subarachnoid hemorrhage External beam radiotherapy All Rights Reserved. 46

47 Bexarotene Synthetic retinoid analog (rexinoid). Specific affinity for the retinoid X receptor. Inhibits the expression of the TSHß gene through its binding to the retinoid X receptor. Approved for treatment of cutaneous T cell lymphoma. 40% incidence of CH Marked reductions in serum TSH and T4 levels All Rights Reserved. 47

50 Adequate testing is lacking Thyroid binding protein dysfunction Deiodinase polymorphisms TSH resistance Thyroid hormone resistance Thyroid hormone uptake across cellular and nuclear membranes into target cells All Rights Reserved. 50

51 Adequate testing is lacking Thyroid hormone regulation of transcription machinery to activate or suppress target genes Ubiquitination mediated regulation of thyroid hormone activation and deiodinase recycling Translation of mrna into thyroid regulated proteins Actions of thyroid hormone regulated proteins All Rights Reserved. 51

53 Local T3 Production Every tissue in the body needs a specific amount of T3. Tissue specific deiodinases regulate the amount of T3 produced for each tissue. Peripheral deiodinase gene expression, translation and posttranslational modifications vary among organs. Liver and kidney express D 1 deiodinase. Bradioactive iodinen expresses D 2 deiodinase All Rights Reserved. 53

54 Selenium Deficiency Causes Deiodinase Dysfunction Nutritional, from low fruit and vegetable consumption Selenium content in soil varies by region (Russia and China have scant amounts of selenium in the soil) Malabsorption Trigger for autoimmune diseases, cancer, heart disease RDA 70 mcg/d Replacement mcg/d All Rights Reserved. 54

55 Type 2 Deiodinase Gene Polymorphism Type 2 deiodinase (D2) converts T4 to T3 in the hypothalamus and pituitary. Pivotal role in the negative feedback regulation of TSH secretion. Common Thr92Ala variant causes decreased D2 enzymatic activity. Delayed T3 Secretion in Response to TSH Changes in pituitary thyroid axis homeostasis Higher T4 intake needed to suppress TSH All Rights Reserved. 55

56 Thyroid Hormone Resistance 1 in 50,000 to 1 in 40,000 live births Maybe 1 3% have subtle resistance Selective pituitary resistance variant TRβ Mutations Most common symptoms are goiter and tachycardia High T4, High TSH, normal alpha subunit May be misdiagnosed as hyperthyroidism All Rights Reserved. 56

57 Thyroid Hormone Resistance Possible links to ADHD, fibromyalgia Patients can be difficult to treat: try dopamine agonists, T3, anti thyroidal drug s Symptomatic therapy with beta blockers Antithyroid medications reduce symptoms of hyperthyroidism but increase goiter size All Rights Reserved. 57

Medications for Hypothyroidism Levothyroxine (LT4) Branded levothyroxine Desiccated

60 T4:T3 Combination Therapy Physiologic is about 5:1 Natural desiccated thyroid is about 4:1 Liothyronine QD, BID, TID T3SR (E4 Methylcellulose) QD, BID T3SR with levothyroxine or compounded with T4 Patients less likely to be compliant with BID or TID Dose of T3 varies with each patient All Rights Reserved. 60

61 Case 50 year old man with 12 year history of hypothyroidism managed by the Chief of Endocrinology at a major University Medical Center Always has taken branded levothyroxine 150 mcg with perfect TSH levels Reports weight gain, fatigue and dry skin Requests new treatment for his thyroid All Rights Reserved. 61

62 Case What would you do? (a) Change to natural desiccated thyroid (b) Add liothyronine (c) Change to compounded T3SR/T4 (d) Change brand, maintain same dose of levothyroxine (e) No change. Evaluate for other problems All Rights Reserved. 62

63 A patient.on levothyroxine 150mcg, normal TFTs but symptomatic. Treatment options: 1. natural desiccated thyroid 90 mg (1 ½ gradioactive iodinens) 2. Levothyroxine mcg + liothyronine mcg BID or TID 3. T4:T3SR 50-70/5-10 BID 4. Levothyroxine mcg + T3SR 5-10 mcg BID 5. Change brands or add ½-1 tablet weekly 6. Evaluate for other problems All Rights Reserved. 63

64 Compounded thyroid hormone Accurate dosing critical. Narrow therapeutic window. Test products. T4 only T3 only T3SR (E4 Methylcellulose) T4/T3SR Tablets: gluten free, lactose free, dye free Thyroid USP All Rights Reserved. 64

65 T4:T3 Dose Considerations 5:1? 4:1? 3:1? QD BID TID Customize to the patient. Give each change at least 6 8 weeks before assessing. Ratio needed to control symptoms may change with time All Rights Reserved. 65

66 T4:T3 Combination Therapy Considerations Monitor q 6-8 weeks and titrate accordingly Monitor q 3-4 months when stable TSH with symptoms is best monitor, T4 and T3 levels are less helpful Try several doses before changing to a new therapy Exact ratios seldom work Variability from obesity, stress, illness, mineral deficiencies, medications and type of thyroid disease all influence dose Urge compliance! All Rights Reserved. 66

67 Adverse Effects of Excessive Thyroid Hormone Replacement Overt, symptomatic thyrotoxicosis Does not cause weight loss Subclinical thyrotoxicosis Excess bone loss Cardiac dysfunction Increased pulse rate Increased cardiac wall thickness Increased cardiac contractility Increased risk of atrial fibrillation Worsening of ischemic heart disease Preterm delivery All Rights Reserved. 67

68 Counseling Patients Counsel patients to know that medications and foods that may interfere with absorption. Do not eat within 1 hour of taking thyroid medications. Do not take antacids, iron, calcium or fiber supplements within 4 hours of taking thyroid medications. Tell your doctor about other medications you take which may also interfere with the absorption (bile acid sequestrants, sertraline, sucralfate, phosphate binders). Soy products will interfere with absorption. Tell your doctor if you become pregnant or are planning to become pregnant All Rights Reserved. 68

69 Counseling Patients Take the medication every day at the same time if possible If you miss a dose, it is OK to take a double dose the following day if on T4 alone Talk to your doctor if you have symptoms of overreplacement or underreplacement. It takes 6 8 weeks for blood levels to stabilize after a change in dosage or brand All Rights Reserved. 69

70 Recommendations: Good Sleep Habits Regular Exercise Good Nutrition Stress Reduction Depression Management Treatment of Co existing Illnesses Thyroid Support Supplements No Proven Benefit All Rights Reserved. 70

Iodine and the Thyroid 75% of the body s iodine is used for thyroid hormone production Iodine is 65% of T 4 's weight, and 58% of T 3 's RDA for iodine is 150 mcg daily Normal iodine

71 Iodine and the Thyroid 75% of the body s iodine is used for thyroid hormone production Iodine is 65% of T 4 's weight, and 58% of T 3 's RDA for iodine is 150 mcg daily Normal iodine consumption in US is mcg Iodine deficiency does exist in the US, more common abroad Iodine deficiency or iodine excess can cause thyroid dysfunction All Rights Reserved. 71

72 Case 1: Unusual Thyroid Tests 47 year old male Complains of fatigue, weight gain, insomnia and palpitations BP 124/76, HR 72, BMI=27 CMP, CBC, lipids all within normal limits Normal TSH 0.91 uiu/ml ( ) High free thyroxine (T4) 1.99 ng/dl ( ) All Rights Reserved. 72

73 Case 1: Unusual Thyroid Tests (more information) Normal thyroid exam No family history of thyroid disease Negative TPO and thyroglobulin antibodies Repeat TSH was normal (1.12 uiu/ml) All Rights Reserved. 73

74 Case 1: Unusual Thyroid Tests (more information) Original free thyroxine was measured by radioimmunoassay. Total T3 and free T3 high normal Repeat free thyroxine measured by equilibrium dialysis was normal All Rights Reserved. 74

75 Familial dysalbuminemic hyperthyroxinemia (FDH) Euthyroid hyperthyroxinemia (normal TSH, high free and total T4). Total T3 and free T3 may be high normal or slightly elevated. Inherited variant of serum albumin with preferential affinity for T4. Autosomal dominant transmission. Prevalence is 0.17% All Rights Reserved. 75

76 Thyroxine carrier proteins Total thyroxine is >99.9% bound to circulating T4 carrier proteins. Thyroid binding globulin Albumin Prealbumin Acquired or inherited alterations of T4 carrier proteins can cause changes in T4 and T3 concentrations All Rights Reserved. 76

78 Familial dysalbuminemic hyperthyroxinemia (clinical pearls) Clinically euthyroid (no clinical manifestations). Can be confused with hyperthyroidism or thyroid hormone resistance syndromes. Patients with FDH may undergo unnecessary diagnostic testing or therapeutic procedures. FDH concurrent with primary hypothyroidism may complicate diagnosis or delay therapy. After a diagnosis of FDH is established, family screening is advisable All Rights Reserved. 78

79 Case 2: Unusual Thyroid Tests 53 year old female Complains of fatigue, weight loss, insomnia and palpitations BP 148/86, HR 100, BMI=23 CMP, CBC, lipids all within normal limits Thyroid gland is diffusely enlarged High TSH 6.45 uiu/ml ( ) High free thyroxine (T4) 2.05 ng/dl ( ) All Rights Reserved. 79

80 TSH producing pituitary adenoma High TSH, high or normal T3 and T4 Clinically hyperthyroid May be mistaken for primary hypothyroidism, hyperthyroidism or selective pituitary resistance to thyroid hormones Patients may be inappropriately treated with radioactive iodine or thyroid surgery Elevated molar ratio of α subunit to total TSH May cosecrete growth hormone All Rights Reserved. 80

81 Case 3: Unusual Thyroid Tests 28 year old female Complains of fatigue, weight gain, heavy menses BP 94/66, HR 80, BMI=27 CMP, CBC, lipids all within normal limits Normal thyroid exam Normal TSH 3.45 uiu/ml ( ) High total thyroxine Normal free thyroxine (T4) 1.02 ng/dl ( ) All Rights Reserved. 81

82 TBG Excess Most common cause of hyperthyroxinemia Clinically euthyroid Normal TSH High total T4 and normal free T4 High serum TBG Low T3 resin uptake (normal calculated free thyroxine index) Congenital or acquired All Rights Reserved. 82

Thank you! Scott Isaacs, M.D., F.A.C.P., F.A.C.E. drisaacs@atlantaendocrine.

Disorders of Thyroid Function

Disorders of Thyroid Function Michael T. McDermott MD Director, Endocrinology and Diabetes Practice University of Colorado Hospital Michael.mcdermott@ucdenver.edu Thyroid Hormone Axis Hypothalamus TRH