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Home , Deiodinase, GPX3, Iodothyronine deiodinase, Thyroid peroxidase

Autoimmune Disease

Michael Friedman, ND Executive Director Association for the Advancement of Restorative Medicine Financial Disclosure:Owner and Science officer of Restorative Formulations

1 Thyroid Prevalence

 Diseases of the thyroid are not common in medical practice - 1967  13 million nationally may have undiagnosed abnormal thyroid function in 1995  11.7% abnormal TSH*  20 million 2017

*Canaris GJ, Manowitz, NR, Mayor G, Ridgway EC. The Colorado Thyroid Disease Prevalence Study. Arch Intern Med.2000;160:526-534 2 Autoimmunity

 Steady increase in the incidence and prevalence of autoimmunity

worldwide.

 Rate of increase (% increase every year) globally – 19.1±

43.1.*

 *Lerner, A. , Jeremias, P. , & Matthias, T. (2015). The World Incidence and Prevalence of Autoimmune Diseases is Increasing.International Journal of Celiac Disease, 3(4), 151-155 4 5 6 Examples of Thyroid Diseases

1°

7 www.hsc.missouri.edu/~daveg/thyroid/thy_dis.html 8 9 Autoimmunity – Genetics Vs Environment

Autoimmune thyroid disease

Genetics ~ Environmental triggers ~

Brent GA. Environmental Exposures and Autoimmune Thyroid Disease.Thyroid. 2010;20(7):755-761. 10doi:10.1089/thy.2010.1636. ❖Life stress Environmental triggers

❖Infections

❖Nutritional deficiencies (,

)

❖Smoking

❖Medications such as Amiodarone and

interferon

❖Radiation

❖Heavy metals & Pesticides ❖Environmental toxicants

11 ❖Intestinal dysbiosis Environmental Factors

 Coal combustion: 400 metric tons a year of mercury

 Rocket Fuel Combustion- 20 million pounds in US per year

(Lausanne). 2017 Mar 20;8:50. doi: 10.3389/fendo.2017.00050. eCollection 2017. Mercury emissions from the eight highest emitting industry sectors. Data for 2010 from the 2013 UNEP Global Mercury Assessment. Total estimated global anthropog Ferrari SM, Fallahi P, Antonelli A, Benvenga S. Environmental Issues 12 in Thyroid Diseases. Front Endocrinol enic mercury emissions are 1960 metric tons. Antibodies and Toxins: The Five Crucial Players That Affect Thyroid Function

Sodium Symporter (NIS) Thyroid Iodothyronine (Conversion) Thyroid Receptors

13 Radiation affects NIS

 Release of Iodine 131 from nuclear power plants and nuclear weapon facilities.

 US atomic weapons tests in Nevada, Millstone nuclear

power plant in Connecticut.

Völzke H1J Clin Endocrinol Metab. 2005 Aug;90(8):4587-92. Epub 2005 May 10. 14 Occupational exposure to ionizing radiation is associated with autoimmune thyroid disease. Halogens affect NIS

 Chlorine, fluorine, and bromine - chemically related to iodine and compete with it, blocking iodine receptors in the thyroid gland.

 Chlorine /Fluoride - once and still used as a treatment option for hyperactive thyroid gland.

15 affects NIS

 Perchlorate - Environmental contaminant that blocks iodine/iodide uptake into the thyroid gland by affecting the iodine transport mechanism (the sodium/iodine symporter).*

*Wolff J. Perchlorate and the thyroid gland. Pharmacol Rev. 1998 Mar;50(1):89-105. 16 Polybrominated diphenyl ethers (PBDEs)  Found in 97% of U.S. residents serum. TSH declined 16% for every tenfold increase in PBDE’s.

Lin SM, Chen FA, Huang YF, Hsing LL, Chen LL, Wu LS, Liu TS, Chang-Chien GP, Chen KC, Chao HR. Negative associations between PBDE levels and thyroid in cord blood. Int J Hyg Environ Health. 2011;214(2):115-20. Chevrier J, Harley KG, Bradman A, Gharbi M, Sjödin A, Eskenazi B. Polybrominated diphenyl ether (PBDE) flame retardants and thyroid during pregnancy. Environ Health Perspect. 2010;118(10):1444-1449. http://www.environmentalhealthnews.org/ehs/news/flame-retardants-linked-to-altered-thyroid-hormones-in-pregnant-women

17 Organochlorine Pesticides affect NIS

 Can result in euthyroid goiter or hypothyroidism.*

Pesticide Exposure

 Thyroid hormone concentration change was consistently a response due to mixtures, but NOT usually to individual chemicals. **

*Howdeshell KL. A model of the development of the brain as a construct of the thyroid system. Environ Health Perspect. 2002; 110 Suppl 3:337-348. **Porter WP, Jaeger JW and Carlson IH. EndoEndocrine, immune and behavioral effects of aldicarb (carbamate), atrazine (triazine) and nitrate (fertilizer) mixtures at groundwater concentrations Toxicology and Industrial Health. 1999; 15 (1-2): 133-150.

18 HYPOTHALAMUS-PITUITARY THYROID AXIS DEIODINASE-CONTAINING TISSUES

TRH

PITUITARY

TSH

Development Growth Metabolism Cognition

WT D2KO

© 2013 BLab Exercise Triples Deiodinase 2 after Exercise

The BiancoLab at RUSH University Medical Center in Chicago

20 Heavy Metals, Sunscreen and Stress Affect Conversion- 5'-deiodination Inhibition

 Cadmium, Mercury, Lead toxicity**  Stress, Poor nutrition, Illness,

4-MBC and Octylmehtoxycinnamate* (found in sunscreen) Bioaccumulation in fish and human milk Decreases 5’ deiodinase activity

**Gupta P, Kar A. Cadmium induced thyroid dysfunction in chicken: hepatic type I iodothyronine 5'-monodeiodinase activity role of lipid peroxidation. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 1999;123:39-44. *Schmutzler C, Hamann I, Hofmann PJ, Kovacs G, Stemmler L, Mentrup B, Schomburg L, Ambrugger P, Grüters A, Seidlova-Wuttke D, Jarry H, Wuttke W, Köhrle J. Endocrine active compounds affect thyrotropin and thyroid hormone levels in serum as well as endpoints of thyroid hormone action in , and . Toxicology. 2004;205(1-2):95-102.

21 BPA –Affects Conversion

 Phthalates/BPA - Alter the body's thyroid hormone levels and potentially aggravate or even lead to thyroid disease.

Andra SS, Makris KC. Thyroid disrupting chemicals in plastic additives and thyroid health. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2012;30(2):107-51. doi: 10.1080/10590501.2012.681487. 22 Polychlorinated biphenyl (PCB) Affects Thyroid Receptors Structure of PCB’s similar to thyroid hormone

Bind to and interact with TH

Agonists or antagonists to TH

23receptor Intestinal Dysbiosis/ Microbiome

 Intestinal microbiota - Crucial for immunologic, hormonal and metabolic

 Functional thyroid disorders - Associated with bacterial overgrowth and a different microbial composition

Virili C, Centanni M. "With a little help from my friends" - The role of microbiota in thyroid hormone metabolism and enterohepatic 24 recycling.Mol Cell Endocrinol. 2017 Feb 4. Impact of Infections on the Thyroid

 Human parvovirus B19 (EVB19) and hepatitis C virus.  Interleukin-1, Interleukin-6 and TNF inhibit thyrotropin secretion.#  Mucocutaneous candidosis - 50% increase in hypothyroidism.*

#Larsen P.R. et al Williams Textbook of Endocrinology 10th ed 2003;p101 *Coleman R and Hay RJ. Chronic mucocutaneous candidosis associated with hypothyroidism: a distinct syndrome? British Journal of Dermatology . 1997;36 (1):24-29. 25 Medications

▪Lithium, ▪Radioactive Iodine

▪Amiodarone ▪Interferon ▪High dose Glucocorticoids ('steroids') ▪Sulfonamides ▪Oral cholecystographic agents for ▪Bexarotene visualization of the gall bladder ▪Ethionamide ▪Sunitinib and other kinase inhibitors ▪Anticonvulsants ▪Angiogenesis inhibitors such as lenalidomide

Drugs that interact with : an observational study from the Thyroid Epidemiology, Audit and Research Study (TEARS) Clin Endocrinol (Oxf). 2014 Jul 17. doi: 10.1111/cen.12559 26 Vitamin D3 and Hashimoto’s Disease  1,25-Vitamin D levels are lower in individuals with Hashimoto’s disease.

 Supplementation with vitamin D3 in animal models prevents the development of and MS.

27 Selenium and Thyroid Antibodies

 During the supplementation trial 50-100 mcg: • Serum selenium (Se) increased by 45%. • Plasma (GPX3) by 21%. • TPO-Ab decreased by 76%. • Graves Ophthalmopathy

28 In Thyroid, What Happens to Iodine After Absorption?

NIS Oxidation (H202+TPO) - - I I I2 Organification

TG TSH δ –Iodolactone and MIT, DIT, T3, T4 other iodinated lipids

However, organification of lipids will only occur with iodine intake in excess of the RDA.

•Prostaglandins Other Lipid Mediat. 2014 Aug;112:27-33. doi: 10.1016/j.prostaglandins.2014.07.001. Epub 2014 Jul 10. •6-iodolactone, key mediator of antitumoral properties of iodine. Environmental Toxins

 Diagnose it

 Decrease toxic load

 Heavy metal removal

 Eliminate halogens in diet and body

 Consider alternatives to certain medications

 Treat and bacterial or myco-overgrowth

30 General Thyroid Autoimmune Protocol

 Nutrition: Hypoallergenic diet, treat dysbiosis  Decrease environmental toxins  Vitamin D3 50,000 IU twice a week, or min 4000 IU daily  Fish oils (Omega 3-6-9)  Ensure healthy gut microbiome  Antioxidant supplements (selenium, vit E) which are thyro- protective

31 Environmental Triggers for Hypothyroid

Lifestyle: Remove Heavy Metals: ➢ Exercise ➢ DMSA 500 MG three ➢ Treat Dysbiosis times a week Remove Halogens: ➢ Liposomal Glutathione ➢ 25-50 mg Iodine a day for 500 mg Daily ➢ Fiber-10 grams several months to remove supplementation daily halogens

32 Specifics for Hypothyroid

Botanicals ➢ 25 mcg T3 BID supplements: Nutrition Supplementation: ➢ Or 100 mcg T4 ✓Iris, Kelp, Myrrh ➢ 5 drops of Lugol’s iodine or iodine supplement solution 12 mg BID for a min of three months to help with halogen displacement and iodine supplementation ➢ Selenium 400 IU ➢ Vitamin D3 4000 IU ➢ Methylcobalamin 800 mcg 33 Hashimoto’s Disease Case Study

TSH TPO AB

Initial After 5 years Initial After 5 years

34 15 year old boy Hashimoto’s Thyroiditis Iodine Case Study

TSH T3

Initial After 3 months Initial After 3 months

35 27 year old female Graves Disease

 B and T lymphocyte-mediated autoimmunity are known to be directed at 4 well-known thyroid antigens: • Thyroglobulin • • Sodium-iodide symporter •

36 Thyroid Stimulating Antibodies

 Thyroid Stimulating Immunoglobulin -Elevated in about 80% patients with Graves Disease (both treated and untreated).

 Elevated in 5 to 10% in patients with Hashimoto’s disease.

37 Different Side of Same Coin

 Graves' disease may sometimes evolve into Hashimoto's thyroiditis (and vice versa), indicating that the two disorders are closely related patho-physiologically.

 Tamai H, Ohsako N, Takeno K, et al. Changes in thyroid function in euthyroid subjects with a family history of Graves' disease: a follow-up study of 69 patients. J Clin Endocrinol Metab 1980; 51:1123.  Kraiem Z, Baron E, Kahana L, et al. Changes in stimulating and blocking TSH receptor antibodies in a patient undergoing three cycles of transition from hypo to hyper-thyroidism and back to hypothyroidism. Clin Endocrinol (Oxf) 1992; 36:211.  Case Rep Endocrinol. 2016;2016:6029415. doi: 10.1155/2016/6029415. Epub 2016 Mar 2.  Hashimoto's Thyroiditis and Graves' Disease in One Patient: The Extremes of Thyroid Dysfunction Associated with Interferon Treatment. 38 Bishay RH1, Chen RC1. Rosmarinic Acid and Thyroid Antibodies

 Botanicals containing Rosmarinic Acid: • Lowers Thyroid Stimulating Immunoglobulin levels

Sourgens H, Winterhoff H, Gumbinger HG and Kemper FH. Effects of Lithospermum officinale and Related Plants on 39 Hypophyseal and in the Rat. Pharmaceutical Biology 1986; 24 (2):53-63. Influences the regulation of T3 levels; an important component of glutathione peroxidase

Decreases inflammatory cytokines via NF- Selenium kappa-B inhibition, attenuating the inflammatory response

An ongoing double-blind placebo controlled clinical trial, the Graves’ Disease Selenium Supplementation trial (GRASS), which aims to establish the clinical role of selenium in the treatment

*Watt T, Cramon P, Bjorner J, Bonnema S, Feldt- Rasmussen U, Gludd C. Selenium supplementation for patients with 40 Graves’ hyperthyroidism (the GRASS trial): study protocol for a randomized controlled trial. Trials. 2013;14:119 Specifics for Hyperthyroid

Botanicals supplements: ➢ Treat Cardiovascular ✓Rosmarinic Acid 335 mg Symptoms Immediately- BID . Beta blockers - ✓Traditional Botanical Nutrient Supplementation: Atenolol (25 to Medicine Formula: 5 drops of Lugol’s iodine or 50 mg/day) Bugleweed, Lemon Balm, iodine supplement (12.5 mg) 3 ➢ Rauwolfia (Reserpine) - Extracts that contain times a day for 3 days; decreases the release and Rosmarinic Acid 12.5 mg followed by 300 mg of accumulation of lithium carbonate 3 times noradrenaline and contributes to hypotensive effects.

➢ Use with thianamides 41 concurrently is safe Graves Disease

TSI

Initial After 2 months

42 TSI Reference Values (under 130) Toxic Multi Nodular Goiter

Total T3

Initial After 3 months

43 TSH Reference Values (.35-5 mIU/ml) Total T3 Reference Values (60-181 ng/dl) Hyperthyroid Lab Report

44 Hyperthyroid Lab Report

45 Acknowledgements

Antonio C. Bianco, MD, PhD  Division of Endocrinology and Metabolism Rush University Medical Center  Chicago, IL 47