Paradigm Shift from Levothyroxine to Combination T3 T4 Thyroid

As regular readers of my work will know, one of the errors in mainstream endocrinology is the dogmatic insistence on T4 mono-therapy only.  Only one single medicine, T4 only, may be prescribed to the hypothyroid patient.  This is the (generic) Levothyroxine or (brand name) Synthroid, which is the most prescribed drugs in America with123 million prescriptions in 2016.(1)   About 7% of the population is hypothyroid and needs treatment.  In my opinion, (NDT) natural desiccated thyroid is preferable to T4 monotherapy.  As we will see below, NDT is more robust, more effective and safer than T4 only monotherapy with Levothyroxine.  Above left image shows chemical structure of T3 and T4. courtesy of Failing.com

The Wheels of Change Are Turning

The wheels of change are turning, as illustrated by Angela M. Leung, MD writing  on the “Love-Hate Relationship with T4“ .(1)  This caught my attention because it represents the beginning of a paradigm shift in mainstream endocrinology.

Subset of Patients Are Dissatisfied with T4-Montherapy

With refreshing honesty, Angela M. Leung, MD points out that a subset of patients are dissatisfied with T4 only Monotherapy, and are actively seeking combination T3 and T4 treatment .  Reasons cited are

1) persistent hypothyroid symptoms even though the TSH is in the “normal range” and
2) the possibility of a genetic mutation in the patient called a De-iodinase polymorphism which impairs conversion of T4 to T3 . (1)

Synthetic T3 T4 Combinations

For the “Synthetic Combination” of T3 and T4, Dr Angela Leung  will prescribe both Cytomel (T3) and Levothyroxine(T4) in dosage that replicates the T3:T4 secretion ratio of the human thyroid:

“To best replicate the physiologic ratio of T3:T4 production, the separate prescriptions should be about 1:13-1:20 that of T3 to T4.[20]…A typical formula for a patient on 112 µg of synthetic T4 once daily, the new prescription is 5 µg of synthetic T3 twice daily and 100 µg of synthetic T4 daily.”(1)

Some Patients Prefer (NDT) Natural Desiccated Thyroid

In another burst of refreshing honesty, Dr Angela Leung actually admits that some patients prefer NDT, which dates back to 1891, and was “grandfathered” in 1938 when the FDA was created.  Since it was “grandfathered-in”, NDT skipped formal new-drug approval by the FDA.(1)

Left Image Figure 1 Show activity of De-Iodinase Enzyme varies according to anatomic location, Courtesy of Gereben B, McAninch EA et al 2015) (4)

Concern About 4:1 T4:T3 Ratio

NDT which contains T4 and T3 in a 4:1 ratio can be regarded as another combination therapy. Although Dr Leung will reluctantly prescribe NDT, she will first try to dissuade the patient by disclosing drawbacks.  Namely,  Dr Leung will argue NDT is suboptimal because the T4:T3 ratio in NDT is 4:1, while the thyroid secretion ratio ranges from 12:1 to 20:1.  Opposing views in support of the 4:1 ratio can be found among prescribers of natural thyroid.  Although the thyroid gland T4:T3 secretion ratio is 12:1, only about 20% of serum T3 comes from thyroid secretion, the other 80% comes from peripheral conversion of T4 to T3.  This means the final serum levels are closer to the 3:1 or 4:1 range of which is found in NDT.   Even though  NDT does not replicate thyroid secretion ratio of 12:1, it does replicate the serum ratio of T4 to T3 (3:1 or 4:1), which in my opinion is more important.

Do the Calculation From Your Own Lab Sheet

Average normal Free T3 is 300  pcg/dl
Average normal Free T4 is 1.0 ng/dl= 1000pcg/dl
FreeT4/Free T3 = 1000/300 = 3.3

The serum Free T4:T3 ratio in the average patient is 3.3:1 a value closer to the 4:1 found in NDT.  Remember, after the thyroid pill is ingested and absorbed, it goes into the circulating blood stream as Free T3 and Free T4.  So, matching the serum T4:T3 ratio is the most logical dosing strategy.

127 Years of Use

In 15 years of clinical practice prescribing NDT to patients and family members the 4:1 ratio in NDT has NEVER been a significant issue, so I would say this is an example of a medical myth, the creation of an “imaginary” objection.  Another thing to think about is this: If there were any significant problems with natural desiccated thyroid requiring a black box warning or removal from the marketplace, it would have happened by now.  Natural Desiccated thyroid has been in use for over 127 years, representing the SOLE thyroid medication available from 1891 until 1955 (64 years),  after which Synthroid entered the marketplace.   For any drug, 127 years of use is a very long track record attesting to safety and efficacy.

Reading the Comment Section

To give you an idea of the typical results we see every week prescribing NDT, read one of the comments by CM below Dr Angela Leung’s article on Medscape.:

From :CM, Health Business/Administration
“For over 15 years of treatment for hypothyroidism with various T4 medications, I complained about continuation of hypothyroid symptoms, only to be told that my blood work was just fine. I finally found a doctor that was open to treating with dessicated thyroid medication and it completely changed my life. All of my symptoms have resolved. If patients speak, please listen and be opened minded enough to try a different medication instead of treating the lab values and not the patient. There are many people that have and would benefit from dessicated thyroid.” Comment section for (1)

Notice in the above comment, there is no mention of a problem with the NDT T4:T3 ratio which is 4:1.  Left Image Shows  Deiodinase activity varies in different cells…Courtesy of  Figure 2 from Gereben B, McAninch EA et al 2015) (4)

My First Thyroid Patient

My first thyroid patient 15 years ago, was a 70 year old female who had been on Synthroid for 50 years ever since her total thyroidectomy for a “benign cyst” at age 20. An operation, which in retrospect, was probably unnecessary. Three weeks after switching her to NDT natural desiccated thyroid, she came back into the office, threw up her hands and said: “I feel so much better.  Why hasn’t any other doctor done this for me before?“, I said ,“I dont know, Mom.”  My very first thyroid patient was my mother.  Over the years, I have found this type of patient result is typical when switching from T4 mono-therapy to natural dessicated thyroid.

Conclusion:  There is no question the winds of medicine are changing in endocrinology regarding dogmatic insistence on T4 Monotherapy.  However, in medicine, the wheels of change turn slowly, so I wouldn’t hold my breathe waiting for the local friendly endocrinolgist to change their prescribing practices anytime soon.  Thank goodness for that, since other wise, I would have nothing to do.

Jeffrey Dach MD
7450 Griffin Road Suite 180/190
Davie, Florida 33314
954-792-4663

Articles with Related interest:

TSH Suppression Benefits and Adverse Effects

Errors in Modern Thyroid Endocrinology

Which Thyroid Pill is Best, T4, T3 , Natural Desiccated thyroid or Combination?

References:

Love Hate T4 Medscape

1) The Love-Hate Relationship With Levothyroxine by Angela M. Leung, MD, MSc October 25, 2018

DTE has been in use since at least 1891, before the FDA in 1938 was required to begin regulating the efficacy and safety of new medications in the United States.[10] Thus, DTE formulations are considered “grandfathered” drugs, which technically remain FDA-unapproved for thyroid hormone replacement to this day.[10]

comments

Dr. None None| General Practice
10 days ago

Amazing that millions of people have been prescribed calcitonin, T3 and T4 from bovine or porcine glands for well over a hundred years. Just think of all that suffering and ill effects those people were put through before synthetic T4 came to the rescue. This reminds me of ivory tower thinking of ACE inhibitors giving added protection to the kidneys during blood pressure treatment that was completely debunked in recent studies. Btw, animal to human ratios of T3/T4 have no meaning unless one can show conclusive evidence. I wonder how many are worried about the exact proper ratio of estradiol and progesterone of each individual female prescribed birth control pills.

Cindy Myers| Health Business/Administration
6 days ago

For over 15 years of treatment for hypothyroidism with various T4 medications, I complained about continuation of hypothyroid symptoms, only to be told that my blood work was just fine. I finally found a doctor that was open to treating with dessicated thyroid medication and it completely changed my life. All of my symptoms have resolved. If patients speak, please listen and be opened minded enough to try a different medication instead of treating the lab values and not the patient. There are many people that have and would benefit from dessicated thyroid.

Victoria Hamman| Other Healthcare Provider
6 days ago

Interesting that it was not mentioned that Synthroid, along with the dessicated thyroid preperations was also grandfathered in without extensive study. The fact that this was not mentioned indicates bias toward the synthetic version of T4. I know this because I was involved in the marketing of the first generic levothyroxine in the early 90s. Up to that point, the makers of Synthroid had a monopoly. Another thing that is not mentioned is the possibility of using T3 alone, which can be the best way to go when the patient is converting a lot of the administered T4 into Reverse T3 – something that is easily tested for. I was taught by one of the leading docs in the country treating hypothyroidism (at that time) to use the following approximate conversions when evaluating each individual: 0.1mg levothyroxine = 1 grain/60mg dessicated porcine thyroid = 25mcg Cytomel (T3.)

3) Jonklaas J, Bianco AC, Bauer AJ, et al; American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid. 2014;24:1670-1751. Guidelines For Treatment Hypothyroidism American Thyroid Association Jonklaas 2014

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4) Gereben B, McAninch EA, Ribeiro MO, Bianco AC. Scope and limitations of iodothyronine deiodinases in hypothyroidism. Nat Rev Endocrinol. 2015;11:642-652.

In humans, thyroid hormones are secreted into the circulation predominantly as a prohormone (T₄), and only ~20% is secreted as the biologically active T₃ form.

These observations, some of which were validated in animal models of levothyroxine monotherapy, challenge the paradigm that tissue levels of T3 and thyroid-hormone signalling can be fully restored by administration of levothyroxine alone. The low serum levels of T3 observed among patients receiving levothyroxine monotherapy occur as a consequence of type 2 iodothyronine deiodinase (DIO2) in the hypothalamus being fairly insensitive to ubiquitination. In addition, residual symptoms of hypothyroidism have been linked to a prevalent polymorphism in the DIO2 gene that might be a risk factor for neurodegenerative disease.

5) Lum SM, Nicoloff JT, Spencer CA, Kaptein EM. Peripheral tissue mechanism for maintenance of serum triiodothyronine values in a thyroxine-deficient state in man. J Clin Invest. 1984;73:570-575. Abstract

The present study was undertaken to define the source of endogenous triiodothyronine (T3) production responsible for maintaining serum T3 levels in euthyroid subjects with depressed serum thyroxine (T4) values. After withdrawal from 4 wk of exogenous T3 administration, a 22% decline in serum T3 values (from 129 +/- 6 to 99 +/- 4 ng/dl) was observed in six euthyroid subjects, despite a twofold reduction in serum T4 concentrations (from 7.5 +/- 0.5 to 3.2 +/- 0.5 micrograms/dl). This was accompanied by a nearly twofold increase in serum T3/T4 ratio values (17 +/- 1 to 29 +/- 6) but no significant alteration in reverse T3/T4 ratio values. This phenomenon did not appear to be thyroid stimulating hormone (TSH) dependent, since base-line serum TSH values were subnormal. Nor was it dependent on changes in thyroid gland function, since a blunted T3 response to exogenous bovine TSH occurred and pharmacologic doses of iodide did not influence the phenomenon. The finding in three athyreotic subjects that serum T3/T4 ratio values increased from 14 +/- 1 on T4 therapy (mean serum T4, 9.6 +/- 0.8 micrograms/dl and T3, 132 +/- 8 ng/dl) to 40 +/- 2 after withdrawal from 2 wk of T3 administration (serum T4 1.2 +/- 0.1 micrograms/dl and T3 46 +/- 3 ng/dl) provided direct evidence that an alteration in peripheral thyroid hormone metabolism was probably responsible for these findings previously observed in euthyroid subjects. The results of this study support the possible existence in euthyroid man of a peripheral tissue autoregulatory mechanism for maintaining serum T3 values in states of T4 deficiency. Whether this process involves an alteration in the efficiency of T4 to T3 conversion or the rate of T3 clearance is presently unknown.

6) Wouters HJ, van Loon HC, van der Klauw MM, et al. No effect of the Thr92Ala polymorphism of deiodinase-2 on thyroid hormone parameters, health-related quality of life, and cognitive functioning in a large population-based cohort study. Thyroid. 2017;27:147-155. Abstract

7) Butler PW, Smith SM, Linderman JD, et al. The Thr92Ala5′ type 2 deiodinase gene polymorphism is associated with a delayed triiodothyronine secretion in response to the thyrotropin-releasing hormone-stimulation test: a pharmacogenomics study. Thyroid. 2010;20:1407-1412. Abstract

De-Iodinase Poymorphism Thr92Ala-DIO2

8) Bianco AC, Kim BS. Pathophysiological relevance of deiodinase polymorphism. Curr Opin Endocrinol Diabetes Obes. 2018;25:341-346.

To assess new findings and clinical implications of deiodinase gene polymorphism. Deiodinases are enzymes that can activate or inactivate thyroid hormone molecules. Whereas the types 1 and 2 deiodinase (D1 and D2) activate thyroxine (T4) to 3,5,3′-triiodothyronine (T3) via deiodination of T4’s outer ring, D1 and D3 inactivate both T4 and T3 and terminate thyroid hormone action via deiodination of T4’s inner molecular ring. A number of polymorphisms have been identified in the three deiodinase genes; the most investigated and likely to have clinical relevance is the Thr92 substitution for Ala substitution in DIO2 (Thr92Ala-DIO2). There are a number of reports describing the association between the Thr92Ala-DIO2 polymorphism and clinical syndromes that include hypertension, type 2 diabetes, mental disorders, lung injury, bone turnover, and autoimmune thyroid disease; but these associations have not been reproduced in all population studies.
RECENT FINDINGS:

A new report indicates that carriers of the Thr92Ala-DIO2 polymorphism exhibit lower D2 catalytic activity and localized/systemic hypothyroidism. This could explain why certain groups of levothyroxine-treated hypothyroid patients have improved quality of life when also treated with liothyronine (LT3). Furthermore, Ala92-D2 was abnormally found in the Golgi apparatus, what could constitute a disease mechanism independent of T3 signaling. Indeed, brain samples of Thr92Ala-DIO2 carriers exhibit gene profiles suggestive of brain degenerative disease. In addition, African American carriers of Thr92Ala-DIO2 exhibit an about 30% higher risk of developing Alzheimer’s disease.
SUMMARY:  The finding of deiodinase polymorphisms that can diminish thyroid hormone signaling and/or disrupt normal cellular function opens the door to customized treatment of hypothyroidism. Future studies should explore how the racial background modulates the clinical relevance of the Thr92Ala-DIO2 gene polymorphism.

9) Garber JR, Cobin RH, Gharib H, et al; American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;18:988-1028. Abstract

10) Medicines use and spending in the U.S. A review of 2016 and outlook to 2021. IQVIA Institute for Human Data Science. May 4, 2017. Source Accessed October 15, 2018.

11) Hennessey JV. Historical and current perspective in the use of thyroid extracts for the treatment of hypothyroidism. Endocr Pract. 2015;21:1161-1170.

To describe the history, refinements, implementation, physiology, and clinical outcomes achieved over the past several centuries of thyroid hormone replacement strategies.
METHODS: A Medline search was initiated using the following search terms: bioidentical thyroid hormone, thyroid hormone extract, combination thyroxine (T4) and tri-iodothyronine (T3) therapy, homeopathic thyroid hormone therapy, and thyroid hormone replacement. Pertinent articles of interest were identified by title (and where available abstract) for further review. Additional references were identified during a review of the identified literature.
RESULTS: A rich history of physician intervention in thyroid dysfunction was identified dating back more than 2 millennia. Although not precisely documented, thyroid ingestion from animal sources had been used for centuries but was finally scientifically described and documented in Europe over 130 years ago. Since the reports by Bettencourt and Murray, there has been a continuous documentation of outcomes, refinement of hormone preparation production, and updating of recommendations for the most effective and safe use of these hormones for relieving the symptoms of hypothyroidism. As the thyroid extract preparations contain both levothyroxine (LT4) and liothyronine (LT3), current guidelines do not endorse their use as controlled studies do not clearly document enhanced objective outcomes compared with LT4 monotherapy. Among current issues cited, the optimum ratio of LT4 to LT3 has yet to be determined, and the U.S. Food and Drug Administration (FDA) does not appear to be monitoring the thyroid hormone ratios or content in extract preparations on the market. Taken together, these limitations are important detriments to the use of thyroid extract products.
CONCLUSION: The evolution of thyroid hormone therapies has been significant over the extended period of time they have been in use to treat hypothyroidism. Although numerous websites continue to advocate the use of thyroid hormone extracts as a superior therapy for hypothyroidism, none of the most recent guidelines of major endocrine societies recommend thyroid extract use for hypothyroidism.

Adding More T4 Does Not Help -Futile

12) Samuels MH, Kolobova I, Niederhausen M, Janowsky JS, Schuff KG. Effects of altering levothyroxine (L-T4) doses on quality of life, mood, and cognition in L-T4 treated subjects. J Clin Endocrinol Metab. 2018;103:1997-2008. Abstract

The brain is a critical target organ for thyroid hormone, but it is unclear whether variations in thyroid function within and near the reference range affect quality of life, mood, or cognition.
Methods:  A total of 138 subjects with levothyroxine (L-T4)-treated hypothyroidism and normal thyrotropin (TSH) levels underwent measures of quality of life (36-Item Short Form Health Survey, Underactive Thyroid-Dependent Quality of Life Questionnaire), mood (Profile of Mood States, Affective Lability Scale), and cognition (executive function, memory). They were then randomly assigned to receive an unchanged, higher, or lower L-T4 dose in double-blind fashion, targeting one of three TSH ranges (0.34 to 2.50, 2.51 to 5.60, or 5.61 to 12.0 mU/L). Doses were adjusted every 6 weeks based on TSH levels. Baseline measures were reassessed at 6 months.
Results:  At the end of the study, by intention to treat, mean L-T4 doses were 1.50 ± 0.07, 1.32 ± 0.07, and 0.78 ± 0.08 μg/kg (P < 0.001), and mean TSH levels were 1.85 ± 0.25, 3.93 ± 0.38, and 9.49 ± 0.80 mU/L (P < 0.001), respectively, in the three arms. There were minor differences in a few outcomes between the three arms, which were no longer significant after correction for multiple comparisons. Subjects could not ascertain how their L-T4 doses had been adjusted (P = 0.55) but preferred L-T4 doses they perceived to be higher (P < 0.001).
Conclusions:  Altering L-T4 doses in hypothyroid subjects to vary TSH levels in and near the reference range does not affect quality of life, mood, or cognition. L-T4-treated subjects prefer perceived higher L-T4 doses despite a lack of objective benefit. Adjusting L-T4 doses in hypothyroid patients based on symptoms in these areas may not result in significant clinical improvement.

13) Leung AM. Levothyroxine dose adjustment resulting in mild variations of serum TSH levels within or near the normal range has no effect on quality of life, mood, and cognition in hypothyroid individuals. Clin Thyroidol. 2018;30:263-265.

14) Peterson SJ, Cappola AR, Castro MR, et al. An online survey of hypothyroid patients demonstrates prominent dissatisfaction. Thyroid. 2018;28:707-721. Online survey hypothyroid patients demonstrates Dissatisfaction with T4 Monotherapy NDT Preferred Peterson Sarah Thyroid 2018

A total of 12,146 individuals completed the survey. The overall degree of satisfaction was 5 (interquartile range [IQR] = 3-8). Among respondents without self-reported depression, stressors, or medical conditions (n = 3670), individuals taking DTE reported a higher median treatment satisfaction of 7 (IQR = 5-9) compared to other treatments. At the same time, the LT4 treatment group exhibited the lowest satisfaction of 5 (IQR = 3-7), and for the LT4 + LT3 treatment group, satisfaction was 6 (IQR = 3-8). Respondents taking DTE were also less likely to report problems with weight management, fatigue/energy levels, mood, and memory compared to those taking LT4 or LT4 + LT3.
CONCLUSIONS:  A subset of patients with hypothyroidism are not satisfied with their current therapy or their physicians. Higher satisfaction with both treatment and physicians is reported by those patients on DTE.

15) Stevens EW, Leung AM. A patient survey of hypothyroid individuals demonstrates dissatisfaction with treatment and with managing physicians. Clin Thyroidol. 2018;30:175-178.

16) 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 Metab. 2013;98:1982-1990. Abstract

17) Alexander EK, Pearce EN, Brent GA, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;27:315-389. Abstract

18) Levothyroxine prices, coupons and patient assistance programs. Drugs.com. Source Accessed October 15, 2018.

19) Synthroid prices, coupons and patient assistance programs. Drugs.com. Source Accessed October 15, 2018.

15) Tirosint prices, coupons and patient assistance programs. Drugs.com. Source Accessed October 15, 2018.

16) Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MP. 2012 ETA guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism. Eur Thyroid J. 2012;1:55-71. Abstract

17)  Dr. Angela M. Leung is an Assistant Professor of Medicine at the UCLA David Geffen School of Medicine and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System.

Jeffrey Dach MD
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Published on November 9th, 2018 by
Jeffrey Dach MD

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