Hypothyroidism. The Best Tests, Meds, &  Vitamins.

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Hypothyroid in a Lyme disease treatment image from Marty Ross MD

"This paper is longer than usual. In it I provide a very detailed analysis of hypothyroidism in Lyme. Be patient as you read it. The "what to do part" is at the end. But to understand my recommendations you need to understand why most physicians approaches to thyroid illness do not work in Lyme." Marty Ross MD

Most of this article is from a paper I provided to my medical board trying to educate them about thyroid illness in Lyme disease. I show that:

  • current hypothyroid guidelines most doctors follow do not work in Lyme disease;
  • people with Lyme have peripheral thyroid disorderwhich is not found using TSH and T4 testing alone;
  • thyroid symptoms matter and often are more reliable in Lyme disease than testing to determine if one has low thyroid;
  • even a person with normal thyroid testing can have low thyroid based on his or her own unique "normal" thyroid levels;
  • comprehensive thyroid testing should include TSH, free T4, free T3, reverse T3, and TPO antibodies;
  • for most dessicated or armour thyroid is the best medicine;
  • low dose naltrexone (LDN) is very helpful for a type of low thyroid called Hashimoto's;
  • selenium, zinc, Vitamin D and non-toxic levels of iodine help.

If you want your physician to diagnoses and treat your low thyroid in Lyme disease as I propose here, print off this article and provide it to your physician. It contains a large number of references which physicians like when using new treatments like I propose here.

Background

Hypothyroidism is the clinical and biochemical consequence of low thyroid hormones and their effects on the tissues and organ systems. (1) It has numerous symptoms including changes in voice, dry skin, coarse hair, cold sensitivity, fatigue, muscle cramps, constipation, depression, slow thinking, poor memory, and changes in menses. (2,3) There are a number of signs including delayed ankle tendon reflexes, increased weight, and dry skin. (2,3) Laboratory abnormalities may include elevated thyroid stimulating hormone (TSH), low T4 and T3 thyroid measured as T4, free T4 (fT4), T3, free T3 (fT3), increased reverse T3 (rT3) and low fT3/fT4. (1,2,4)

In this paper I review current guidelines for the diagnosis and treatment of hypothyroidism. While the existence of these guidelines suggest some consensus regarding how to diagnose and treat this illness, there remains a large degree of controversy, and therefore, room for clinical judgment. There is a body of science and clinical experience that suggest the one size fits all population-based approach of relying just on TSH levels and free T4 levels along with using only T4 replacement therapy for a number of people is inadequate. In this paper I review the science and propose a different approach for my practice. This calls for treating people for a condition known as peripheral hypothyroidism.

Current Hypothyroid Guidelines

In 2012 The American Association of Clinical Endocrinologists and the American Thyroid Association (AACE/ATA Guidelines) published clinical practice guidelines for hypothyroidism in adults. (4) These guidelines conclude:

A serum thyrotropin (TSH) is the single best screening test for primary thyroid dysfunction for the vast majority of outpatient clinical situations. The standard treatment is replacement with L-thyroxine. The decision to treat subclinical hypothyroidism when the serum thyrotropin is less than 10 mIU/L should be tailored to the individual patient.

These guidelines did not support the use of nutritional supplements in the management of hypothyroidism.

However, in publishing the guidelines the authors state:

The guidelines are not inclusive of all proper approaches or methods, or exclusive of others. The guidelines do not establish a standard of care, and specific outcomes are not guaranteed. Treatment decisions must be made based on the independent judgment of health care providers and each patient’s individual circumstances. A guideline is not intended to take the place of physician judgment in diagnosing and treatment of particular patients ….

The European Thyroid Association published guidelines in 2012 (ETA Guidelines) regarding the use of T4 and T3 in the treatment of hypothyroidism. (1) The ETA Guidelines, recommended the experimental use of combination T4/T3 therapy. This recommendation is based on evidence showing 5 to 10% of people treated with T4 continue to have symptoms of low thyroid with low T3/T4 ratios while on T4. The ETA considered evidence showing increased patient preference for combination therapy and improved symptoms of low thyroid.

Subsequently, The American Thyroid Association reviewed the data on combination therapy and published updated guidelines in 2014 (ATA 2014 Guidelines). (2) The ATA recommended T4 only therapy and further research on the potential benefits of combination therapy. The ATA also suggested research on the use thyroid replacement with thyroid extracts (dessicated thyroid) citing a lack of research to make accurate recommendations for or against this form of combination T4/T3 therapy. They noted a survey of practice showing that 22% of endocrinologist test T3 in patients who are biochemically euthyroid but continue to have symptoms. That survey also showed that 3.6% of endocrinologist use T3 in addition to T4. (5)

Thyroid Production

The thyroid gland produces T4, T3, and very small amounts of reverse T3 (rT3). About 90% of thyroid hormone produced by the thyroid is T4 and 10% is T3. Approximately 80% of T3 comes from peripheral conversion of T4 to T3. The peripheral conversion is both intercellular and intracellular. (2) T4 is a prohormone for T3 and is metabolically inactive. Peripherallyin the tissues through the action of deiodinase enzymes T4 is converted into T3 or rT3. T3 controls metabolism in cells. Under periods of stress and illness more T4 is shunted to rT3. Both T3 and rT3 are inactivated by deiodinase enzymes into T2 which is considered inactive. rT3 is thought to be a brake for peripheral production of T3. Under stress metabolism slows as a protective mechanism through the production of increased rT3 resulting in decreased T3 with normal T4 levels and TSH. In an extreme situation this leads to Euthyroid Sick Syndrome. (6)

Serum T3 levels are also influenced by specific thyroid hormone transporters in the cell membrane and by cellular deiodinases which locally activate or inactivate thyroid hormone. (7) And there is wide variation in how specific tissues handle thyroid hormone. For instance the liver is rich in deiodinase type I while the brain is rich in deiodinase type 2. The ETA task force notes:

In hypothyroidism, liver D1 activity is decreased but brain D2 activity is increased. Such tissue-specific regulatory mechanism may jeopardize simultaneous normalization of thyroid hormone concentrations in all hypothyroid tissues. (1)

What this means is the reliance on TSH and T4 testing alone may miss peripheral hypothyroid disease.Differences in tissue deiodinases, T3 cellular transport mechanisms, and shunting of T3 to rT3 can explain why TSH measurement alone or even in concert with T4 measurements may miss what is happening intracellularly and intracellularly in the periphery or in different organs. Thus people can have hypothyroidism even when TSH and T4 are normal.

To be thorough, the ETA Guidelines also note persistent symptoms could occur because of awareness of chronic disease, associated autoimmune illness, and thyroid autoimmunity. (1)

My Unique Patient Population

The current standard to rely on TSH and T4 testing while replacing T4 alone does not work well for the types of patients I treat in my practice. These various guidelines are based on large population-based studies rather than studies for disease-specific populations. For instance there are no studies looking at thyroid illness for people with Lyme disease.

My practice focuses on treating people with severe fatiguing illnesses like Lyme disease, post Lyme syndrome, mold toxicity illness, fibromyalgia and chronic fatigue syndrome. Prior to treating patients with these illnesses, I treated hypothyroidism using the approach recommended in the guidelines discussed above. I found such an approach for my primary care family practice population worked quite well with good clinical outcomes. But that is not my experience in my current practice with a much different patient population skewed to conditions for which conventional medicine approaches do not often have easy or successful answers.

In reviewing the studies used to develop the various guidelines, there are no studies focusing on patients with the conditions I regularly see to know what happens with T3 in peripheral tissues even when TSH and T4 are normal, and there are no studies testing which formulation of thyroid provides the best outcome biochemically or with symptoms. Given this I also must rely on clinical experience informed by the existing guidelines and science. Because of this, I work successfully on behalf of my patients creating a better quality of life working beyond the limited model of TSH, fT4, and and T4 only therapy.

Lyme disease is well known to increase inflammatory cytokines. Mold toxicity also triggers excess cytokines. (8) Fibromyalgia is shown to do this too. (9) Increased levels of cytokines are associated with depressed levels of active thyroid hormone T3 in fibromyalgia patients. In a review of peripheral metabolism of thyroid hormones, Kelly reviews research showing increased levels of rT3 and decreased levels of T3 due to various cytokines in Euthyroid Sick Syndrome and in other stressful health conditions producing low peripheral T3 with normal TSH and T4. (6)

So it is possible that some of my patients may have peripheral hypothyroidism due to cytokine excess or other mechanisms like emotional or physical stress of illness that shunt T4 to rT3 rather than active T3. These patients would have normal TSH and fT4. The ETA guidelines note:

Because of tissue heterogeneity, pituitary TSH secretion may not reflect what happens in other target tissues, and therefore serum TSH alone may not be a good marker for the adequacy of thyroid hormone replacement.

Thus in my patients normal TSH and T4 levels could occur in a state of peripheral hypothyroidism. Another way to understand what is happening peripherally is to measure peripheral markers including rT3, tT3/rT3 and ft3/ft4. (10)

Types of Thyroid Medication

There are four different types of thyroid medications. The oldest type is desiccated thyroid (armour thyroid or Naturethroid) derived from pork. Pharmaceuticals also manufacture synthetic T4 and T3. It is possible to have T4 and T3 compounded together in one pill. Some, although a minority, advocate for the use of desiccated Thyroid. This is for a number of reasons:

  • Desiccated thyroid includes all the compounds secreted by human thyroid gland.
  • It includes T4, T3,T2, and T1. It is possible T1 and T2 will prove to have some function although it is not clear at this time.
  • It includes thyroglobulin and glandular content that may have useful functions. (10)
  • In addition limited research suggest some hypothyroid patients prefer dessicated thyroid with equal or better outcomes compared to T4 only therapy.(11)

One problem in assessing the effectiveness of desiccated thyroid versus T4 therapy is the lack of long term studies. According to the ATA 2014 Guidelines “There are no published long-term outcome trials of the use of desiccated thyroid extract.” The Hoang study on dessicated thyroid cited above was only a 32 week randomized double blind crossover study study in which participants took 16 weeks of one medicine and then crossed over to receive 16 weeks of the other medicine. (11)

On the other hand, the majority opinion in the published guidelines is against the use of desiccated thyroid. They opine the T3 component has a short half-life that could lead to short term hyperthyroid. Desiccated thyroid contains T4 to T3 at 4.2 to 1 while the ratio of secretion in the human thyroid gland is 14 to 1. (1) However, there are no outcome studies that have been done evaluating the risk of T3 in using desiccated thyroid. Thus recommendations against dessicated thyroid are opinion-based rather than science-based.

Synthetic T4 has a long half-life of 7 days. T3 has a half-life of one day. Because of its long half-life T4 produces a more even thyroid level allowing for 1 time a day dosing. To maintain more steady levels, recommendations call for 2 time a day dosing of T3. (1,2)

One problem that can occur with T4 monotherapy is low and lower T3 levels that occur when TSH and T4 levels are normal. It is also noted that symptoms of hypothyroidism remain 5-10% of the time in T4 treatment when TSH is normal.

In developing the ETA Guidelines for combination therapy, the task force reviewed 13 studies looking at outcomes of combination therapies of T4 and T3 versus T4 alone. None of the studies used desiccated thyroid for the replacement therapy. Of note these studies revealed no differences in adverse outcomes. In other words it appears it is safe to use T3 in combination with T4.

The task force did find evidence in 3 of the studies of better outcomes in some or all of the following: quality of life measures, mood, cognition and thyroid symptoms. In seven of the thirteen studies participants were asked if they prefer T4/T3 combination therapy. Of these seven, six were reviewed for patient preference. One study was excluded because there were too many hyperthyroid side effects due to a relatively high dose of T3 used in the study. In the remaining 6 studies 48% of participants preferred combination therapy with T4/T3 while 52% had no preference. These studies suggest that for some there is a better outcome clinically using combination therapy. In addition some patients prefer this therapy too.

Selenium

Selenium is an essential mineral required for thyroid production. The deiodinase enzymes used to produce T3 from T4 are selenoproteins. A meta-analysis of studies on randomized, placebo-controlled blinded trials and a systematic review of prospective studies involving patients with Hashimoto’s thyroiditis shows selenium supplementation is helpful. The review shows decreased TPO antibodies at 3 months with improvement in the clinical symptoms of mood and general well being. (12). A common supplemental dose in the literature is 200ug a day. (13)

Low Dose Naltrexone

Naltrexone is an opioid receptor blocker that can help autoimmune illness by modulating the immune system. Evidence indicates that opioids alter the development, differentiation, and function of immune cells, and that both innate and adaptive systems are affected. (14,15) This should help improve auto-immune illnesses.

Low dose naltrexone (LDN) is “low” because it is used at much lower doses than physicians use for people who have narcotic addictions (or overdose) and alcoholism. It is manufactured only as a 50 mg pill. When it is used to regulate the immune system, it is dosed at 1.5 to 4.5 mg a day. Compounding pharmacies that make medicines in-house are able to produce naltrexone in low doses by crushing the 50 mg pill and dividing it into to “low” dose 1.5 to 4.5 mg pills.

At low doses LDN attaches to opioid receptors on a temporary basis of around 4 hours. Sensing the blockade, the body produces more endorphins and enkephalins to overcome this. In theory, increased endorphins and enkephalins then regulate the immune system.

There is limited science showing it helps in fibromyalgia, multiple sclerosis, and Crohn's disease. (16,17,18) There is no research showing what it does for people with Hashimoto’s thyroiditis.

I find LDN treatments helpful in the management of autoimmune illnesses like Crohn's disease and Multiple Sclerosis. In addition, I currently find benefit in the management of Hashimoto’s thyroiditis with improvements in TPO Ab levels and need for reduced levels of thyroid medication to maintain a euthyroid state.

Read more how LDN helps in Lyme disease in On Low Dose Naltrexone (LDN) & Lyme. Does It Help?.

Thyroid Testing

Thyroid Stimulating Hormone

There is controversy over the upper limit of normal in TSH levels. The AACE/ATA Guidelines recommend a TSH range of .45 to 4.12 mIU/L based on National Health and Nutrition Examination Survey III conducted for 1988 to 1994. (4,19) However, In 2005 The National Academy of Clinical Biochemistry (NACB) recommended lowering the upper limit of TSH to 2.5 mIU/L. The NACB noted in its recommendation when people with occult autoimmune thyroid disease detected only with ultrasound are removed from the results of population studies the upper end of normal for TSH moves to 2.5 mIU/L. (20) There is no consensus on the upper end of TSH levels. Biondi writes about this continued controversy and notes in determining which TSH level to use clinicians should also consider gender, age, physiological and pathological conditions, drugs, symptoms, and quality of life. (21)

Taking all of this into consideration, generally in my patient population I find clinical benefit using a TSH upper limit of 2.5 mIU/L rather than the 4.12 mIU/L proposed in the AACE/ATA Guidelines.

There is also concern over clinical problems when TSH is too low. A hyperthyroid state can cause cardiovascular disease, dysrhythmias and fractures. A population-based observational cohort study involving 17,684 participants in Tayside Scotland who were taking T4 examined cardiovascular disease, dysrhythmia, and fractures relative to TSH levels. The study showed increased risk of these adverse events when TSH was less than or equal to .03 mIU/L. (22) Note the .03 mIU/L is less than the lower limit of .45 mIU/L called for in the AACE/ATA Guidelines.

Based on the Tayside study and the NACB recommendations a safe and therapeutic range for TSH is .04 to 2.5 mIU/L. However, as Biondi notes above regarding the upper end of TSH, a physician must consider many other clinical factors as well.

Population-based Normal Is Not Individual Normal

The various thyroid guidelines rely on population-based reference ranges to determine if someone has normal thyroid. However, such averages may not relate to to normal for the individual patient. Andersen and his colleagues performed a small study involving 16 people to evaluate thyroid levels over a year. While the study is small and therefore its reproducibility could be limited, it does provide useful information. They wrote:

In conclusion, we found that individual reference ranges for serum T3 and T4 are about half the width of population based reference ranges. Hence a test result within the laboratory reference limits is not necessarily normal for the individual.

Based on this finding it is possible for someone to have clinical low thyroid based on symptoms, but to have laboratory measures of thyroid in population-based normal limits.Treating an individual with symptoms of low thyroid but normal population-based thyroid lab studies could move them into his/her normal thyroid lab range and remove clinical symptoms of low thyroid. Gaby provides a number of examples from his practice showing benefit for treating hypothyroidism in patients who have normal population-based labs. (24) This area needs more high quality research rather than observational reports and small cohort studies.

fT3, fT4, rT3, fT3/fT4, tT3/rT3,TPO antibodies

To better understand the full thyroid hormone status one could use measures of thyroid production and peripheral status. For thyroid production, the standard in the major guidelines calls for measuring TSH and T4. Most T4 is protein bound and not available. A better measure is free T4 (fT4).

To evaluate peripheral thyroid status The ETA report uses a measure of fT3 and a ratio of fT4/fT3 in determining adequacy combined T4/T3 treatment. They used a ratio of fT4/fT3 of 3.1 based on population studies. Lukaczer(10) in his 2017 presentation to the Institute for Functional Medicine Conference on Hormones suggest a fT3/fT4 ratio of over .33 is normal. This is similar to the fT4/fT3 ratio of 3.1 cited in the ETA guidelines. Lukaczer also suggests measuring rT3 and tT3/rT3 ratio. He suggest, based on his experience in his practice and discussion with colleagues, a tT3/rT3 ratio above 6. Note to calculate the fT3/fT4 ratio both convert both values into pmol/L. The formulas are: fT4 ng/dl X 12.9 = fT4 pmol/L and fT3 pg/ml X 1.563 = fT3 pmol/l.

Finally measure TPO antibodies (TPO Ab) at least one time. The leading cause of hypothyroidism is Hashimoto’s thyroiditis. It is also the most prevalent autoimmune disease and the most common endocrine disorder in the US. (25) In this disorder the immune system attacks the thyroid. The AACE/ATA Guidelines do not support routine TPO testing. However there is some evidence that using selenium can improve Hashimoto’s thyroiditis. Furthermore there is an experimental treatment with LDN that can help autoimmune illness.

The Role of Symptoms

The major thyroid guidelines suggest using a combination of symptoms and labs to guide therapy. Symptoms of low thyroid have low sensitivity and specificity, and therefore they should not be used exclusively to determine if one has low thyroid. However Canaris in a small cross sectional study did show that when people have 7 or more symptoms of hypothyroidism there is correlation with elevated TSH. (26) This suggest that the positive predictive value of symptoms in determining hypothyroidism improves with the quantity of symptoms.

Treatment: When and How

The goal of hypothyroidism treatment is to normalize the symptoms, signs, and biochemical markers while avoiding thyrotoxicosis. The ETA Guidelines recommend normalization of TSH with improvement in thyroid hormone levels while considering patient symptoms. (1)

Treat Hypothyroidism Based on Abnormal Labs

Another approach is to consider peripheral thyroid status which is a better approach for many patients and especially those in my practice population. However this is inadequately captured by TSH and fT4 levels. To do this consider fT3, fT3/fT4 and tT3/rT3 ratios. Test for TPO Ab or review previous test at least once to determine if the patient also has Hashimoto’s thyroiditis which may require selenium supplementation or LDN in addition to thyroid replacement.

In addition to labs consider if the patient has symptoms of low thyroid or signs too. Generally treat for hypothyroidism if there are symptoms that are not adequately explained by another illness and if there is any combination of:

  • TSH > 2.5 mIU/l,
  • low fT4 or low fT3,
  • fT3/fT4 < .33,
  • T3/rT3 <6, or
  • positive TPO Ab.

This is the approach suggested by the Institute for Functional Medicine and Lukaczer.(10)

Treat Hypothyroidism Based on Symptoms Even with Normal Labs

At times, even when lab testing is normal, if a patient has a number of symptoms of hypothyroidism, treat to reduce symptoms and move the thyroid tests further into normal range while not causing physical or biochemical hyperthyroidism. This approach is based on the Anderson study showing that thyroid testing in population-based reference range is not the same as individual normal. (23) Gaby’s practice experience also supports this type of an approach. (24)

This hypothyroidism treatment method is a clinical approach based on my own observations of what works in my patient population using science and published guidelines to guide me. Note the published thyroid guidelines are not intended to create a standard and do allow for clinical judgment. (4)

Start with Desiccated Thyroid

My preferred form of thyroid is desiccated thyroid (armour or Naturethroid) which I start at ¼ to ½ grain. This is similar in potency to the 25 - 50ug starting range suggested in the AACE/ATA Guidelines. In 4-6 weeks If the patient still has many symptoms suggesting low thyroid and/or labs suggesting it then increase the desiccated thyroid by ¼ to ½ grain.

Start with desiccated thyroid based on the study discussed earlier showing patient preference for this form of thyroid and my own observation that it works better for my patient population. In theory with this approach it is possible patients will receive too much T3 relative to T4. To assure this does not happen monitor fT3/fT4 and fT3. My goal is resolution of symptoms and a biochemical euthyroid state with TSH of .04 or higher and less than 2.5, fT3/fT4 greater than .33. Follow tT3/rT3 to keep this greater than 6 and rT3 within the laboratory reference range.

On dessicated thyroid if the patient is receiving too much T3 to maintain a euthyroid state decrease the dessicated thyroid dose and add T4 or switch to a combination of T4 and T3 trying to maintain a ratio of T4 to T3 initially of 13 to 1 as proposed in the ETA guidelines.

For People on Synthroid or Levothyroxine Add T3

If a patient does not want to start armour thyroid or is already on levothyroxine but symptoms and/or labs suggest low thyroid, based on the ETA guidelines start a combination of T4 and T3 trying to maintain the dosage near a 13 to 1 ratio with 2 time a day dosing of the T3. For instance start someone who is not on thyroid medication with 50ug T4 1 time a day with T3 at 2.5ug 2 times a day or at 25ug with T3 at 1.25ug 2 times a day. Note it is not possible to easily reach true 13 to 1 ratios using existing T4 levothyroxine products that come as 25 and 50ug as the lowest available pill strength and T3 triiodothyronine that comes as 5ug and 25ug pill strengths. Use T3 based on:

  • studies showing 5 to 10% of the general population remains symptomatic on T4 alone therapy,
  • patient preference for using T3,
  • improved clinical outcome for those on T3,
  • the report of no adverse outcomes using T3 with T4, and
  • my clinical experience showing T3 and T4 combination therapies work better for my specific patient population.

When to Use T4 Alone

For those who do not want desiccated thyroid or combination T4 - T3 therapy use T4 alone following the standards of the AACE/ATA Guidelines.

Selenium, Zinc, Vit D, and Iodine

In addition to thyroid medication, for TPO Ab positive patients start selenium at 200ug a day. Also begin a 3 month trial of LDN beginning at 1.5mg 1 time a day advancing the dose based on tolerance every 2 weeks to 4.5mg a day. It is also helpful to use 15-30mg a day of Zinc, maintain Vit D3 levels at 50-80 using at least 2000IU of Vit D3a day. I also recommend iodine at 150ug a day. Iodine at high doses can be toxic to the thyroid. So I do not recommend using it over 500ug a day.

Curcumin

As I mentioned above, increased cytokines triggered by the Lyme infection cause thyroid dysfunction. So I also recommend liposomal curcumin 500mg 3 times a day to lower cytokines. Read more about the role of this wonderful herbal supplement in the management of Lyme disease in my article: Curcumin.

Adjust Dosing

Regardless of therapeutic agent(s), after 4 to 6 weeks check TSH, fT4, fT3, fT3/fT4, tT3/rT3 and consider the patient’s symptoms. Note this testing frequency is similar to that recommended in the AACE/ATA Guidelines.

Safety

The hypothyroidism testing and treatment approach above goes beyond the recommendations of the ETA, ATA and AACE. The established guidelines essentially call for T4 only therapy and TSH, fT4 and symptom follow up to guide treatment decisions. As I mentioned earlier, the evaluation of the the 13 studies on the addition of T3 for the AACE/ATA Guidelines show no increase in adverse events in using T3 combination over T4 alone therapies. The Tayside populations studies show increased health risk only if TSH is .03 mIU/L or less. The approach above mitigates any risk by keeping TSH greater than .04 and following labs to assure normal ratios of fT3/fT4, tT3/rT3, and normal range levels of T3 and T4. Washington law (RCW.18.130.180) provides for the use of non traditional therapies and approaches as long as they do not injure a person or create unreasonable risk of harm. The studies on safety along with close monitoring of symptoms and labs in this approach mitigates any risk of harm while providing patient benefit beyond that offered in T4 only population-based therapeutic approaches.

References

  1. Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MPJ. 2012 ETA guidelines: the use of l-t4 + l-t3 in the treatment of hypothyroidism. Eur Thyroid J 2012;1:55-71.
  2. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, Sawka AM. Guidelines for the Treatment of Hypothyroidism. Prepared by the American Thyroid Association Taskforce on Thyroid Hormone Replacement. Thyroid 2014;24(12):1670-1751.
  3. Canaris GJ, Steiner J, Ridgway C. Do Traditional Symptoms of Hypothyroidism Correlate with Biochemical Disease? J Gen Intern Med 1997;12:544-550.
  4. Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanik JI, Pessah-Pollack R, Singer PA, Woeber KA. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;18(6):988-1028.
  5. Burch HB, Burman KD, Cooper DS, Hennessey JV. A 2013 survey of clinical practice patterns in the management of primary hypothyroidism. J Clin Endocrinol Metab 99: 2077-2085.
  6. Kelly G. Peripheral metabolism of thyroid hormones: a review. Alt Med Review 2000;5(4):306-333.
  7. Bianco AC, Kim BW: Deiodinase: implications of the local control of thyroid hormone action. J Clin Invest 2006;116:2571-2579.
  8. Shoemaker R. “The Biotoxin Pathway.” The Biotoxin Pathway | Surviving Mold, www.survivingmold.com/diagnosis/the-biotoxin-pathway.
  9. Riedel W, et al. Secretory pattern of GH, TSH, thyroid hormones, ACTH, cortisol, FSH, and LH in patients with fibromyalgia syndrome following systemic injection of the relevant hypothalamic-releasing hormones. Z Rheumatol. 1998;57 Suppl 2:81-7.
  10. Lukaczer D. Advanced assessment and treatment of thyroid dysfunction. Oral presentation at: The Institute for Functional Medicine Hormone Advanced Practice Module; July, 2017; Chicago, IL.
  11. Hoang TD, Olsen CH, Mai VQ, Clyde PW, Shakir MK, Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover study. J Clin Endocrinol. 2013 May;98(5):1982-90.
  12. Toulis KA Anastasilakis AD, Tzellos TG, Goulis DG, Kouvelas D. Selenium supplementation in the treatment of Hashimoto’s thyroiditis: a systematic review and a meta-analysis. Thyroid 2010 Oct;20(10):1163-73.
  13. Van Zuuren EJ, Albusta AY, Fedorowicz Z, Carter B, Pijl H. Selenium supplementation for Hashimoto’s thyroiditis: summary of a Cochrane systematic review. Eur Thyroid J 2014;3:25–31.
  14. Roy S, Loh HH, Effects of opioids on the immune system. Neurochem Res 1996;21: 1375-1386.
  15. Risdahl JM, Khanna KV, Peterson PK, Molitor TW, Opiates and infection. J Neuroimmunol 1998;83:4-18.
  16. Younger, Jarred, et al. Low‐dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double‐blind, placebo‐controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis & Rheumatism 2013 Feb;65(2):529-38.
  17. Smith JP, et al. Low-dose naltrexone therapy improves active Crohn's disease. American Journal of Gastroenterology 2007;102(4):820-828.
  18. Bruce AC, et al. Pilot trial of low dose naltrexone and quality of life in MS. Annals of Neurology 2010 August;68(2):145–150.
  19. Howell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2022: 489-499.
  20. Kratzsch J, Fiedler GM, Leichtle A, et al. New reference intervals for thyrotropin and thyroid hormones based on National Academy of Clinical Biochemistry criteria and regular ultrasonography of the thyroid. Clin Chem. 2005 51:1480-1486.
  21. Biondi B. The normal TSH reference range: what has changed in the last decade? J Clin Endocrinol Metab, September 2013, 98(9): 3584-3587.
  22. Flynn, RW, SR Bonellie, RT Jun, et al. Serum thyroid stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab 2010;95:1.
  23. Andersen S, Pedersen KM, Gruun NH, Laurberg P. Narrow individual variations in serum T4 and T3 in normal subjects: a clue to the understanding of subclinical thyroid disease.J Clin Endocrinol Metab. 2002 Mar;87(3):1068-72.
  24. Gaby AR. “Sub-laboratory” hypothyroidism and the empirical use of armour thyroid. Alt Med Review 2004 (9)2:157-179.
  25. Caturegli P, De Remigis A, Chuang K, Dembele M, Iwama S. Hashimoto’s thyroiditis: celebrating the centennial through the lens of the Johns Hopkins hospital surgical pathology records. Thyroid 2013. Feb; 23(2):145-50.
  26. Canaris GJ, Steiner J, Ridgway C. Do Traditional Symptoms of Hypothyroidism Correlate with Biochemical Disease? J Gen Intern Med 1997;12:544-550.

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