Original thread: http://www.definitivemind.com/forums/showthread.php?t=254

@wolverine 1394 wrote:

Dr. Mariano, do T4 and T3 cross the blood brain barrier only as free T4 and free T3? Or do all forms of T4 and T3 get across? Some forms easier than others?

Since T4 and T3, in whatever form, are all measurements of serum concentrations, can Total T4, Free T4, Total T3, and/or Free T3 (or some combination) be used to infer CSF concentrations?

I believe that this becomes an issue when desiccated thyroid is used as sole replacement therapy. Often this results in normal (or high normal) Free T4, Free T3, and Total T3, but markedly sub-normal Total T4. In this scenario, if CNS hypothyroidism were suspected (and I’m not sure what symptoms would differentiate CNS from peripheral hypothyroidism), would it be desirable, e.g., to achieve a normal Total T4 by decreasing the dose of desiccated thyroid and adding pure T4?
Thanks.

T3 and T4 are bound to three proteins in the blood:

• Thyroid Binding Globulin (also called Thyroxine-Binding Globulin, TBG)
• Transthyretin
• Albumin

The distribution of thyroid hormones and binding proteins are approximately:
T4: 68% to TBG, 11 % to Transthyretin, 20 % to Albumin
T3: 80 % to TBG, 9 % to Transthyretin, 11 % to Albumin

T4 has a stronger bond to TBG.
T3 has a stronger bond to Transthyretin
Both T3 and T4 have a much weaker bond (approximately 100 to 1000 x less) to Albumin.

The thyroid hormones dynamically change between the free state and the bound state. Since the bond to Albumin is weaker, much of what is bound to Albumin may be free at any given moment, but won’t be registered as Free T3 or Free T4. Some portion of T3 and T4 is also free at any given moment but may not be registered as Free T3 or Free T4.

Free T3 and Free T4 give you only a snapshot – one moment in time – of the state. But this state varies from moment to moment.

This is why it is useful to take Total T3 and Total T4 into account to help determine total thyroid function.

This is analogous to Testosterone. Some use “bioavailable” testosterone as a measure of testosterone signaling activity. This would represent testosterone that is free and testosterone that is loosely bound to albumin. However, even tightly bound testosterone to sex-hormone binding globulin (SHBG) has signaling functions via induced conformational changes in the SHBG molecule then binding of testosterone-bound SHBG to SHBG receptors.

—

Thyroid hormone does not directly diffuse into cells.

Thyroid hormone is transported across cell membranes by various transporter molecules. In the brain and in the blood brain barrier (BBB), two known transporter molecules are Thyroid Hormone Transporter Molecule MCT8 and Organic Anion Transporting Polypeptide OATP1C1. MCT8 is also produced in heart, kidney, liver, and skeletal muscle.

There are two blood brain barriers: The Blood Brain Barrier Endothelial cells that line the blood vessels of the brain and are connected to astrocytes of the brain, and the Blood Cerebral Spinal Fluid Barrier Choroid Plexus Epithelial Cells that connect the blood to the Cerebopinal Fluid. The Choroid Plexus filters blood in order to produce Cerebrospinal Fluid.

From blood, T3 and T4 enter the brain via two paths:

1. T3 and T4 are transported into a BBB Endothelium Cell (via OATP). T3 and T4 are then transferred into an attached Astrocyte. In the Astrocyte, Deiodinase D2 coverts T4 to T3. T3 then exits the Astrocyte via MCT8. T3 then enters neurons via MCT8 transporters.

2. T3 and T4 are transported into Blood Cerebral Spinal Fluid Barrier Choroid Plexus Epithelial Cells (via MCT8). They they exit the choroid plexus (via OATP) and enter the Cerebrospinal Fluid (CSF). From the CSF, T3 and T4 are taken up by Tanycytes or Astrocytes. These cells have D2 Diodinase, which convert T4 to T3. Upon exiting these cells, T3 enters neurons.

Notably, neurons have Diodinase D3 enzyme which converts T4 to reverse T3 and T3 to T2.

The presence of thyroid hormone can reduce production of OATP as part of a negative feedback loop control.

—

Within brain cells, there are variations nuclear membrane thyroid transporters. Usually, 90 % of the intracellular T3 is located in the cytosol and 10 % is in the nucleus. In the pituitary gland’s cells, however, 50 % of T3 is in the nucleus.

—

Adding to the complexity of how thyroid hormone works, there is an Intracellular T3 Binding Protein (CTPB) which is produced in high amounts in the brain and heart, though is also widespread in production in the body.

—

Serum measurements of thyroid hormone can’t be used to infer CSF concentrations. Only a spinal tap will be able to tell what the CSF concentrations are.

—

Brain thyroid hormone levels and T3 to T4 ratios are going to be determined at several levels.

For example, the number and types and location of thyroid transporters determines what amount of thyroid hormone gets through.

Variations in the genes for the thyroid transporter molecules will determine how effective they are and how selective they are for T3 or T4 transport – creating a difference between Blood and Brain concentrations of Thyroid hormones.

Variations in Astrocyte and Tanycyte Diodinase D2 production will determine T3 to T4 conversions in the brain, which may be different from the blood.

etc.

—

From my point of view, given the differences that can arise in blood versus brain levels of thyroid hormone and thyroid hormone conversion, it is important to consider in some patients to not only optimize T3 but to also optimize T4 levels.

This is important, for example, in mood disorders. Here, the difference between T3 and T4 treatment becomes apparent.

In major depressive disorder, historically, T3 is a more effective treatment than T4 in reducing depressive symptoms. Spectulating: perhaps T4 to T3 conversion in the brain’s astrocytes and tanycytes is impaired by lack of D2 Diodinase production, among other possible problems in brain thyroid hormone metabolism.

In bipolar disorder, historically, T4 is much more effective than T3 in stabilizing mood. T4 may be used medicinally to reach “hyperthyroid” levels – based on TSH measurements – in psychiatry to stabilize mood in bipolar disorder. Speculating: perhaps, in bipolar disorder, there is a gene mutation in one of the thyroid transport molecules which selectively impairs T3 transport.

If a person is having problems with a T3 treatment or Armour Thyroid Treatment (which is primarily a T3 treatment), then perhaps adding a T4 treatment would be useful. Some patients benefit from combinations of thyroid treatments (e.g. T3 + T4, Armour Thyroid + Levothyroxine) better than single treatments alone.