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Thyroid Dysfunction: The Role of Nutrients, Toxins and Stress d Patrick P t i k Hanaway, H MD Genova Diagnostics Sex Hormones Thyroid Adrenals © 2012 2008 Patrick Hanaway, MD Mi h ll M dd ND Michelle Maddux, ND © 2012 2008 Technical Issues Clinical Questions Clinical Questions will be answered during the final fifteen (15) minutes of the webinar. © 2012 2010 Clinical Concerns – Hormonal Assessment Sex Hormones Thyroid Adrenals © 2012 2010 STRESS HPA Axis Hypothalamus & Pituitary ACTH Ad Adrenal l Cortex C t DHEA (anabolic) Cortisol (catabolic) Stress © 2012 2010 Cholesterol Pregnenolone Progesterone 17-OH-Pregnenolone 17-OH-Progesterone DHEA Androstenediol Androstenedione Testosterone DHT Corticosterone Cortisol (Glucocorticoids) (Androgens) Estrone (E1) Estradiol (E2) Aldosterone 2-OHE1 Cortisol & DHEA derive from same precursors 16α-OHE1 4-OHE1 2-MeOE1 Estriol (E3) 4-MeOE1 (Estrogens) Cholesterol Pregnenolone (Anabolic) Progesterone Androstenediol DHEA 17-OH-Pregnenolone Androstenedione Testosterone DHT Aldosterone Cortisol Cortisone (Catabolic) Androsterone Estrone (E1) Androstanediol Estradiol (E2) © 2012 2010 Stage - One © 2012 2010 Stage - Two © 2012 2010 Stage - Three © 2012 2010 STRESS HPA Axis Hypothalamus & Pituitary ACTH Ad Adrenal l Cortex C t DHEA (anabolic) Cortisol (catabolic) Stress © 2012 2010 HPA Axis STRESS HPT Axis Hypothalamus & Pituitary Hypothalamus & Pituitary y ACTH TSH Ad Adrenal l Cortex C t Thyroid T4 DHEA (anabolic) Cortisol (catabolic) Liver & Kidney rT3 T3 Cell Nucleus © 2012 2010 Factors that Affect Thyroid Factors that Affect Thyroid Function Function Factors that contribute to proper production of thyroid hormones • Nutrients: iron, iodine, Nutrients: iron iodine tyrosine, zinc, selenium vitamin E, B2, B3, B6, C, D Factors that increase conversion of T4 to RT3 • St Stress ess • Trauma • Low‐calorie diet • Inflammation (cytokines, etc.) • Toxins T i • Infections • Liver/kidney dysfunction • Certain medications T4 Factors that increase conversion of T4 to T3 • Selenium • Zinc RT3 T3 T3 and RT3 compete for binding sites it Nucleus/ Mitochondria Cell Courtesy of IFM Factors that inhibit proper production of thyroid hormones • Stress • Infection, trauma, radiation, Infection trauma radiation medications • Fluoride (antagonist to iodine) • Toxins: pesticides, mercury, cadmium, lead • Autoimmune disease: Celiac Factors that improve cellular sensitivity to thyroid hormones • Vitamin A Vitamin A • Exercise • Zinc © 2012 2010 Thyroid y Questionnaire Put a check by the following statements that apply to your family history, your personal history and the symptoms that you have: Hi History ___ My family (parent, sibling, child) has a history of thyroid disease ___ I've had a thyroid problem (i.e., hyperthyroidism, Graves' disease, Hashimoto's thyroiditis, postpartum thyroiditis, goiter, nodules, thyroid cancer) in the past ___ A member of my family or I have currently or in the past been diagnosed with an autoimmune disease ___ I have had radiation treatment to my head, neck, chest, tonsil area, etc. ___ I grew up, live, or work near or at a nuclear plant ___ Women: I have a history of infertility or miscarriage Signs and Symptoms ___ I am gaining weight for no clear reason or am unable to lose weight with a diet and exercise program ___ My "normal" body temperature is low (below 98.2° when I take it) ___ My y hands and feet are cold to the touch and I frequently y feel cold when others do not ___ I feel fatigued or exhausted more than normal ___ I have a slow pulse, and/or low blood pressure ___ I have been told I have high cholesterol © 2012 2010 Signs g of Low Thyroid y Function • Dry skin, elbow keratosis, brittle nails • Diffuse hair loss • Puffyy face, swollen eyelids; y edema in legs, g feet, hands • Elevated cholesterol, generally LDL • Easy bruising g Achilles tendon reflex • Prolonged • Keratoderma g thyroid y g gland • Enlarged © 2012 2010 Symptoms of Low Thyroid Function • Fatigue, usually persistent, especially on waking; less toward the evening • Cold C ld iintolerance, t l with ith cold ld extremities t iti • Slow speech, movement, heart rate • Morning stiffness, arthralgias, muscle pain/cramps, particularly in calves, thighs, and upper arms © 2012 2010 Symptoms of Low Thyroid Function • • • • Memory and concentration problems Memor Diffuse headache, migraines D Depression; i melancholia l h li Constipation: hard bowel movements and d decreased d ffrequency • Low libido • Reactive R ti h hypoglycemia l i © 2012 2010 Top 10 Signs and Symptoms when Suspecting Suboptimal Thyroid Function b l h d 1. Fatigue g 2. Weight Gain 3. Feeling Cold 4. Dry Hair and Skin 5. Hair Loss 6. Menstrual Irregularities 7. Edema 8 Muscle Aches and Joint Pain 8. 9. Constipation 10. Depression © 2012 2010 Comprehensive Thyroid Assessment © 2012 2010 © 2012 2010 What is the ‘optimal’ level of TSH? a) b) c) d) e) 0.4 – 4.5 0 4 – 3.0 0.4 30 0.4 – 2.5 0.4 – 2.0 1 3 – 1.8 1.3 18 © 2012 2010 TSH Controversy What is the Reference Range? In 2002, the National Academy of Clinical Bi h i t (NACB) iissued Biochemistry d new guidelines id li ffor the diagnosis and monitoring of thyroid disease. • TSH reference range may be too wide. • Newer research suggested that these older ranges included individuals with borderline thyroid disease disease. • When more sensitive screening was performed, 95% of the p population p tested actually y had a TSH level between 0.4 and 2.5 uIU/ml. © 2012 2010 TSH Controversy THEN, American College of Clinical THEN Endocrinologists (AACE) suggested that a new reference range of 0 0.3 3–3 3.0 0 uIU/ml should be adopted. American A i A Association i ti off Clinical Cli i l E Endocrinologists d i l i t medical di l guidelines id li ffor clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract, 2002. 8(6): p. 457-69. © 2012 2010 TSH Controversy • In NHANES III, of over 17,000 people evaluated, more then 80% had a serum TSH below 2.5 mIU/L. • TPOAb prevalence was lowest (<3%) with TSH 0.1 –1.5 mIU/L in women and 0.1 – 2.0 mIU/L in men and progressively increased to above 50% when TSH exceeded 20 mIU/L. • TSH upper reference limits may be skewed by TPOAb TPOAb-negative ti individuals i di id l with ith occult lt autoimmune thyroid dysfunction. Hollowell H ll ll JG, JG ett al.l S Serum TSH TSH, T(4) T(4), andd th thyroid id antibodies tib di in i the th U United it d St States t population l ti (1988 tto 1994) 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. Feb 2002;87(2):489-99. Spencer CA, et al, National Health and Nutrition Examination Survey III thyroid stimulating hormone (TSH) thyroperoxidase antibody relationships demonstrate that TSH upper reference limits may be skewed by occult thyroiddysfunction J Clin Endcrinol Metab 2007 Nov;92(11):4236-40. thyroiddysfunction. Nov;92(11):4236-40 Epub 2007 Aug 77. © 2012 2010 Clinical Concerns – Hormonal Assessment Sex Hormones Thyroid Comprehensive y Assessment Thyroid How to Review a Report Adrenals Adrenocortex Stress Profile How to Review a Report © 2012 2010 Adrenocorticol Hyperactivity • Life-saving Life saving in the short-term! short term! (catabolism frees up energy reserves) • Persistent cortisol production Æ immune suppression, hyperglycemia, insulin resistance, central adiposity, hypertension, memory impairment (hippocampal damage), hyperlipidemia, impaired hepatic T4ÆT3 conversion i © 2012 2010 Hypothalamus TRH Pituitary TSH Liver or Kid Kidney (5’deiodinase) (Se) rT3 T3 (Inactive) (Active) ~ 85% Thyroid y Gland 5% % T3 (5 deiodinase) 95% T4 Cell Nucleus © 2012 2010 TRH Hypothalamus Pituitary TSH Liver or Kid Kidney 95% T4 rT3 T3 (Inactive) (Active) 5% % T3 STRESS Thyroid y Gland Cell N l Nucleus © 2012 2010 Reverse T3 (rT3) • T4 is also converted to rT3 which is metabolically inactive but binds to the same nuclear receptors as T3 • In Euthyroid Sick Syndrome (ESS) and in Low T3 Syndrome, T4 is normal or high, TSH is normal or slightly low, but T3 is low, and rT3 levels are high, © 2012 2010 Adrenocorticol Hypoactivity yp y • High CRH is also possible in adrenal h hypoactivity ti it (lack (l k off iinhibitory hibit cortisol ti l feedback f db k Æ persistent output of CRH Æ excessive adrenalin production) • Low cortisol Æfatigue, hypotension, hypoglycemia, sugar cravings, increased inflammatory response, conversion T4 to T3. © 2012 2010 TRH Hypothalamus Pituitary TSH Liver or Kid Kidney 95% T4 rT3 T3 (Inactive) (Active) 5% % T3 Chronic Stress Thyroid y Gland Cell N l Nucleus © 2012 2010 Factors Promoting g Conversion of T4 to T3 Micro-nutrients: Micro nutrients: selenium, potassium, iodine, iron, zinc Vitamins: A, E, riboflavin Hormones: cortisol (physiologic doses) growth hormone, testosterone insulin, glucagon melatonin © 2012 2010 Other 5’ 5 -Deiodinase Deiodinase Inhibitors • • • • • • • • • Excess cortisol,, catecholamines Selenium deficiency protein, excess sugar g Deficient p Chronic illness (cytokines, free radicals) Compromised liver or kidney function Cd, Hg, Pb toxicity Herbicides, pesticides Polycyclic aromatic hydrocarbons Oral contraceptives, excess estrogen © 2012 2010 Thyroid’s Relationship t Other to Oth Hormones H • High adrenal activity impairs 5’ deiodinase Æ hi h T4 higher T4, llower T3 T3, normall or elevated l t d TSH • Low adrenal activity may result in lower T4, higher T3 T3, normal or elevated TSH • With Low Cortisol and elevated CRH Æ XS adrenalin desensitizes T3 receptors p Æ T3 resistance AND higher T3, despite symptoms of hypothyroid • XS adrenalin d li Æ lowering l i T4 Æ symptoms t off hypothyroid Æ patient intolerant of thyroid supplementation (balance adrenals first!) © 2012 2010 Thyroid’s Relationship t Other to Oth Hormones H • Hypothyroidism yp y associated with less deactivation of cortisol to cortisone (hyperthyroidism Æ opposite) • Hypothyroidism stimulates CYP3A4 Æ increased production of 16αOHE1 • Hypothyroid decreases concentration of SHBG Æ more bioavailable E2 and testosterone • Hyperthyroid increases SHBG Æ less bioavailable E2 and testosterone © 2012 2010 (Serum)… Case Study TSH = high ee T3 3 = high g normal o a Free Anti-TPO antibodies elevated e e ated © 2012 2010 (Saliva)… Case Study Cortisol = Normal DHEA = Low Normal (age-adjusted) © 2012 2010 Auto-Immunity and Thyroiditis Three major thyroidal auto-antigens: • • • Thyroglobulin (Tg) y p peroxidase ((TPO)) Thyroidal TSH receptor (TSH-R) © 2012 2010 What % of Americans have auto-immune Thyroid Ab? a) b) c) d) e) 2.5% 5.0% 7.5% 10 0% 10.0% 12.5% J Clin Endo Metab ePub Aug 7, 2007 doi:10.1210/jc.2007.0287 © 2012 2010 Why Test Thyroid Antibodies? • It is the most common autoimmune disease in the United States. • It is the most common cause of hypothyroidism yp y in the United States. • It affects women four times more than men: – Up to 20% of menopausal women – Up to 24% of allergic women – 5–10% of postpartum women © 2012 2010 Autoimmune Thyroid Disease • Anti-TPO: attacks thyroid peroxidase, which is important in the production of thyroid hormones. • TgAb: attacks thyroglobulin, which is essential in the production of the T4 and T3 thyroid hormones hormones. © 2012 2010 © 2012 2010 Anti-Tg and Anti-TPO Antibodies (formerly known as microsomal antibody) • Most sensitive measure to diagnose g chronic thyroiditis • Elevated in 85-90% of chronic thyroiditis patients • Elevated in 97% of patients with Graves disease or Hashimoto’s thyroiditis • Titers will fall with successful treatment of either Graves or Hashimoto’s • CHECK FOR OTHER AUTOIMMUNE Dz © 2012 2010 Diet: Gluten,, Celiac Disease and Thyroid Function Study St d off 241 untreated t t d celiac li disease di patients ti t vs. 212 controls confirmed that patients with celiac disease are at increased risk for developing thyroid disease with an overall tthreefold ee o d higher g e frequency eque cy than t a in controls co t o s (30% vs. 11%). Sategna-Guidetti S t G id tti C, C ett al.l Prevalence P l off thyroid th id disorders di d in i untreated t t d adult d lt celiac disease patients and effect of gluten withdrawal: an Italian multicenter study. Am J Gastroenterol. 2001 Mar;96(3):751-7. © 2012 2010 After 1 year on a gluten-free diet: • Subclinical hypothyroidism normalized in 10 of 14 (71%) patients with non-autoimmune disease. • In three of five (60%) patients with autoimmune th thyroid id disease di (AIT), (AIT) there th was a shift hift to t AIT with ith euthyroidism. • In four of five subjects j with no improvement in thyroid function, compliance with the diet was poor. Sategna-Guidetti C, et al. Prevalence of thyroid disorders in untreated adult celiac disease patients and effect of gluten withdrawal: an Italian multicenter study. Am J Gastroenterol. 2001 Mar;96(3):751-7. © 2012 2010 “Molecular mimicryy has longg been implicated as a mechanism by which microbes can induce autoimmunity. autoimmunity.” Endocrine Rev 1993;14(1):107-133. © 2012 2010 Thyroid Auto-Immunity and Bacterial Overgrowth • Small Intestinal Bacterial Overgrowth (SIBO) is an abnormally high bacterial population in the small intestine • Luminal bacterial modulate gastrointestinal symptoms and interfere with ith T4 absorption b ti • 54% of patients with hypothyroidism due to o au autoimmune o u e thyroiditis y o d s were e e pos postive e for SIBO. J Clin Endocrin Metab ePub Aug 14, 2007 doi: 10.1210/jc.2007-0606 © 2012 2010 Thyroid Autoimmunity – Cli i l A Clinical Approach h • Rule out antigenic and inflammatory triggers: – Celiac/gluten sensitivity (may promote multiple autoimmune endocrinopathies) – Food hypersensitivities – Dysbiosis, leaky gut – Heavyy metal toxicityy • Rule out adrenal insufficiency (low cortisol) Anti-inflammatory inflammatory measures, e.g., fatty acid • Anti balancing • Correct nutrient imbalances © 2012 2010 Factors that Affect Thyroid Factors that Affect Thyroid Function Function Factors that contribute to proper production of thyroid hormones • Nutrients: iron, iodine, Nutrients: iron iodine tyrosine, zinc, selenium vitamin E, B2, B3, B6, C, D Factors that increase conversion of T4 to RT3 • St Stress ess • Trauma • Low‐calorie diet • Inflammation (cytokines, etc.) • Toxins T i • Infections • Liver/kidney dysfunction • Certain medications T4 Factors that increase conversion of T4 to T3 • Selenium • Zinc RT3 T3 T3 and RT3 compete for binding sites it Nucleus/ Mitochondria Cell Courtesy of IFM Factors that inhibit proper production of thyroid hormones • Stress • Infection, trauma, radiation, Infection trauma radiation medications • Fluoride (antagonist to iodine) • Toxins: pesticides, mercury, cadmium, lead • Autoimmune disease: Celiac Factors that improve cellular sensitivity to thyroid hormones • Vitamin A Vitamin A • Exercise • Zinc © 2012 2010 Questions & Answers Register R i ffor upcoming i LiveGDX Li GDX Webinars W bi online @ www.gdx.net © 2012 2010 © 2012 2010 © 2012 2010 © 2012 2010 LiveGDX © 2012 2010 Upcoming LiveGDX Webinars The Endocrine Pyramid • 6/27/12 – Sex Hormone Dysfunction: » The Role of Stress, Nutrients & Inflammation • 7/23/12 – Cortisol Steal & A/C Balance: » Stress and Steroid Metabolism • 8/22/12 – Essential Estrogens » Diet and Cancer Risk Sex Hormones Thyroid Adrenals © 2012 2010