Thyroid

Thyroid Hormone Metabolism in Down Syndrome

The endocrine system influences every function, organ and cell of the body. No other endocrine gland exemplifies this as much as the thyroid gland. Active thyroid hormone, triiodothyronine (T3), literally turns on every cell of our bodies by entering through the cell membrane, attaching itself to DNA which ultimately alters gene transcription (decreases or increases). This process starts with the thyroid gland which is a butterfly-shaped organ located in the lower part of the neck. It secretes mostly thyroxine (T4) and some triiodothyronine (T3). These hormones are responsible for controlling cellular metabolism, growth, development, as well as body temperature, heart rate, muscle and nervous system function, just to name a few.

Normally, the thyroid gland secretes about 80-90% T4 and 10-20% T3. T4 is an inactive hormone, or sometimes called a prohormone, and does not serve to control cell function until it is converted to T3. T4 is so named because it has 4 iodine atoms attached to it while T3 has 3 iodine atoms attached to it. The conversion of T4 to T3 is accomplished by deiodinase enzymes. The role of these enzymes is to remove one iodine which converts T4 to T3. There are several types of deiodinase enzymes, each with their own function. 5-deiodinase (D2) converts T4 into active T3 by removing an iodine from the outer ring and 5′-deiodinase (D3) converts T4 to reverse T3 by removing an iodine from the inner ring (see image below).

Active T3 plays the largest role in activating all biological activities and has a large effect on regulating gene expression. Genes that are most effected by T3 are:

Growth hormone
Osteocalcin (bone)
Myosin alpha chains (muscle)
TSH
T3 receptor gene
And many, many more

When intracellular T3 levels are low genes not only are not expressed, they can also be completely inhibited. T3 also has receptors on the mitochondria which are the powerhouse of the cell, generating energy in the form of ATP. Without active T3 mitochondria do not function as well.

The brain is particularly dependent on active T3 hormone, especially during fetal development (Patel, 2011).

Reverse T3 has the opposite effect of T3 given that it is an inactive form of T3. In addition to being inactive within the cell it can actually block the activity of active T3. When the equilibrium between T4 conversion to active T3 and reverse T3 starts to lean toward the production of reverse T3 cellular activity is reduced and symptoms of hypothyroidism appear. This can happen despite adequate amounts of T4.

The real driving force behind the conversion of T4 to active T3 versus reverse T3 is based on D2 and D3 enzyme activity. The physiological process that either up-regulate D3, producing more reverse T3, or down-regulate D2, producing less active T3 are:

Low iron
High or low cortisol
Inflammation
Oxidative stress

Low active T3 production can be a vicious cycle, especially when genes for T3 receptors are inhibited. As well, hypothyroidism leads to a further decrease in iron absorption, increased inflammation and oxidative stress as well as stress on the body that leads to high or low cortisol levels.

All of these processes that contribute to elevated rT3 levels and/or reduced T3 receptors on cell membranes are experienced by children and adults with Down syndrome. Many, if not all, of the symptoms of Down syndrome mirror those of congenital hypothyroidism, including low muscle tone, delayed development, delayed tooth eruption, dry skin, pulmonary hypertension, delayed cognition, poor circulation, constipation, reflux, low body temperature, tongue protrusion, umbilical hernia, slow growth and many others.

This photo depicts the action of T4, T3 and rT3 upon the mitochondria and DNA of the cell.

(Image credit: Influence of T3 and T4 in the regulation of gene expression and basal metabolism.)

Conventional Endocrinologists do not recognize this process because their only tool to help hypothyroid patients is Levothyroxine (Synthroid), which is a T4-only medication and does not address issues with conversion of T4 to active T3.

Dr. Peirson has scoured hundreds of studies, scientific articles and medical textbooks in order to understand all of the biochemical processes that support proper thyroid hormone function, particularly in infants and children. She has included a sample of some of the best studies and articles here that support the need for optimizing thyroid hormone function in children and adults with Down syndrome.

This list begins with studies and articles explaining the need for more in-depth testing of thyroid hormone function in children and adults with Down syndrome. The subsequent resources are divided by organ system or symptoms that are commonly accepted as a consequence of Down syndrome, but are in fact due to cellular hypothyroidism.