Dr. John C. Lowe
August 17, 2005

In 2002, a Portuguese molecular biologist, Dr. Joana Palha, reported study findings that, although not intended to, show that an argument for using T4 alone is false. The findings should change the beliefs and clinical practice of many doctors, enabling more hypothyroid patients to get effective treatment.

Since the 1950s, some thyroid researchers believed there was only one way thyroid hormone got from the blood into the brain: by binding to a protein called “transthyretin”(trans-th-r-tin). Transthyretin is one of three proteins that bind and transport thyroid hormone. The main protein is “thyroxine-binding globulin” and the other is “albumin.”

Cell membranes have sites that strongly bind transthyretin. The binding sites are probably transthyretin receptors that are instrumental in delivering thyroid hormone into cells.[4]

The transthyretin that transports thyroid hormone in the blood is manufactured by the liver. Transthyretin that transports thyroid hormone from the blood into the brain is produced in a brain structure called the “choroid plexus.” The choroid plexus is a complex outgrowth of blood vessels. Its situated just above the brain stem and below the brains fluid containing cavities called “ventricles.” The plexus produces and secretes
the fluid, called “cerebrospinal fluid,” that the brain and spinal cord float in.

Thyroid hormone travels to the choroid plexus through the blood. When the hormone encounters the transthyretin the plexus has produced, the hormone binds to it. Then the protein transports the hormone into the brain.

T3-Binding to Transthyretin. In the 1950s, limited information led some researchers to conclude that transthyretin only transports T4 into the brain. Based on this conclusion, they believed that brain cells get their T3 only by converting T4 to T3. Some doctors adopted these two beliefs. And based on the beliefs, they wouldnt let their patients use T3 alone. These false beliefs probably contributed to conventional doctors rigid use of T4-replacement (patients use of T4 alone with their dosages adjusted by their TSH levels). All of this happened despite studies in the 1950s and early 1960 that showed T3 alone was highly effective for patients who failed to benefit from T4 alone or T4/T3 therapy.

Let me illustrate the types of problems that resulted from doctors holding these false beliefs. I used to co-treat patients with a neuropsychiatrist in Houston, Texas. More than once, he expressed frustration at an experience he occasionally had. After he prescribed T3 for depressed and cognitively-impaired hypothyroid patients, endocrinologists would switch them to T4-replacement. The endocrinologists would argue that without taking T4, the patients brain cells wouldnt have enough T3. But soon after being switched to T4, their depression and cognitive dysfunction returned. So, when the patients went back to the neuropsychiatist to complain, he switched them back to T3. Quickly, their depression and cognitive dysfunction cleared up again.

At that time, it appeared to the neuropsychiatrist and me that transthyretin must transport T3 as well as T4 into the brain. We assumed this because we trusted that the researchers were right about thyroid hormone getting into the brain only by piggybacking on transthyretin.

Dr. Pilha, author of the Portuguese studies I cite here, appears to agree with the researchers and doctors who believe that transthyretin delivers only T4 into the brain. She recently wrote that transthyretin “binds virtually no T3.”[3,p.1293] She then went further, stating that transthyretin “is not a T3 carrier.”[3,p.1296]

But other researchers contend that transthyretin binds and transports both T4 and T3.[1][2] Some of these investigators have measured how readily T4, T3, and T2 bind to transthyretin. By far, T4 binds most strongly to the protein. T3 binds to it but with 10-times lower affinity than T4. T2 also binds to transthyretin, although with 100-times less affinity than T4.[6] (An enzyme converts T3 to T2 when it removes one of T3’s three
iodine atoms.)

The conclusion that T3 binds to transthyretin is consistent with findings of other studies.Researchers have documented that T3 passes the blood-brain barrier and enters the brain.[9][10][11]

One study showed that how readily T3 enters the brain depends on the shape of its molecule. The molecule comes in two shapes, right and left. We call the right-handed molecule dextro-T3 or DT3, and the left-handed molecule levo-T3 or LT3. LT3 enters thebrain about three times more readily than DT3.[7]

The T3 in products such as Cytomel and Cynomel is LT3.[8] Even in the absence of transthyretin, LT3 (along with less DT3) still readily passes the blood-brain barrier and
enters the brain.

New Studies. Some doctors, as I wrote above, long denied patients the use of T3 alone because they thought that transthyretin only carries T4 into the brain. But whether the protein carries only T4 or both T4 and T3 into the brain has become an irrelevant question in view of the new studies cited by Dr. Pilha.

The researchers who conducted the studies found that transthyretin isnt essential for T4 or T3 to get into the brain, at least not in mice. Nor is transthyretin necessary for a normal T3 concentration in brain cells. Dr. Pilha wrote that this is now shown “conclusively” by studies of mice whose cells produce no transthyretin at all.[3,p.1292 ]Despite the mice having no transthyretin, they have normal amounts of T3 in their brain cells.[3][12][13]

Proteins that transport thyroid hormone through the blood also arent essential for T4 and T3 to enter tissues other than the brain. Nor are the proteins necessary to having a normal concentration of thyroid hormone in the cells. For example, humans who have no “thyroxine-binding globulin” (the major transport protein in humans) still have normal thyroid hormone regulation. The same is true of rats that have no albumin, which is their major thyroid hormone binding protein.

Some researchers used to disagree with the “free hormone hypothesis,” which states that its the free thyroid hormone in the blood thats important to normal biological function. These new findings, however, show that the free hormone hypothesis is correct.[3]

Conclusion. In a critique I wrote in 2004,[5] I documented some disturbing findings about T4-replacement: in five studies, it left hypothyroid patients suffering from hypothyroid symptoms.[14][15][16][17][18] And in one study, patients on T4-replacement used more drugs and had an increased incidence of potentially fatal diseases.[18]

Our long line of research shows that some patients with too little thyroid hormone regulation dont benefit at all from T4-replacement or from T4/T3 combination therapy. Virtually all these patients, however, improve or recover with high enough doses of T3 alone.

On such patients behalf, we need to get word of these studies out to their doctors. I hope that doctors whove falsely believed that the brain gets T3 solely from T4 will consider the treatment implications of the study results. If so, perhaps theyll then allowtheir patients who respond poorly to T4-replacement or T4/T3 therapy to switch to T3 alone, the only approach likely to work for them.

References

1. Robbins, J. and Rall, J.E.: The iodine containing hormones. In Hormones in Blood, Vol. 1, 3rd edtion, edited by C.H. Gray and V.H.T. James, London, Academic Press, 1979, p. 576.
2. Robbins, J.: Thyroid hormone transport proteins and the physiology of hormone binding. In Werner and Ingbars The Thyroid: A Fundamental and Clinical Text, 6th edition. Edited by L.E. Braverman and R.D. Utiger, New York, J.B. Lippincott Co., 1991, pp.111-125.
3. Palha, J.A.: Transthyretin as a thyroid hormone carrier: function revisited. Clin.. Chem. Lab. Med., 40(12):1292-1300, 2002.
4. Schussler, G.C.: The thyroxine-binding proteins. Thyroid, 10(2):141-149, 2000.
5. Lowe, J.C.: http://www.drlowe.com/frf/t4replacement/intro.htm.
6. Wojtczak, A., Luft, J., and Cody, V.: Mechanism of molecular recognition. Structural aspects of 3,3′-diiodo-L-thyronine binding to human serum transthyretin. J. Biol. Chem., 267(1):353-357, 1992.
7. Terasaki, T. and Pardridge, W.M.: Stereospecificity of triiodothyronine transport into brain, liver, and salivary gland: role ofcarrier- and plasma protein-mediated transport. Endocrinology, 121(3):1185-1191, 1987.
8. http://www.kingpharm.com/uploads/pdf_inserts/Cytomel_PI.pdf.
9. Mooradian, A.D.: Blood-brain transport of triiodothyronine is reduced in aged rats. Mech. Ageing Dev., 52(2-3):141-147, 1990.
10. Cheng, L.Y., Outterbridge, L.V., Covatta, N.D., et al.: Film autoradiography identifies unique features of
[125I]3,3’5′-(reverse) triiodothyronine transport from blood to brain. J. Neurophysiol., 72(1):380-391, 1994.
11. Rudas, P. and Bartha, T.: Thyroxine and triiodothyronine uptake by the brain of chickens. Acta Vet. Hung,
41(3-4):395-408, 1993.
12. Palha, J.A., Fernandes, R., Morreale de Escobar, et al.: Transthyretin regulates thyoid hormone levels in the choroid plexus, but not in the brain parenchyma: study in a transthyretin-null mouse model. Endocrinology, 141:3267-3272, 2000.
13. Palha, J.A., Nissanov, J., Fernandes, R., et al.: Thyroid hormone distribution in the mouse brain: the role of transthyretin. Neuroscience, 113:837-847, 2002.
14. Walsh, J.P., Shiels, L., Mun Lim, E.E., et al.: Combined thyroxine/liothyronine treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J. Clin. Endocrinol. Metab., 88(10):4543-4550, 2003.
15. Sawka, A.M., Gerstein, H.C., Marriott, M.J., et al.: Does a combination regimen of thyroxine (T4) and
3,5,3′-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J. Clin. Endocrinol. Metab., 88(10):4551-4555, 2003.
16. Clyde, P.W., Harari, A.E., Getka, E.J., and Shakir, K.M.M.: Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. J.A.M.A., 290:2952-2958, 2003.
17. Cassio, A., Cacciari, E., Cicgnani, A., et al.: Treatment of congenital hypothyroidism: thyroxine alone or thyroxine plus triiodothyronine? Pediatrics, 111(5):1055-1060, 2003.
18. Saravanan, P., Chau, W.F., Roberts, N., et al.: Psychological well-being in patients on adequate doses of L-thyroxine: results of a large, controlled community-based questionnaire study. Clin. Endocrinol. (Oxf.), 57(5):577-585, 2002.

see work on:- MCT8/MCT10 (by Theo Visser et al)
http://dx.doi.org/10.1210/en.2013-1800