Reverse T3, Helpful, or Waste of Time?
by Jeffrey Dach MD
Linda is a stay at home mom sitting in my office with Hashimoto’s autoimmune thyroid disease with typical symptoms of fatigue, hair loss, weight gain and “foggy brain” despite taking levothyroxine 125 mcg/d prescribed by her endocrinologist. Upper left Image: Young Woman Sleeping, by Domenico Fetti, oil on canvas 1615, Budapest Museum of Fine Arts. Courtesy of wikimedia.
Linda asks me the question:
Why isn’t the thyroid pill working for me?
Linda’s initial thyroid labs last year before starting Levothyroxine, showed the following:
TSH of 8.4 (0.40-4.50 mIU/L)
Free T4 of 0.6 (0.8-1.8 ng/dL)
After seeing Linda in the office for the first visit, I sent Linda back to the Lab while still on the levothyroxine 125 mcg. These follow up labs showed:
TSH has decreased to 1.46 mIU/L (0.40-4.50 mIU/L)
Free T4 has increased to 1.4 ng/dL (0.8-1.8 ng/dL)
Free T3 was low end of range 240 ng/dL (range 230-420)
Reverse T3 was upper end of range 22 (range 8-25 ng/dL)
This laboratory panel is typical for patients not doing well with Levothyroxine. The TSH has gone down, and the Free T4 has gone up. The Free T3 is at the lower end of normal range, and the reverse T3 is at the upper end of the normal range. What does this mean? This means trouble, and explains Linda’s lingering symptoms of chronic fatigue, hair loss, weight gain and “foggy brain.
The Deiodinase System
This lab pattern means the Linda’s D1 deiodinase system in the periphery is preferentially converting the levothyroxine (T4 monotherapy) to reverse T3, the inactive form of the thyroid hormone. At the same time, centrally in the hypothalamus and pituitary of the brain, the deiodinase system is converting the T4 to T3 normally. The pituitary responds to this abundant T3 by lowering the TSH to reduce production of thyroid hormone. The resulting lower TSH looks good to the endocrinologist thinking the thyroid function is normal, even though the patient is still suffering from peripheral cellular hypothyroidism. Typically, the endocrinologist will tell the patient the labs are perfect, and ignore the patient’s complaints of lingering hypothyroid symptoms. At this point, the endocrinologist may give the patient a pat on the back and a referral to the psychiatrist for SSRI antidepressant, obviously the wrong treatment.
Switching from Levo to NDT
We then switched Linda’s thyroid medication from the levothyroxine (Levo) to natural desiccated thyroid, NDT (NP thyroid from Acella). Linda was started on 60 mg/ day (one grain) and gradually increased to 120 mg/day (two grains), and then returned to the lab 6 weeks later for a follow up thyroid lab panel which showed:
TSH has decreased further to 0.26 mIU/L (0.40-4.50 mIU/L)
Free T4 has decreased to 1.0 ng/dL (0.8-1.8 ng/dL)
Free T3 has increased to 340 ng/dL (range 230-420)
Reverse T3 has decreased to 14 (range 8-25 ng/dL)
This shows the D1 deiodinase is working nicely, and the circulating Free T3 has gone up from the original 240 on Levo to 340 ng/dL on the NDT. The reverse T3 which had been higher, is now back down to the middle of the range. Linda now reports all her low thyroid symptoms have resolved and she is feeling so much better. This is a typical recurring scenario when seeing patients not doing well on Levothyroxine.
The typical pattern on levothyoxine shows skewed values: Although still within the lab range, the labs show a high reverse T3, high free T4 and low Free T3. This pattern indicates these patients will feel better switched to NDT. The reason for this is levothyroxine is T4 only mono-therapy, while NDT contains both T4 and T3, a form of combination therapy. For endocrinologists, combination therapy means levothyroxine (T4) combined with a small dose of generic cytomel (T3). Some endocrinologists are starting to use combination therapy. Most are not.
Note: Both D1 deiodinase and D2 deiodinase convert T4 to T3, while D3 deiodinase converts T4 to reverse T3, the inactive form, a protective mechanism to protect the cell from hyperthyroidism. For example in Graves’ thyrotoxicosis with very high Free T4 levels, the D3 deiodinase will shunt the T4 to its inactive metabolite, reverse T3. Thus D3 is protecting the peripheral cells from toxic effects of hyperthyroidism.
D1 is responsible for most of the circulating T3, while D2 produces T3 for cell use, for entry into the nuclear compartment, involved in nuclear signalling. pathway.
Free T3 to reverse T3 Ratio
Notice the Free T3 to reverse T3 ratio is very useful here. It alerts the astute physician to the problem with T4 monotherapy, showing the ineffectiveness of levothyroxine.
The Chinese Finger Trap
When confronted with a patient on levothyroxine with this laboratory pattern, and lingering symptoms of hypothyroidism, some endocrinologists will try a higher dose of levothyroxine, finding this suppresses the TSH further, yet makes the patient feel worse. The more levothyroxine the endocrinologist gives, the greater the inhibition of D1 deiodinase in the periphery, and the more profound is the cellular hypothyroidism. This reminds me of the Chinese Finger Trap Toy (upper left image). The more you pull, the tighter it gets.The solution is to stop pulling.
Left Image Finger trap toy courtesy of wikimedia commons.
Combination Therapy is the Solution to D1 Deiodinase Inhibition by Levothyroxine.
Animal studies show the solution to this problem is combination therapy with both T4 and T3. The only manufactured combination thyroid pill at the moment is NDT, natural desiccated thyroid, such as NP Thyroid from Acella or Armour from Abbvie. Another combination therapy is to add a small dose of generic Cytomel to the levothyroxine.
Animal Studies Show Only Combination T3 and T4 Restores T3 Metabolic Markers
D2 in the Pituitary (Centrally) Acts Differently from D2 in Periphery
According to a 2015 animal study by Dr. De Castro, the D2 deiodinase enzyme system in the pituitary acts differently from the D2 in the peripheral tissues. In the peripheral tissues, D2 is inactivated by T4. High T4 levels inactivate D2 deiodinase as a safety mechanism to protect the cells from local hyperthyroidism.
However in the centrally, D2 in the hypothalamus and pituitary is a different type that is relatively insensitive to T4 inhibition. Here, in the hypothalamus and pituitary, the abundant T4 in circulation is promptly converted to intracellular T3, which then suppresses the TSH to low levels. This results in the pattern we see on Linda’s labs while on levothyroxine. Even though the TSH was reduced from 8.4 to 1.46, there is relatively higher serum T4 and relatively lower serum T3 indicating inhibition of D1 and poor conversion of T4 to T3. The peripheral cells are starved of T3 because of the inactivation of D2 deiodinase by the excess T4 from levothyroxine, thus inhibiting intracellular conversion of T4 to T3 in the periphery. The higher reverse T3 means the D3 deiodinase is activated, and is preferentially shunting T4 to reverse T3 to protect the cell from hyperthyroid effect of the extra T4 from levothyroxine. This is all very bad.(6)
Animal Studies of Combination Therapy
The benefit of combination therapy with both T3 and T4 was demonstrated in animal studies by Dr. de Castro. In 2015, Dr. De Castro studied the deiodinase system in mice, finding only constant infusion of both T4 and T3 normalized thyroid levels. Dr. De Castro writes:
These studies reveal that tissue-specific differences in D2 ubiquitination are an inherent property of the TRH/TSH feedback mechanism and indicate that only constant delivery of L-T4 and L-T3 fully normalizes T3-dependent metabolic markers and gene expression profiles in Tx rats.(6)
Above Image: Schematic of chemical structures of Thyroxine (T4), and conversion of T4 to either T3 (lower left) or reverse T3 (lower right) courtesy of Dr. Cristiane Gomes-Lima (1)
The Reverse T3 Debate
Linda’s endocrinologist does not use the reverse T3 test, believing reverse T3 to be of no clinical value. Why is this? The medical literature says so. In 2019, Dr. Cristiane Gomes-Lima states there is no evidence to support the use of reverse T3 to monitor T4 monotherapy with levothyroxine. Dr Gomes-Lima writes:
Reverse T3 is physiologically relevant to thyroid economy. However, its clinical use as a biochemical parameter of thyroid function is very limited. Currently, no evidence supports the use of rT3 [reverse T3] to monitor levothyroxine therapy, either given alone or in combination with liothyronine [generic Cytomel]. (1)
In my opinion, future studies will demonstrate the above conclusion to be in error, and the pattern of higher reverse T3, higher Free T4, and lower Free T3 (within the lab range) will be adopted as a valid strategy for predicting good outcomes when switching from T4 monotherapy to NDT or combination T4/T3 therapy.
Free T4 and Reverse T3/Free T3 Ratio, A Useful Window into Status of Deiodinase System
In 1984, 35 years before Dr. Gomes-Lima wrote her article in 2019, Dr. Shimada in Japan studied T3, T4, and reverse T3 in 61 hyperthyroid, 31 hypothyroid patients, 8 subacute thyroiditis, and 40 normal subjects. Dr. Shimada concluded “the relationship between serum T4 level and rT3/T3 ratio should be examined for adequate information concerning the peripheral conversion of thyroid hormones under various thyroid diseases.” Examining the Free T4 and ratio of free T3 to reverse T3 is a useful window into the status of the deiodinase system. If the T4 in levothyroxine is being preferentially converted to reverse T3, this is useful information the levothyroxine is not working, and best to try a combination drug containing both T4 and T3 such as NDT. In 1984 Dr. Shimada writes:
In order to clarify the conversion of thyroxine (T4) to triiodothyronine (T3) or to reverse T3 (rT3), serum concentrations of T4, T3, rT3, thyrotropin (TSH), thyroxine-binding globulin (TBG) and values of T3 uptake (T3U) were measured in 61 hyperthyroid and 31 hypothyroid patients, 8 patients with subacute thyroiditis, and 40 normal subjects. Then, free T4 index (FT4I), T3/T4, rT3/ T4, and rT3/T3 ratio were calculated…The rT3/T3 ratio was high in the hyperthyroid patients and low in the hypothyroid patients compared with that in the normal subjects…Our results indicated that thyroid hormones themselves could regulate the conversion of T4 to T3 or rT3 by activating 5-monodeiodinase [D3 deiodinase] in hyperthyroidism and by activating 5’-monodeiodinase [D2 deiodinase] and suppressing 5-monodeiodinase [D3 deiodinase] in hypothyroidism. Serum rT3 level was a more sensitive parameter than serum T4 or T3 for evaluating thyroid dysfunction….we concluded that the relationship between serum T4 level and rT3/T3 ratio should be examined for adequate information concerning the peripheral conversion of thyroid hormones under various thyroid diseases. (2)
When Dr. Shimada in Japan writes about peripheral conversion of thyroid hormones, this refers to the D1, D2 and D3 deiodinase system elucidated only recently in the U.S. by Dr Antonio Bianco’s group in Chicago. I think it is fair to say, starting with Dr. Hakaru Hashimoto’s discovery of auto-immune thyroid disease in 1912, Japanese thyroid researchers and specialists have always been way ahead of their counterparts in the United States. (16-17)
Dr. Alan B. McDaniel in Townsend Letter
In agreement with Dr. Shamadzu is Dr. Alan B. McDaniel who says in 2021, “the ratio of tT3/ RT3 is the most accurate measure of the actual thyroid hormone function in the body,” writing in the Townsend Letter:
Unfortunately, TSH is often suppressed by the NDT [natural desiccated thyroid] dose that gives the best symptom-relief. My best explanation is that the patient’s thyroid gland continues making too much T4 (converted to RT3) until it is suppressed by NDT’s richer mix of T3. Simply put, more than 80% T4 is often too much…As long as blood levels of the thyroid hormones are normal, low TSH is no physiological problem. Low TSH does not damage bones – high T4 does! …However, some practitioners incorrectly assume low TSH means that you’ve made the patient hyperthyroid. So, your TSH-suppressed patient must understand this to defend her treatment from “good intentions.” …Over the years during which I logged hundreds of patients for whom T4-only treatment gave poor results, I also recorded many scores of patients who had suboptimal results from NDT thyroid. Here again, the “post-analytical analysis” of lab reports is so important! As with T4, incorrect dosing occurs—either too much or too little, as the patients above demonstrate—but by far the most frequent problem was dysfunctional deiodination of T4, indicated by low tT3/RT3…In closing, I’d like to remind you of the four most important points I have tried to prove in this review:
1. Thyroid hormone doses should be divided at least every 12 hours.
2. Therapeutic blood levels must be tested according to peak/trough fluctuations; preferably at mid-dose.
3. The ratio of tT3/ RT3 is the most accurate measure of the actual thyroid hormone function in the body.
4. Some people need to take T3 along with T4 for their best clinical results. (3)
Note: RT3= reverse T3. Note: tT3=total T3.
Reverse T3, Helpful or Waste of Time?
In 2020, Dr. Theodore Friedman measured reverse T3 (rT3) in 98 consecutive hypothyroid patients seen in a tertiary Endocrinology clinic, all with severe fatigue, and many of them already treated with different thyroid preparations. Dr. Theodore Friedman writes:
Measuring rT3 may be helpful in patients who are already on T4-containing thyroid treatments who still have hypothyroid symptoms.(4)
In 2021, Dr. Theodore Friedman again writes:
Measuring rT3 may be helpful in patients who are already on thyroid treatments, and is of greater importance in patients taking synthetic preparations [levothyroxine T4 monotherapy].(5)
The Diodinase System: The Paradigm Shift in Thyroid Endocrinology
The paradigm shift in thyroid endocrinology occurred with the elucidation of the deiodinase system which controls local thyroid hormone levels at the cellular level. Much of this work can be attributed to Dr. Antonio Bianco’s group at Rush Medical School in Chicago . T4 is a prohormone with only low biological activity. The D1 and D2 deiodinase convert T4 to T3, the biologically active form. The D3 deiodinase converts T4 to reverse T3, the inactive form, a protective mechanism to protect the cell from hyperthyroidism. D1 is membrane bound and is responsible for most of the circulating T3. D2 is intracellular with access the the nuclear compartment, involved in nuclear signalling. Currently, modern medicine has no direct lab test to measure the deiodinase activity. However, by examining the ratios of Free T4 to Free T3 and Free T3 to reverse T3 this gives us a window into the deiodinase system, and the true state of thyroid levels at the cellular level. thus representing one of the most clinically significant tools for the thyroid specialist. (7-15)
Conclusion: When someone asks about the Reverse T3, Helpful or a Waste of Time? You can say with confidence, yes it is helpful in the levothyroxine treated patient to determine if the levothyroxine is working, and if not, then the patient should be switched from levothyroxine to combination therapy with NDT. And no, it is not a waste of time to measure reverse T3.
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Florida, 33314
954-792-4663
Articles with Related Interest:
All Thyroid Articles by Jeffrey Dach MD
Links and References:
1) 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.
2) Shimada, T. “The Conversion of Thyroxine to Triiodothyronine (T3) or to Reverse T3 In Patients with Thyroid Dysfunction.” Nihon Naibunpi Gakkai Zasshi 60.3 (1984): 195-206
3) Diagnose and Treat Hypothyroidism in 2021, Part 3: New Endocrinology By Alan B. McDaniel, MD Townsend Letter
4) Friedman, Theodore C., and Julian B. Wilson. “SUN-410 Reverse T3 in Patients with Hypothyroidism, Helpful or a Waste of Time?.” Journal of the Endocrine Society 4.Supplement_1 (2020): SUN-410.
5) Wilson, Julian Bryant, and Theodore C. Friedman. “Reverse T3 in Patients With Hypothyroidism, Helpful or a Waste of Time?.” Journal of the Endocrine Society 5.Supplement_1 (2021): A952-A952.
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 125.2 (2015): 769.
7) Russo, Samuel C., Federico Salas-Lucia, and Antonio C. Bianco. “Deiodinases and the metabolic code for thyroid hormone action.” Endocrinology 162.8 (2021): bqab059.
8) Bianco, Antonio C., et al. “Paradigms of dynamic control of thyroid hormone signaling.” Endocrine reviews 40.4 (2019): 1000-1047.
TH signaling is unique for each cell (tissue or organ), depending on circulating TH levels and on the exclusive blend of transporters, deiodinases, and TRs present in each cell.
9) Bianco, Antonio C., and Brian W. Kim. “Deiodinases: implications of the local control of thyroid hormone action.” The Journal of clinical investigation 116.10 (2006): 2571-2579.
10) Gereben, Balázs, et al. “Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling.” Endocrine reviews 29.7 (2008): 898-938.
11) Drigo, Rafael Arrojo, et al. “Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling.” Biochimica et biophysica acta 1830.7 (2013): 3956.
12) Fonseca, Tatiana L., et al. “Coordination of hypothalamic and pituitary T3 production regulates TSH expression.” The Journal of clinical investigation 123.4 (2013): 1492-1500.
13) Ettleson, Matthew D., and Antonio C. Bianco. “Individualized therapy for hypothyroidism: is T4 enough for everyone?.” The Journal of Clinical Endocrinology & Metabolism 105.9 (2020): e3090-e3104.
14) Idrees, Thaer, et al. “Liothyronine and desiccated thyroid extract in the treatment of hypothyroidism.” Thyroid 30.10 (2020): 1399-1413.
15) Salvatore, Domenico, et al. “The relevance of T3 in the management of hypothyroidism.” The Lancet Diabetes & Endocrinology (2022).
16) Duntas, Leonidas H., Yuji Hiromatsu, and Nobuyuki Amino. “Centennial of the description of Hashimoto’s thyroiditis: two thought-provoking events.” Thyroid 23.6 (2013): 643-645.
17) Paunković, Nebojša, and Džejn Paunković. “The life and work of Dr. Hakaru Hashimoto.” Timočki medicinski glasnik 41.1 (2016): 55-56.
Jeffrey Dach MD
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