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.
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 Show Only Combination Therapy Restores Euthyroidism in All Tissues
The benefit of combination therapy with both T3 and T4 was demonstrated in animal studies in 1995-1996 by Dr. Hector Escobar-Morreale and confirmed in 2015 by Dr. Joao de Castro. Dr. Hector Escobar-Morreale writes in 1996:
Only the combined treatment with thyroxine [T4] and triiodothyronine [T3} ensures euthyroidism in all tissues of the thyroidectomized rat. (18)
In 2015, Dr. Joao 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) (18-20)
Note: euthyroidism means normal thyroid hormone levels.
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.
Natural Thyroid Toolkit
If you liked this article, you might like my new book, 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.
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.
18) Escobar-Morreale, Héctor F., et al. “Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat.” Endocrinology 137.6 (1996): 2490-2502.
19) Escobar-Morreale, Hector F., et al. “Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats.” The Journal of clinical investigation 96.6 (1995): 2828-2838.
20) 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): 769-781.
21) Kaplan, Michael M., David H. Sarne, and Arthur B. Schneider. “In search of the impossible dream? Thyroid hormone replacement therapy that treats all symptoms in all hypothyroid patients.” The Journal of Clinical Endocrinology & Metabolism 88.10 (2003): 4540-4542.
================================================
Free T4 and Reverse T3/Free T3 Ratio, A Useful Window into Status of Deiodinase System
In 1984, Dr. Shimada 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.
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 (T3
U) 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. (10)
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
—————————————–
In the hypothyroid patient on levothyroxine, the lab finding of shunting
to reverse T3 predicts the patient will do well switching from levothyroxine to NDT (natural desiccated thyroid), which contains a combination
of T3 and T4, the solution to T4 shunting to reverse T3. In these cases, the Free T4 may be higher than usually seen, and the Free T3
lower than usually seen. Unfortunately, the use of the reverse T3 test for this purpose has been ignored by conventional endocrinology which
dogmatically clings to the idea that reverse T3 has no clinical utility in monitoring levothyroxine therapy.
In 2019, Dr. Cristiane 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. (46-47)
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.
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.
https://www.frontiersin.org/articles/10.3389/fendo.2019.00856/full
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.
Most physicians caring for hypothyroid patients on T4 monotherapy see a significant subset of subjects who still complain of symptoms suggestive of thyroid hormone insufficiency in spite of TSH levels within the reference range. The argument made is that these patients suffer from insufficient T3 generation from T4. To attempt to generate T3 levels equivalent to those seen with thyroidal secretion of T3, the potential role and efficacy of combination T4/T3 treatment has been assessed. Having a blood test like rT3 to successfully address appropriate dosing of a T4/T3 combination agent could allow clinicians to more effectively treat patients with primary hypothyroidism.
————————————————————
Chopra, Inder J., et al. “Opposite Effects of Dexamethasone on Serum Concentrations of 3, 3′, 5′-Triiodothyronine (Reverse T3) and 3, 3′,
5′-Triiodothyronine (T3).” The Journal of Clinical Endocrinology & Metabolism 41.5 (1975): 911-920.
Euthyroid Sick Syndrome
High reverse T3 may also be found in a condition referred to as “euthyroid sick syndrome” in acute or chronic illness, starvation, and eating disorders. Although elevated reverse T3 in chronic illness can be observed, it is poorly understood. Treatment with T3 (liothyronine)
is a matter of debate. Central hypothyroidism may resemble euthyroid sick syndrome, except that central hypothyroidism will have
a low reverse T3. In contrast, euthyroid sick syndrome will have a high reverse T3, as an adaptation to protect the severely ill patient
from excess thyroid hormone. (48-55)
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, high reverse T3 is a protective mechanism in the thyrotoxic patient. A different scenario is
the reverse T3 in the normal range, yet higher than usually seen, a pattern found in patients who remain symptomatic while under treatment
with levothyroxine, as discussed above. Alternatively, a low reverse T3 usually confirms hypothyroidism in the untreated patient or confirms central hypothyroidism with HPA dysfunction.
Patients with central hypothyroidism typically show a low serum TSH even though they are clinically hypothyroid and have a low
Free T3 and T4. These patients benefit from treatment with thyroid hormone.
Reverse T3 Elevated in Metastatic Cancer
Occasionally, it may be challenging to interpret a high reverse T3. For example, I recall an asymptomatic 85-year-old female patient in no
acute distress. The thyroid labs were all normal except for an elevated reverse T3 of 28 ng/ dL (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 developed shoulder pain; subsequent x-rays, and bone scans by the orthopedic surgeon showed lytic bone lesions indicating
extensive metastatic cancer. Sadly, the patient succumbed quickly to the extensive metastatic disease. In retrospect, the high reverse T3 was
a marker for metastatic cancer. (56-63)
In 2021 Dr. Annarita Nappi found D3 deiodinase which converts T4 to inactive reverse T3, is barely detectable in adult tissues yet is
upregulated in many cancer types and other chronic illnesses, thus explaining high reverse T3 levels in the cancer patient. Dr. Annarita
Nappi writes:
Although its expression is barely detectable in adult tissues, the D3 enzyme has been reactivated in several physiopathological
conditions in which cell proliferation is enhanced, such as chronic inflammation, myocardial infarction, tissue repair, and
critical illness… Interestingly, in adult life, D3 is also re-expressed in cancer. D3 was initially identified in various immortalized
cell lines derived from adenocarcinoma, breast cancer, endometrium carcinoma, neuroblastoma basal cell carcinoma, ovarian cancer, and colon. Accordingly, D3 is upregulated in many murine and human
tumors tissues, including the vascular tumors infantile hemangiomas and hepatic hemangioendothelioma as well as in various brain tumors, among which, gliosarcoma and glioblastoma multiforme. (60)
=============================
https://stopthethyroidmadness.com/reverse-t3/
Reverse T3 (also called Reverse Triiodothyronine)
======================
Diagnose and Treat Hypothyroidism in 2021, Part 3: New Endocrinology
Diagnose and Treat Hypothyroidism in 2021, Part 3: New Endocrinology
By Alan B. McDaniel, MD
Unfortunately, TSH is often suppressed by the DTE 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 DTE’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! 237
Low TSH doesn’t affect the heart; high T3 does.238
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 DTE 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
https://www.optimaldx.com/blog/free-t3-free-t4-ratio
Thyroid hormones are the spark plugs of metabolism.
Dicken Weatherby, N.D. and Beth Ellen DiLuglio, MS, RDN, LDN
Decreased FT3:FT4 ratio
A reduced FT3:FT4 ratio may indicate the use of T4 only therapy, hypothyroidism, selenium deficiency, disrupted deiodinase activity, and reduced production of T3 and free T3. A ratio of less than 2 suggests the presence of low T3 syndrome.[17] Critical illness, inflammation, and hypoxia may interfere with the conversion of T4 to T3 and increase degradation of T4, essentially leading to a rise in FT3:FT4 ratios.
================================================
https://pubmed.ncbi.nlm.nih.gov/19428128/
Pimentel, Carlos Roberto Alves, et al. “Reverse T3 as a Parameter of Myocardial Function Impairment in Heart Failure.” International journal of cardiology 145.1 (2010): 52-53.
================================
free pdf
Click to access 9d19d173dbcd7334602b919ad5a4532824fd.pdf
Gomes-Lima, Cristiane. “Reverse T.” Cleveland Clinic Journal of Medicine 85.6 (2018): 451.
Unfortunately therefore, at the present time there are no data that support for or against the use of rT3 to monitor LT4 + LT3 combination therapy.
Conclusion 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 to monitor levothyroxine therapy, either given alone or in combination with liothyronine.
————————-
2021
https://www.scirp.org/journal/paperinformation.aspx?paperid=110736
Exley, Sarah, Sonal Banzal, and Udaya Kabadi. “Low Reverse T3: A Reliable, Sensitive and Specific in Diagnosis of Central Hypothyroidism.” Open Journal of Endocrine and Metabolic Diseases 11.7 (2021): 137-143.
Reverse T3 is a reliable laboratory test differentiating between Central Hypothyroidism and “Euthyroid Sick Syndrome” in subjects with low free T4 and low/normal TSH levels.
Results: Reverse T3 established two distinct groups: 1) subnormal concentrations, 8.31 ± 0.52 [range, 11 – 14 ng/dl]; 2) supernormal levels; 32 ± 4 [normal Range 12 – 26]. Free T3 concentrations were subnormal or normal, 1.6 – 2.9 [normal range, 2.3 – 4.2 ng/ml] in individuals amongst both groups. On reassessment after 3 – 6 weeks, free T4, free T3, TSH and reverse T3 normalized in group with normal or elevated reverse T3 indicating recovery from “Euthyroid Sick Syndrome” whereas free T4 and reverse T3 remained subnormal in the other group suggesting presence of Central Hypothyroidism. Conclusion: Reverse T3 is a reliable laboratory test differentiating between Central Hypothyroidism and “Euthyroid Sick Syndrome” in subjects with low free T4 and low/normal TSH levels.
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
HELPFUL OR WASTE OF TIME ?
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
free pdf
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.
Methods rT3 was measured in 98 consecutive patients seen
in a tertiary Endocrinology clinic with possible or confirmed
hypothyroidism (all with severe fatigue) with many of them
were already treated with different thyroid preparations.
Results: The figure shows the 25%-75% quartiles, ranges
and ratio of rT3 above the normal range/patients in that
category. The cutoff of 24 ng/dL (upper limit of normal for
rT3 at either Quest or LabCorp) is indicated by the line.
Overall, 18 of the 98 patients had a rT3 above the normal
range. Patients on L-T4 alone or desiccated thyroid plus
L-T4 had the highest levels of rT3 and the highest % above
the cut-off. Three of the patients with a high rT3 were not on
any thyroid medicine, and in 2 of them, the rT3 normalized
when repeated. The 8 patients with a high rT3 on L-T4 was
a relatively high percentage (29%).
Measuring rT3 may be helpful in patients who are already on T4-containing thyroid treatments who still have hypothyroid symptoms.
——————————————- —
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.
Background: Reverse T3 (rT3) is a biologically inactive form of T3 that is created by peripheral 5 deiodination of T4 by type 1 and type 3 deiodinases and may block T3 binding to the thyroid hormone receptor. As about 15% of patients on L-T4 replacement with a normalized TSH report continued fatigue and other hypothyroid symptoms, efforts are needed to understand why this occurs and how it can be corrected. Decades ago, endocrinologists realized that in severe illnesses, rT3 is often high and T3 is often low and termed this “sick euthyroid syndrome”. However, more recently, alternative doctors, including functional medicine doctors, have argued that high rT3 is detrimental and can block T3 from binding to the thyroid hormone receptor. Without peer-reviewed publications, these functional medicine doctors rely heavily on rT3 levels to treat patients that may have no other laboratory findings of hypothyroidism and often prescribe them L-T3-only preparations to try to lower the rT3. Also poorly characterized in the literature are the effects of hypercortisolism and hypopituitarism, both of which should modulate the expression of deiodinases to increase rT3. Hypotheses: 1) Patient rT3 levels will vary significantly with the type of thyroid medication taken. 2) Patient rT3 levels will be clinically significant in the management of patients on thyroid medications. 3) Hypercortisolism and hypopituitarism will increase rT3 levels. Methods: The most recent rT3 measurements were analyzed from 621 patients currently being managed by TCF. The upper limit of normal for rT3 at either Quest or LabCorp, which is usually 24.1 ng/dL was used as a cut-off for a high result and below 9.2 ng/dL as the low cut-off. Results: Elevate rT3 levels was seen in 3% of patients of patients not on thyroid replacement (5/143), seen in 8% of patients (17/203) taking desiccated thyroid. It was more prevalent in patients taking desiccated thyroid with synthetic T3 (27%, 7/26) or T4 (15%, 16/104) and was seen in 15% of patients (9/58) taking synthetic T4 alone. Changes were made to the amount or type of medications in 199 patients. Levels of rT3 levels were outside the normal range in 27% of these patients (54/199), being above normal range in 16% of these patients (32/199). Hypercortisolism was seen in 37 patients, 36 from Cushing’s disease, however above normal rT3 was seen in only 2 patients. Hypopituitarism was diagnosed in 22 patients, only one had above normal rT3 levels because they couldn’t afford their growth hormone replacement.
Conclusion: Measuring rT3 may be helpful in patients who are already on thyroid treatments, and is of greater importance in patients taking synthetic preparations. It is not recommended in patients who are not taking thyroid medicine (even if experiencing hypercortisolism) or in patients with hypopituitarism that are taking adequate hormone replacement.
https://pubmed.ncbi.nlm.nih.gov/31581295/
McKeever, Liam, et al. “Higher caloric exposure in critically ill patients transiently accelerates thyroid hormone activation.” The Journal of Clinical Endocrinology & Metabolism 105.2 (2020): 523-533.
Higher caloric exposure in NTIS patients transiently attenuates the drop of the plasma T3/rT3 ratio, an effect that is minimized and finally lost over the following 3 days of continued higher caloric exposure.
—————————————————
https://pubmed.ncbi.nlm.nih.gov/30943372/
Lin, Hung-Yun, et al. “Action of reverse T3 on cancer cells.” Endocrine Research 44.4 (2019): 148-152.
Background: Reverse T3 (rT3; 3,3′,5′-triiodo-L-thyronine) is widely regarded as an inactive naturally occurring analog of thyroid hormone. rT3 is known to bind to the thyroid hormone analog receptor on plasma membrane integrin αvβ3. This integrin is generously expressed by tumor cells and is the initiation site for the stimulation by L-thyroxine (T4) at physiological free concentrations on cancer cell proliferation. Results: In the present studies, we show that rT3 caused increases of proliferation in vitro of 50% to 80% (P < 0.05-0.001) of human breast cancer and glioblastoma cells. Conclusion: rT3 may be a host factor supporting cancer growth.
—————————–
1995
https://pubmed.ncbi.nlm.nih.gov/8808092/
Burmeister, Lynn A. “Reverse T3 does not reliably differentiate hypothyroid sick syndrome from euthyroid sick syndrome.” Thyroid 5.6 (1995): 435-441.
To assess the efficacy of reverse T3 in differentiating between the hypothyroid and euthyroid state in the setting of illness, all reverse T3 determinations obtained over a 4-year period in a University teaching hospital were analyzed in the context of concurrent thyroid function tests, bilirubin, albumin, creatinine, subsequent treatment, and follow-up. Based on T4 (or free T4 index) and TSH, the thyroidal state of the patient and the appropriateness of the reverse T3 determination were assigned. A total of 262 reverse T3 determinations were made in 246 patients. There is an inverse linear relationship between the log TSH and the reverse T3. Patients with hypothyroidism plus illness may have a normal reverse T3 and patients with euthyroidism may have a low reverse T3. Reverse T3 is linearly related to bilirubin up to a bilirubin of approximately 171 microM (10 mg/dL). Sixty percent of the reverse T3 determinations were obtained for seemingly inappropriate indications. In association with a low free T4 index/T4, an unmeasurable reverse T3 did not lead to institution of thyroid hormone treatment in over 52% of cases. Although reverse T3 may be elevated in the setting of nonthyroidal illness, it is not reliable in distinguishing between the hypothyroid sick patient and the euthyroid sick patient. This is probably because of drug and disease effects on thyroid hormone metabolism as well as the presence of sufficient T4 substrate for conversion to reverse T3 in many hypothyroid sick patients.
—————————-
eating disorder
Eating Disorders – Treatment with Thyroid Hormone?
Anorexia is an eating disorder and is considered
a psychiatric disease. Patients with
anorexia may appear cachectic from starvation,
and as such, can represent a life-threatening
medical emergency requiring hospitalization
and hyper-alimentation. (70-72)
In 2011, Dr. Michelle Warren reviewed the
endocrine manifestations of eating disorders,
finding a similarity with the euthyroid sick syndrome,
with low Free T3 and high reverse T3,
a pattern suggesting central hypothyroidism,
writing:
Also typical in anorexia are changes seen
with the euthyroid sick syndrome. T3 levels
are low, whereas rT3 [reverse T3] is elevated.
In some patients, T4 is also decreased. TSH
levels are normal or occasionally slightly
reduced, suggesting a hypothalamic origin of
the suppressed thyroid function…Treatment
with thyroid hormone is inappropriate and
leads to undesirable weight loss and loss of
muscle mass. (73)
On the other hand, Dr. Richard Shames disagrees
with Dr. Warren regarding thyroid hormone
treatment for eating disorders. In 2022,
Dr. Richard Shames found eating disorder
patients have the low-T3 syndrome and should
be treated with T3-containing thyroid medication
with good results. He says T3 “acts directly
on the hypothalamus to stimulate feeding.” Dr.
Richard Shames writes:
Calorie restriction reduces circulating
triiodothyronine (T3) – the most active
thyroid hormone – inducing hypothyroidism,
constipation, and reduced appetite that
inhibit eating, acting to sustain and
sometimes precipitate eating disorders.
Thyroid-hormone treatment can be
effective but is rarely employed… Circulating
T3 levels decrease in eating disorders (EDs)
and in most severe and chronic illnesses
in the eponymous medical condition low-
T3 syndrome (LT3S)… LT3S occurs broadly
in severe and chronic illnesses including
trauma, sepsis, heart failure, COVID-19, and
during calorie restriction aside from EDs…
LT3S has major role in sustaining eating
disorders by causing chronic constipation
that inhibits eating and weight gain. T3
also acts directly on the hypothalamus to
stimulate feeding (independent of energy
expenditure). Reduced circulating T3 in LT3S
is likely a factor in appetite suppression…
Though thyroid-hormone dysfunction is
central to EDs, thyroid-hormone treatment
is rarely considered by doctors or presented
as an option to patients. Emphasis Mine
(Reference Shames 2022) Note: Euthyroid
sick syndrome is synonymous with low-T3
syndrome. (74)
Warren, Michelle P. “Endocrine Manifestations
of Eating Disorders.” The Journal of Clinical
Endocrinology & Metabolism 96.2 (2011): 333-343.
Shames, Richard, and Stuart Wenzel. “On the
Fundamental Efficacy of Thyroid Hormone Therapy
in Eating Disorders: Review of Mechanisms and Case
Study.” Journal of Restorative Medicine 12.1 (2022).
————————————————
https://europepmc.org/article/med/6696490
Desai, M., et al. “The importance of reverse triiodothyronine in hypothyroid children on replacement treatment.” Archives of disease in childhood 59.1 (1984): 30-35.
Reverse triiodothyronine (rT3), triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH) values were measured by radioimmunoassay in 40 children with congenital hypothyroidism who were being given levothyroxine (0.05-0.35 mg/day) and in 14 normal controls. In 15 of the children with hypothyroidism the treatment, judged by serum T4 and TSH values and thyrotrophin releasing hormone (TRH) test, seemed to be adequate and their mean rT3 value and rT3:T4 ratio were comparable with the controls. The remaining 25 children had a raised serum T4 and a low TSH value. Only 4 (16%) of these children had an abnormally high T3 concentration but the rT3 value was raised in 23 (92%) and their mean rT3 value and rT3:T4 ratio were significantly higher than in the control children. Less than 20% of this ‘overtreated’ group, however, had clinical hyperthyroidism. We suggest that in patients on T4 replacement treatment the peripheral thyroid homeostatic mechanisms produce larger amounts of rT3, thereby preventing high T3 values where serum T4 values are raised. This may explain why the ‘overtreated’ children showed no clinical evidence of hyperthyroidism. These findings emphasise the protective and selective role of peripheral monodeiodination.
Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
www.jeffreydachmd.com
www.drdach.com
Heart Book by Jeffrey Dach
www.naturalmedicine101.com
www.bioidenticalhormones101.com
www.truemedmd.com
Click Here for: Dr Dach’s Online Store for Pure Encapsulations Supplements
Click Here for: Dr Dach’s Online Store for Nature’s Sunshine Supplements
Web Site and Discussion Board Links:
jdach1.typepad.com/blog/
disc.yourwebapps.com/Indices/244066.html
disc.yourwebapps.com/Indices/244067.html
http://sci.med.narkive.com/covV2Qo2/jeffrey-dach-book-announcment-natural-medicine-101
The reader is advised to discuss the comments on these pages with his/her personal physicians and to only act upon the advice of his/her personal physician. Also note that concerning an answer which appears as an electronically posted question, I am NOT creating a physician — patient relationship. Although identities will remain confidential as much as possible, as I can not control the media, I can not take responsibility for any breaches of confidentiality that may occur.
Copyright (c) 2023 Jeffrey Dach MD All Rights Reserved. This article may be reproduced on the internet without permission, provided there is a link to this page and proper credit is given. See Repost Guidelines.
FAIR USE NOTICE: This site contains copyrighted material the use of which has not always been specifically authorized by the copyright owner. We are making such material available in our efforts to advance understanding of issues of significance. We believe this constitutes a ‘fair use’ of any such copyrighted material as provided for in section 107 of the US Copyright Law. In accordance with Title 17 U.S.C. Section 107, the material on this site is distributed without profit to those who have expressed a prior interest in receiving the included information for research and educational purposes.
Serving Areas of: Hollywood, Aventura, Miami, Fort Lauderdale, Pembroke Pines, Miramar, Davie, Coral Springs, Cooper City, Sunshine Ranches, Hallandale, Surfside, Miami Beach, Sunny Isles, Normandy Isles, Coral Gables, Hialeah, Golden Beach ,Kendall,sunrise, coral springs, parkland,pompano, boca raton, palm beach, weston, dania beach, tamarac, oakland park, boynton beach, delray,lake worth,wellington,plantation
Leave a Reply
You must be logged in to post a comment.