Errors in Modern Thyroid Endocrinology

Errors in Modern Thyroid Endocrinology by Jeffrey Dach MD Web Sites like Janie Bowthorpe's, Stop the Thyroid Madness and Dana Trentini's, Hypothyroid Mom are very popular for a very good reason. They identify and alert readers to the errors in modern thyroid endocrinology. Before we discuss these errors in detail, you might first ask the question, "How is this possible, that there could be errors in modern thyroid medical practice?" How Are Errors in Thyroid Medical Practice Possible? The answer to this question becomes obvious considering the money flowing from the drug industry to thyroid societies and doctors. In various forms, your doctor might be taking financial incentives (AKA bribes) from the drug industry. For example the American Thyroid Association and the Endocrine Society, the Endocrine Journals, Endocrine Research Grants, Endocrine Speakers Fees and Endocrine Meetings are all heavily funded by the Major Drug Companies, including the ones that make Synthroid, Levothyroxine and T4 only thyroid medications. This is all public information. Creating Guidelines For the Benefit of the Benefactors In 2012, the American Association of Endocrinologists and the American Thyroid Association, (ATA), published Guidelines for prescribing thyroid pills, which says: “There is no evidence to support using desiccated thyroid hormone in preference to L-thyroxine monotherapy in the treatment of hypothyroidism and therefore desiccated thyroid hormone should not be used for the treatment of hypothyroidism.” By some strange coincidence. the ATA (American Thyroid Association) receives substantial financial support from three drug companies: Pfizer, AbbVie, and Akrimax, makers of Levothyroxine, the same drug which is "Standard of Care" according to their "Guidelines". Endocrine Society is proud to publicly disclose their funding which comes from (among others) : AbbVie Inc. Akrimax Pharmaceuticals Alexion Pharmaceuticals, Inc. Amarin Pharma Inc. Bayer HealthCare Boehringer Ingelheim Pharmaceuticals, Inc. & Lilly USA, LLC Burroughs Wellcome Fund Corcept Therapeutics Incorporated Dexcom, Inc. Eisai Inc. Endo Pharmaceuticals Inc. Esaote North America, Inc. Ethicon Endo-Surgery, Inc. FNA Path Genentech, Inc. Janssen Pharmaceuticals, Inc. Lilly USA, LLC Merck & Co., Inc. Mindray Thyroid Ultrasound by CSD Novartis Pharmaceuticals Corporation Noven Pharmaceuticals, Inc. Novo Nordisk Inc. NPS Pharmaceuticals, Inc. Pfizer, Inc. Salix Pharmaceuticals, Inc. sanofi-aventis U.S. Inc sanofi-aventis U.S. Inc, Regeneron Pharmaceuticals Alliance Takeda Pharmaceuticals U.S.A., Inc. Toshiba Head and Neck Ultrasound Veracyte, Inc. I think you are starting to get the idea. You might be surprised to know that these Guidelines are wrong, a fact admitted by the ATA when they came up with different guidelines in 2014. nonetheless, the new Guidelines still serve the Drug Industry by rejecting natural desiccated thyroid in favor of T4 only medications, a recommendation having no basis in medical science. We will discuss this in detail below. Medical practice in the US is strongly influenced by guidelines promulgated by the medical societies. So when the leading Thyroid Endocrinology societies issue incorrect guidelines, you can understand how this leads to errors in the practice of thyroid endocrinology. Why Won't My Endocrinologist Listen to Me ? A frequent question that comes up a few times a day in my office is: "Why won't my endocrinologist listen to me?" Many of these patients are actually escapees from the endocrinology office, having been ignored and mistreated by a succession of "cookie cutter" endocrinologists who give them minuscule amounts of T4 only medication (usually Levothyroxine), which keeps the TSH in the "reference range" These poor miserable souls finally arrive in my office where we switch them from Levothyroxine to natural desiccated thyroid in a dosage that gives them some relief from low thyroid symptoms. We use Natural Desiccated Thyroid, One Grain Tab (60mg) contains 38 mcg T4 and 9 mcg T3 per tab, the same ratio produced by the normal thyroid gland. Author's note (Nov, 2020): Due to voluntary recall of Naturethroid by RLC, we have switched to NP thyroid from Acella, another similar natural desiccated thyroid product. Patients Prefer NDT over Levothyroxine A number of cross-over studies published in the mainstream endocrinology literature reveal a subset of patients don't feel well on T4-Only thyroid medication (Synthroid and Levothyroxine). This subset reports they prefer and feel better taking natural desiccated thyroid (NDT).(16-17) Shorter Half Life Makes Natural Thyroid Safer T3 has a shorter half life (T1/2) of one day (24 hrs), compared to the 7 day half life of T4 (Levothyroxine). This difference explains why NDT is a safer choice compared to T4 only meds such as levothyroxine. Symptoms of thyroid excess dissipate within a few hours of stopping NDT, while for the T4 only Levothyroxine, it may take a week for symptoms to resolve. We check labs prior to starting and after 6 weeks: TSH, FT4, FT3, TPO and Thyroglobulin Abs. We also routinely check serum selenium and spot urinary iodine. Thyroid Physiology The Thyroid Gland Produces T4/T3 in a ratio of 14:1 .(12) However the serum ratio of T4 to T3 is 4:1, similar to the ratio in NDT Natural Dessicated thyroid.(14)(1) `Each grain of Natural Dessicated Thyroid contains 38 Mcg of T4 and 9 Mcg of T3, thus the 4:1 ratio. Thyroid hormone is made by organifying iodine to thyroglobulin in the follicle at the apical membrane of the thyrocyes. This organification requires oxidation of Iodine by the TPO enzyme using hydrogen peroxide as a substrate. According to Dr Song in 2007, various thyroid pathologies can be explained by overproduction and lack of degradation of hydrogen peroxide (H2O2), such as thyroiditis, cancer etc. (7) Hydrogen peroxide is degraded by seleno-proteins such as (Glutathione) GSH peroxidase and thioredoxin reductase. Selenium deficiency is associated with thyroid damage from excess hydrogen peroxide. We routinely check the serum selenium level and give selenium supplements to those with low selenium levels. For more on, this see the Selenium and the Thyroid. The List of Errors in Thyroid Endocrinology Reliance on TSH Only to Monitor Treatment. (2) TSH Suppression may be needed for Adequate Treatment.(4) Reliance of T4 Only-Monotherapy (Levothyoxine or Synthoid) (5) NDT –Natural Desiccated Thyroid Better Choice. (17) Shorter Half Life-makes NDT safer choice. NDT Combines T3 and T4 - more robust for poor converters. Ignoring the Beneficial Effects of Selenium, Vitamin D and Gluten Free Diet in Hashimotos Auto-Immune Thyroid Disease.(19) TSH Can Be Unreliable The TSH can be unreliable in a number of medical conditions such as: Hypothalamic Dysfunction, Chronic Fatigue, Fibromyalgia Patients (20-22) More on this can be found in "The Unreliable TSH". Relying on TSH WIthin Reference RAnge In 2016, Antonio Bianco studied 469 Levothyroxine (T4) treated patients compared to controls. The Levothyroxine treated patients more likely to have lower serum T3:T4 ratios, higher BMI (Weight), more likely to be taking Beta-Blockers drugs, Statin drugs, and SSRI Anti-depressant drugs. And they were more likely to suffer from cognitive Impairment.(2) In 2016, Antonio C. Bianco, MD, PhD, past president of the American Thyroid Association and professor of medicine at Rush Medical School says this (2): Despite normal TSH tests, these patients still have many nagging symptoms of hypothyroidism. “Patients complain of being depressed, slow and having a foggy mind,” said “They have difficulty losing weight. They complain of feeling sluggish and have less energy. Yet we doctors keep telling them, ‘I’m giving you the right amount of medication and your TSH is normal. You should feel fine.’” “Better medications (than Levo) are needed to treat hypothyroidism....Patients who continue to have symptoms on Levothyroxine monotherapy might try a pill that contains both T3 and T4. “ (2) TSH Suppression May be Needed for Adequate Treatment Dr. Ito from Japan says in 2012, TSH-Suppressive doses of Levothyoxine may be needed to achieve pre-operative T3 levels after thyroidectomy.(4) More than 20% of patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion.” (4-6) Levothyroxine-T4 Alone does not resolve symptoms of Hypothyroidism Dr Elizabeth A. McAninch from Rush in Chicago writes in 2015.(3): "Unfortunately therapy with L-T4 alone does not resolve symptoms in all hypothyroid patients, with approximately 12% of the patients remaining symptomatic despite normalization of serum TSH and TH (thyroid hormone) levels. Impaired cognition, fatigue, and difficulty losing weight are the main residual symptoms of these patients, for which we lack understanding and have no mechanistic explanation."(3) Iodine Excess and Selenium Deficiency In the face of selenium deficiency, excessive iodine intake will Induce Goiter, lead to thyroiditis, worsen lymphocytic infiltration, and damage the thyroid follicular structure in a dose-dependent manner in NOD autoimmune mice.(8) However, addition of selenium is protective in this NOD mouse model, alleviates this iodine toxicity effect, and the anti-thyroid antibodies gradually decline. (9,18) Iodine Suppresses Thyroid Function Occasionally a patient will walk into the office after taking high dose iodine for a few months, and report they feel fine, however, their thyroid labs are "out of wack" which disturbs their endocrinologust or primary care doctor.(11) The TSH may be quite elevated (in the 50-70 range), caused by the suppressive effect of Iodine on the thyroid.(10-11) Dr Man studied the effect of iodine on thyroid function in a mouse model and writes in 2006: (10) "Moderate iodine excess continuously suppresses the thyroid iodine uptake and organification, which presents a mechanism for iodine-induced thyroid failure."(10) This reverses upon stopping the high dose iodine, and thyroid labs return to normal in a few weeks. High dose Iodine reduces TPO activity(9), reduces Iodine Uptake and reduces Iodine organification by the thyroid gland.(10) Autoimmune thyroid patients with Hashimotos or Graves are more sensitive to this suppressive effect of Iodine. (24) Peripheral Conversion of T4 to T3 The D2 deiodinase enzyme is responsible for the peripheral conversion of T4 to its more biologically active cousin, T3. This is done by removing an iodine molecule from the tyrosine skeleton. About 20% of patient have difficulty with peripheral conversion of T4 to T3. In this case, the thyroid labs in a patient taking Levothyroxine may show a lower ratio of T3 to T4 than in the general population. Thyroid labs on these patients may show Free T3 in the lower end of the lab range, while the Free T4 will be higher than usually seen, or at the high end of the normal range. These are the patients who do well by switching from Levothyroxine to NDT (Natural Desiccated thyroid) which contains T3 as well as T4. Central Conversion of T4 to T3 -The TSH Issue Here, it should be mentioned that the D2 deiodinase in the periphery is very sensitive to inhibition by Free T4. However centrally, in the hypothalamus of the brain which controls TSH, D2 deiodinase is relatively insensitive to inhibition by Free T4. This means that Levothyroxine (T4) will be converted to T3 in the hypothalamus which is then recognized by the brain as thyroid excess and will suppress the TSH (thyroid stimulating hormone). While in the periphery, at the cellular level, this T4 from thyroxine is sensed as "thyroid excess" and triggers a "protective effect" which inhibits the D2 deiodinase, and upregulates the D3 deiodinase. This results in shunting of T4 to reverse T3, the inactive form. Thyroid labs may show lower Free T3 levels, higher Free T4 (from the levothyroxine) and higher reverse T3, yet the TSH will be suppressed down into the lab range or even below the lab range in some cases. This patient is symptomatic with a low thyroid condition, yet the clinician who dogmatically relies on the TSH "in the normal range" will fail to recognize this. Typically the patient will be offered an SSRI antidepressant with a pat on the back, or referral to a psychiatrist, obviously the wrong treatment. Under this scenario, these patients do much better switching from Levothyroxine to NDT which allows for better Free T3 levels at the cellular level, and resolves the patients symptoms of a low thyroid condition. This is one of the errors in modern thyroid endocrinology. Reverse T3- The Inactive Form Another Deiodinase Enzyme, called D3 orType 3, converts T4 into Reverse T3, the inactive form and stereo-isomer of T3. High reverse -T3 is typical for thyrotoxicosis of Graves' Disease, Toxic Nodular Goiter and the Autonomous Thyroid Nodule. Reverse T3 conversion is a safety mechanism protecting the patient from toxic effects of massively elevated levels of thyroid hormones. The low thyroid condition (hypothyroidism) typically shows a low reverse T3 on lab testing. In this scenario, the cells in the peripheral tissues upregulate the D2 Deiodinase enzyme to convert T4 to T3, its active form. At this same time the D3 deiodinase enzyme is down regulated to prevent conversion of T4 to reverse T3, the inactive form. High reverse T3 may also be found in other conditions referred to as: "euthyroid sick syndrome" . This can be seen in acute or chronic illness. Although elevated reverse T3 in chronic illness can be observed, it is poorly understood, and the question of treatment is a matter for debate. After routinely measuring reverse T3 over the years, I have found this lab test usually confirms what we already know from the history, physical exam and other routine labs. For example, a high Reverse T3 in may be found in the thyrotoxic patient. A high Reverse T3 may be found in a low thyroid patient who remains symptomatic in spite of suppressed TSH under treatment with levothyroxine as discussed above. Alternatively, a low reverse T3 usually confirms hypothyroidism in the untreated patient. However, occasionally it may be difficult to interpret a high reverse T3. For example, I recall an asymptomatic patient who seemed well with hormal thyroid labs with the exception of a very high reverse T3 of 28 (normal range 10 - 24 ng/dL). Since the patient seemed fine and the other thyroid labs were normal, I interpreted this as a lab error ! A few weeks later my office was informed the patient had undetected advanced cancer, and quickly succumbed to the extensive metastatic disease. In retrospect, the high reverse T3 was a marker of a critical illness, and cancer. Reverse T3 is upregulated in cancer cells, serving as a cancer marker. (30-37) Supraphysiologic Dosing T3 ? Studies show that human thyroid T4/T3 secretion ratio is 14:1, while for the natural desiccated thyroid pill this ratio is about 4:1. One major criticism of NDT (natural desiccated thyroid) is that the 4:1 T4/T3 ratio in the natural thyroid pill provides excessive amounts of T3, producing "supra-physiologic dosing".(12) For example, Dr Dayan in 2018 Thyroid Research says : "The doses (for NDT) give a T4:T3 ratio of 4.2:1 significantly more T3 than the 14:1 secreted by the normal thyroid and the doses recommended above. This makes dosing difficult as displayed by several studies which have shown supraphysiological T3 doses post dose, fluctuating T3 levels during the day and more hyperthyroid symptoms in subjects taking DTE compared to LT4 monotherapy." (12) "Furthermore, it has also been shown that the majority of circulating T3 comes from peripheral conversion of T4 to T3 and not secretion of T3 from the thyroid , hence a T4:T3 secretion ratio of approximately 14:1 appears average in humans, suggesting only a small role for secreted T3.:(12) This 14:1 (T4:T3) ratio is quite different from the article by Dr Milner in 2007 Townsend Letter who says the ratio is 4:1 for T4/T3.(14) Dr Milner's 4:1 ratio is closer to the reported values of Dr. Grmek in the 2015 Slovenian Medical Journal who studied the free thyroxine to free triiodothyronine ratios (FT4:FT3) in 225 patients.(1) Dr Grmek studied 225 patients average age 44 years old. The mean Free T4 to Free T3 ratio was found to be 2.86 ± 0.52.(1) This discrepancy in ratios can be explained by the peripheral conversion of T4 to T3. Of the circulating Free T3, about 20 % comes from thyroid secretion, the remaining 80% from peripheral conversion of T4 to T3 via the Type 2 De-Iodinase Enzyme. Although studies show a transient rise in serum Free T3, 2-3 hours after ingestion of cytomel (T3), it is very rare that patients have a problem with this. If reported, then dosage is decreased and symptoms resolve. Likewise, we have patients taking 50 mcg of Cytomel a day (in 2 or three doses) and most seem to do well with it. If there are symptoms of transient hyperthyroidism then dosage is decreased until symptoms resolve. In other words we have not found "supraphysiologic dosing of T3" to represent an actual clinical problem with the short acting T3 in Liothyronine (cytomel) or in natural desiccated thyroid. Perhaps this is because our patients are carefully instructed to hold and then decrease dosage if thyroid excess symptoms are noted. Compounded Slow Release T3 A strategy which avoids the peak in Serum T3 and avoids "supraphysiologic dosing" is the use of compounded slow release T3. Some practitioners will prefer to use a combination of Levothyroxine (T4-half life 7 days) and compounded slow release T3. The nuts and bolts of dosing with this combination is explained nicely by Dr Martin Milner in the 2007 Townsend Letter (NDT and compounded slow release T3), and by Dr Colin Dayan in this 2018 article in Thyroid Research.(Levothyroxine and T3-Cytomel) Errors in Compounding T3 Capsules When using compound slow release T3 preparations, one must be careful to select a high quality pharmacy with experience with this product. If an error is made in the formulation with unusually high dosages of T3 in the capsule by mistake, this could lead to hospitalization for thyrotoxicosis. An FDA warning letter to a New Jersey Compounding pharmacy illustrates an error in compounded T3 formulation.(15) The misbranded T3 capsules contained by error 2.5 mg T3, instead of the correct dosage 2.5 mcg T3, a dosage one thousand times higher than prescribed by the doctor. (15) One obvious advantage of manufactured thyroid tablets whether T4-only Levothyroxine or Natural Dessicated Thyroid is greater standardization in the manufacturing process which eliminates this type of human error in compounding thyroid capsules by hand. For this reason, I avoid prescribing compounded thyroid capsules. T4 and NDT Combination A number of practitioners and thyroid internet experts have written about adding a small dose of Levothyroxine to their NDT regimen. This idea is based on the difference in the T4: T3 ratio of NDT (4:1) and the ratio of secretion by the human thyroid (12:1). By adding a small dose of Levothyroxine to the daily regimen, this ratio comes closer to the ideal 12:1, and more importantly, some patients report feeling better with it. 98:1 Ratio for T4:T3 Dr Kenneth Blanchard, an endocrinologist who practiced in Newton, Mass wrote, Functional Approach to Hypothyroidism , describing his routine use of small doses of slow release compounded T3 added for patients on T4 only medications (Levothyroxine). The doses he used are less than 2.5 micrograms of compounded slow release T3. Dr Blanchard states that in his opinion, higher doses of T3 (cytomel) such as to 25 or 50 mcg tablets are much too high, and explains the failure of mainstream endocrinology clinical trials using combinations of T4 and T3. The T3 dosage was too high !! (26) So, as we have seen above, expert practitioners claim success with T4:T3 ratios with a considerable range, from 4:1 all the way up to 98:1 (T4:T3) ratio. How do we reconcile these apparently contradicting treatment ratios? My best guess is that the Deiodinase System for intracellular conversion is more robust than we had originally thought, and is able to compensate for various T4:T3 ratios and keep things running smoothly. Many of the millions of thyroid patients on T4 Monotherapy, (Synthroid or Levothyroxine), prescribed by their endocrinologist are doing quite well with it. However, a subset of these patients feel better when switched to Natural Desiccated Thyroid which contains T4:T3 in a 4:1 ratio. NDT is the preferred thyroid tablet in my practice. Two renowned endocrinologists, Broda Barnes MD and William McKJeffries found the 4:1 T4:T3 ratio in NDT quite satisfactory without the need to experiment with other ratios.(27-28) Yet another smaller subset of patients feel better with the combination of NDT and Levothyroxine (T4-Only) providing a 14:1 ratio. Yet another subset, according to Dr Kenneth Blanchard, does well on T4 monotherpy with even smaller doses (1-2 mcg) of slow release compounded T3. What is the correct ratio? My answer is: "The one that works for you!" Medical Model Determines Thyroid Usage CASH Model-NDT: Doctor spends more Time with patient. (30 min) Suppressed TSH May be required for adequate treatment. Labs: Doctor looks at TSH, FT3, FT4, RT3 ,TPO and Thyroglob Abs. Doctor spends 5 min explaining risks and adverse effects of thyroid pills. Insurance Model - Synthroid Levo : Doctor spends less time with patient.(3-10 min.) Doctor keeps TSH within lab-range (0.3-3.0), Doctor Adjusts T4 Dosage based on keeping TSH within lab range. The Doctor has no time to explain adverse effects. Conclusion: Errors in Modern Thyroid Endocrinology are understandable considering the corrupting influence of industry funding of thyroid endocrine societies, meeting, research and key opinion leaders. The main error is dogmatically insisting the TSH stay within the reference range when TSH suppression may be required for adequate therapy. The second error is dogmatically insisting on T4 monotherapy, when natural desiccated thyroid (containing both T3 and T4) is more effective and safer than T4 monotherapy. Articles with related interest: Which Thyroid is Best, Natural Synthetic or Combination? Antonio Bianco says TSH Inadequate for Levothyroxine Dosage TSH Suppression, Benefits and Adverse Effects Natural Thyroid is Better than Synthroid Part One Natural Thyroid is Better than Synthroid Part Two Link to Free Download pdf file of Power Point Presentation: Errors in Modern Thyroid Endocrinology_2017_JDach_A4 Link to this article: http://wp.me/p3gFbV-5b4 Natural Thyroid Toolkit If you liked this article, you might like to buy ebook for $9.99 as pdf file format. Also available as paperback on Amazon for 39.95 as Natural Thyroid Toolkit available on Amazon. If you purchase a book, remember to leave a favorable review. That would be much appreciated. See the book cover, left image. FREE: Or, you might like my Free: Natural Thyroid Toolkit Video Series. Jeffrey Dach MD 7450 Griffin Road, Suite 180 Davie, Fl 33314 954-972-4663 www.jeffreydach.com www.drdach.com www.naturalmedicine101.com www.bioidenticalhormones101.com www.truemedmd.com Jeffrey Dach MD 7450 Griffin Road, Suite 190 Davie, Fl 33314 954-792-4663 Links and References 1) Grmek, Jernej, et al. "Usefulness of free thyroxine to free triiodothyronine ratio for diagnostics of various types of hyperthyroidism." Slovenian Medical Journal 84.5 (2015). Usefulness of free thyroxine to free triiodothyronine ratio for diagnostics of various types of hyperthyroidism Grmek Jernej Slovenian Medical Journal 2015. 225 pts 44 y/o Free T4 to Free T3 ratio 2.86 ± 0.52 the mean fT4/fT3 ratio in HS (2.86 ± 0.52) 2) Peterson, Sarah J., Elizabeth A. McAninch, and Antonio C. Bianco. "Is a Normal TSH Synonymous With “Euthyroidism” in Levothyroxine Monotherapy?." The Journal of Clinical Endocrinology & Metabolism 101.12 (2016): 4964-4973. 3) McAninch, Elizabeth A., et al. "Prevalent polymorphism in thyroid hormone-activating enzyme leaves a genetic fingerprint that underlies associated clinical syndromes." The Journal of Clinical Endocrinology & Metabolism 100.3 (2015): 920-933. 4) Ito, Mitsuru, et al. “TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy.” European Journal of Endocrinology 167.3 (2012): 373-378. TSH-suppressive doses of levothyroxine are required to achieve levels post thyroidectomy Ito 2012 Center for Excellence in Thyroid Care, Kuma Hospital, 8-2-35, Shimoyamate-Dori, Chuo-Ku, Kobe-City, Hyogo 650-0011, Japan 5) Gullo, Damiano, et al. "Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients." PloS one 6.8 (2011): e22552.. 6) de Castro, Joao Pedro Werneck, et al. “Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine.” The Journal of clinical investigation 125.125 (2) (2015): 0-0. quote:“normalization of serum TSH with L-T4 monotherapy results in relatively low serum 3,5,3′-triiodothyronine (T3) and high serum thyroxine/T3 (T4/T3) ratio” 7) Song, Yue, et al. "Roles of hydrogen peroxide in thyroid physiology and disease." The Journal of Clinical Endocrinology & Metabolism 92.10 (2007): 3764-3773. Roles of hydrogen peroxide in thyroid physiology and disease Song Yue J Clin Endo Metab 2007 8) Teng, X., et al. "Experimental study on the effects of chronic iodine excess on thyroid function, structure, and autoimmunity in autoimmune-prone NOD. H-2h4 mice." Clinical and experimental medicine 9.1 (2009): 51. However, supplemental Selenium alleviates the toxic effects of excessive Iodine on thyroid." (See Xu and Wang) 9) Xu, Jian, et al. "Supplemental selenium alleviates the toxic effects of excessive iodine on thyroid." Biological trace element research 141.1-3 (2011): 110-118. 10) Man, N., et al. "Long-term effects of high iodine intake: inhibition of thyroid iodine uptake and organification in Wistar rats." Zhonghua yi xue za zhi 86.48 (2006): 3420-3424. 11) TAJIRI, JUNICHI, et al. "Studies of Hypothyroidism in Patients with High Iodine Intake." The Journal of Clinical Endocrinology & Metabolism 63.2 (1986): 412-417. 12) Dayan, Colin, and Vijay Panicker. "Management of hypothyroidism with combination thyroxine (T4) and triiodothyronine (T3) hormone replacement in clinical practice: a review of suggested guidance." Thyroid research 11.1 (2018): 1. Furthermore, it has also been shown that the majority of circulating T3 comes from peripheral conversion of T4 to T3 and not secretion of T3 from the thyroid , hence a T4:T3 secretion ratio of approximately 14:1 appears average in humans, suggesting only a small role for secreted T3. The three methods give a final dose T4:T3 ratio between 13:1 and 20:1, much closer to normal human thyroid secretion but in generally lower than those used in the T4/T3 studies, in some cases significantly lower. Furthermore, many of the studies had variable ratios due to a fixed substitution (eg. 10μg T3 for 50μg T4). This dose ratio is also significantly lower than that of animal thyroid extracts in which the T4:T3 ratio is generally around 4:1 (see later). Note also however that for a patient previously on 100μg of T4 a day the T3 dose from these methods is between 4 and 6μg a day which with most current formulations would be difficult to deliver in a split dose. Table 3 displays commonly available brands and doses contained. The doses above give a T4:T3 ratio of 4.2:1 significantly more T3 than the 14:1 secreted by the normal thyroid and the doses recommended above. This makes dosing difficult as displayed by several studies which have shown supraphysiological T3 doses post dose, fluctuating T3 levels during the day and more hyperthyroid symptoms in subjects taking DTE compared to LT4 monotherapy 14) Hypothyroidism: Optimizing Medication with Slow-Release Compounded Thyroid Replacement by Martin Milner, ND National College of Naturopathic Medicine From the Townsend Letter February/March 2007 USP desiccated thyroid or Armour Thyroid is made with a ratio of four parts of T4 for every one part of T3. This ratio is comparable to those in the human and porcine thyroid glands, which produce 75% T4 and 25% T3. One grain of Armour Thyroid contains 36 µg of T4and 9 µg of T3. The T3 is released all at once, not slowly. As already discussed, the thyroid gland maintains a T4:T3 ratio of 4:1, but most patients who are symptomatic are converting an excessive amount of T4 into reverse T3. They need a ratio of T4:T3 of perhaps 3:1 or 2:1 or, rarely, even more T3 relative to T4. 15) FDA Warning Letter August 1, 2016 FDA WARNING LETTER Plainsboro Pharmacy 9 Schalks Crossing Road Plainsboro, NJ 08536 "As noted, FDA received a MedWatch report dated July 17, 2014, regarding an adverse event reportedly experienced by a patient who received sustained release liothyronine (T3) capsules prepared by your firm. The product was labeled liothyronine 2.5 meg per capsule. FDA analysis of a sample of the product received from the patient found that it contained approximately 2.3 mg of liothyronine per capsule, which far exceeds the label claim." 16) Pepper, Gary M., and Paul Y. Casanova-Romero. "Conversion to Armour thyroid from levothyroxine improved patient satisfaction in the treatment of hypothyroidism." Journal of Endocrinology, Diabetes & Obesity 2 (2014): 1055-1060. Conversion to Armour Thyroid_endocrinology-2-1055 17) Hoang, Thanh D., et al. "Desiccated Thyroid Extract Compared With Levothyroxine in the Treatment of Hypothyroidism: A Randomized, Double-Blind, Crossover Study." J Clin Endocrinol Metab 98.5 (2013): 1982-1990. Desiccated Thyroid Extract Compared With Levothyroxine Treatment of Hypothyroidism Hoang Thanh J Clin Endo Metab 2013 18) Wang, W., et al. "Effects of Selenium Supplementation on Spontaneous Autoimmune Thyroiditis in NOD. H-2h4 Mice." Thyroid: official journal of the American Thyroid Association 25.10 (2015): 1137. Selenium ameliorates toxic effect of Iodine in NOD mice (auto-immune prone) Antibody levels gradually decrease. 19) Liontiris, Michael I., and Elias E. Mazokopakis. "A concise review of Hashimoto thyroiditis (HT) and the importance of iodine, selenium, vitamin D and gluten on the autoimmunity and dietary management of HT patients. Points that need more investigation." Hell J Nucl Med 20.1 (2017): 51-56. Hashimoto thyroiditis and iodine selenium vitamin D gluten autoimmunity Liontiris Hell J Nucl Med 2017 20) Teitelbaum, Jacob. "Effective treatment of chronic fatigue syndrome." Integrative Medicine 4.4 (2005): 23-29. Effective Tretament of Chronic Fatigue Syndrome JAcob Teitelbaum 2005 Integrative Medicine 21) Holtorf, Kent. "Diagnosis and treatment of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in patients with chronic fatigue syndrome (CFS) and fibromyalgia (FM)." Journal of Chronic Fatigue Syndrome 14.3 (2007): 59-88. hypothalamic-pituitary-adrenal HPA dysfunction chronic fatigue syndrome fibromyalgia Holtorf 2007 22) Skinner GR, Thomas R, Taylor M, Sellarajah M, Bolt S, Krett S, et al. Thyroxine should be tried in clinically hypothyroid but biochemically euthyroid patients BMJ. 1997;314:1764. 23) Song, Yue, et al. "Roles of hydrogen peroxide in thyroid physiology and disease." The Journal of Clinical Endocrinology & Metabolism 92.10 (2007): 3764-3773. Roles of hydrogen peroxide thyroid physiology disease Song Yue J Clin Endo Metab 2007 24) Autoimmune_Thyroiditis_Dayan_NEJM_1996 (Full pdf) http://www.ncbi.nlm.nih.gov/pubmed/8649497 Dayan, Colin M., and Gilbert H. Daniels. "Chronic autoimmune thyroiditis." New England journal of medicine 335.2 (1996): 99-107. "However, iodine reduces thyroid secretion in both subjects with thyroid autoantibodies and those without thyroid autoantibodies, suggesting that it acts by inhibiting the biosynthesis and release of thyroid hormone rather than by augmenting thyroid autoimmunity." 47,48 "Euthyroid patients with (subclinical) chronic autoimmune thyroiditis would be expected to be more susceptible to the antithyroid effects of iodine because of the inability of the thyroid to escape from the inhibitory effects of excess iodine on the biosynthesis of thyroid hormone (Wolff–Chaikoff effect)" 25) Functional Approach to Hypothyroidism: Bridging Traditional and Alternative Treatment Approaches for Total Patient Wellness Paperback – November 27, 2012, by Kenneth Blanchard M.D. (Author) Hatherleigh Press 26) Hypothyroidism: The Unsuspected Illness by Broda Barnes (Author) Harper; 1 edition (January 1976) 27) Safe Uses of Cortisol 3rd Edition by William McK. Jefferies Charles C Thomas Pub Ltd; 3 edition (August 1, 2004) 28) Bianco, Antonio C., et al. "Paradigms of Dynamic Control of Thyroid Hormone Signaling." Endocrine Reviews 40.4 (2019): 1000. 29) Ganesan, Kavitha, and Khurram Wadud. "Thyroid, Euthyroid Sick Syndrome." (2018). 30) Patki, Vinayak, Aniket Kumbhojkar, and Praveen Khilnani. "Sick Euthyroid Syndrome: A Myth or Reality." Journal of Pediatric Critical Care (2017). Sick Euthyroid Syndrome Myth or Reality J of Pediatric Critic Care Patki Vinayak 2017 31) Peeters, Robin P., et al. "Serum 3, 3′, 5′-triiodothyronine (rT3) and 3, 5, 3′-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities." The Journal of Clinical Endocrinology & Metabolism 90.8 (2005): 4559-4565. 32) Moskovich, Dotan, et al. "Targeting the DIO3 enzyme using first-in-class inhibitors effectively suppresses tumor growth: a new paradigm in ovarian cancer treatment." Oncogene 40.44 (2021): 6248-6257. 33) Nappi, Annarita, et al. "Deiodinases and cancer." Endocrinology 162.4 (2021): bqab016. 34) Dentice, Monica, Dario Antonini, and Domenico Salvatore. "Type 3 deiodinase and solid tumors: an intriguing pair." Expert opinion on therapeutic targets 17.11 (2013): 1369-1379. 35) Goemann, Iuri Martin, et al. "Current concepts and challenges to unravel the role of iodothyronine deiodinases in human neoplasias." Endocrine-Related Cancer 25.12 (2018): R625-R645. 36) Teitelbaum, Jacob. "Part 2--protocols for treating an under active thyroid--despite normal blood tests." Townsend Letter for Doctors and Patients 241-242 (2003): 174-176. 37) Gomes-Lima, Cristiane, Leonard Wartofsky, and Kenneth Burman. "Can Reverse T3 Assay Be Employed to Guide T4 vs. T4/T3 Therapy in Hypothyroidism?." Frontiers in Endocrinology 10 (2019): 856. 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