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).
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:
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 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.
- 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.)
(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.
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.
Hypothyroidism and Down Syndrome
Thyroid dysfunction in patients with Down syndrome.
Zinc sulfate supplementation improves thyroid function in hypozincemic Down
children.
Is zinc deficiency a cause of subclinical hypothyroidism in Down syndrome?
Low adherence to national guidelines for thyroid screening in Down syndrome.
Thyroid hypofunction in Down's syndrome: is it related to
oxidative stress?
Trisomy 21 causes persistent congenital hypothyroidism presumably of thyroidal origin.
Hypothyroidism in Down Syndrome: Screening Guidelines and Testing Methodology
Thyroid dysfunction in patients with Down syndrome.
Zinc sulfate supplementation improves thyroid function in hypozincemic Down
children.
Is zinc deficiency a cause of subclinical hypothyroidism in Down syndrome?
Low adherence to national guidelines for thyroid screening in Down syndrome.
Thyroid hypofunction in Down's syndrome: is it related to
oxidative stress?
Trisomy 21 causes persistent congenital hypothyroidism presumably of thyroidal origin.
Hypothyroidism in Down Syndrome: Screening Guidelines and Testing Methodology
Limitations of the TSH Lab Test and the Importance of Additional Tests
Hypothyroidism and the Limitations of Blood Tests
Hypothyroidism and the Limitations of Blood Tests
Reverse T3 and Deiodinase Enzymes Explained
Oxidative stress regulates type 3 deiodinase and type 2 deiodinase in cultured rat astrocytes.
Deiodinases: implications of the local control of thyroid hormone action
Deiodinases: The Balance of Thyroid Hormone
The Non-Thyroidal Illness Syndrome
Cracking the Code for Thyroid Hormone Signaling
Understanding Local Control of Thyroid Hormones: Deiodinases Function and Activity
The Challenges and Complexities of Thyroid Hormone Replacement
Pre- and Posttranslational Mechanisms of Regulation of the Type 3 Iodothyronine Deiodinase
Peripheral Metabolism of Thyroid Hormones: A Review
Evidence for thyroid hormone deficiency in iron-deficient anemic rats.
Metabolism of Thyroid Hormone
Physiology and pathophysiology of type 3 deiodinase in humans
Biochemistry, cellular and molecular biology, and physiological roles of the iodthyronine selenodeiodinases. (full text pdf)
Local impact of thyroid hormone inactivation. Deiodinases: the balance of thyroid hormone
Reawakened interest in type III iodothyronine deiodinase in critical illness and injury
Thyroid Hormone Transport (printable version)
Oxidative stress regulates type 3 deiodinase and type 2 deiodinase in cultured rat astrocytes.
Deiodinases: implications of the local control of thyroid hormone action
Deiodinases: The Balance of Thyroid Hormone
The Non-Thyroidal Illness Syndrome
Cracking the Code for Thyroid Hormone Signaling
Understanding Local Control of Thyroid Hormones: Deiodinases Function and Activity
The Challenges and Complexities of Thyroid Hormone Replacement
Pre- and Posttranslational Mechanisms of Regulation of the Type 3 Iodothyronine Deiodinase
Peripheral Metabolism of Thyroid Hormones: A Review
Evidence for thyroid hormone deficiency in iron-deficient anemic rats.
Metabolism of Thyroid Hormone
Physiology and pathophysiology of type 3 deiodinase in humans
Biochemistry, cellular and molecular biology, and physiological roles of the iodthyronine selenodeiodinases. (full text pdf)
Local impact of thyroid hormone inactivation. Deiodinases: the balance of thyroid hormone
Reawakened interest in type III iodothyronine deiodinase in critical illness and injury
Thyroid Hormone Transport (printable version)
Benefits of Alternative Treatment Options
Stability, Effectiveness and Safety of Dessicated Thyroid vs. Levothyroxine
Hypothyroidism: Optimizing Medication with Slow-Release Compounded Thyroid Replacement
T3 may be a better agent than T4 in the critically ill hypothyroid patient: evaluation of transport across the blood-brain barrier in a primate model
Does synthetic thyroid extract work for everybody?
Stability, Effectiveness and Safety of Dessicated Thyroid vs. Levothyroxine
Hypothyroidism: Optimizing Medication with Slow-Release Compounded Thyroid Replacement
T3 may be a better agent than T4 in the critically ill hypothyroid patient: evaluation of transport across the blood-brain barrier in a primate model
Does synthetic thyroid extract work for everybody?
Cognition
The role of thyroid hormone in fetal neurodevelopment.
Developmental thyroid hormone insufficiency and brain development: a role for brain-derived neurotrophic factor (BDNF)?
Influence of thyroid hormone on 5-HT(1A) and 5-HT(2A) receptor-mediated regulation of hippocampal BDNF mRNA expression.
Age-related changes in plasma levels of BDNF in Down syndrome patients.
Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior.
Thyroid Hormone Action in Cerebellum and Cerebral Cortex Development
Brain Development: Sonic Hedgehog at thy(roid) service
Thyroid Hormones in Brain Development and Function
Thyroid hormone regulates hippocampal neurogenesis in the adult rat brain
Timing of Thyroid Hormone Action in the Developing Brain: Clinical Observations and Experimental Findings
The role of thyroid hormone in fetal neurodevelopment.
Developmental thyroid hormone insufficiency and brain development: a role for brain-derived neurotrophic factor (BDNF)?
Influence of thyroid hormone on 5-HT(1A) and 5-HT(2A) receptor-mediated regulation of hippocampal BDNF mRNA expression.
Age-related changes in plasma levels of BDNF in Down syndrome patients.
Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior.
Thyroid Hormone Action in Cerebellum and Cerebral Cortex Development
Brain Development: Sonic Hedgehog at thy(roid) service
Thyroid Hormones in Brain Development and Function
Thyroid hormone regulates hippocampal neurogenesis in the adult rat brain
Timing of Thyroid Hormone Action in the Developing Brain: Clinical Observations and Experimental Findings
Mitochondria
Thyroid hormone action in mitochondria.
Thyroid hormones and mitochondria.
Mitochondrial dysfunction and Down's syndrome.
Oxidative stress and mitochondrial dysfunction in Down syndrome.
Thyroid hormone action in mitochondria.
Thyroid hormones and mitochondria.
Mitochondrial dysfunction and Down's syndrome.
Oxidative stress and mitochondrial dysfunction in Down syndrome.
Digestion
A case of Hirschsprung disease: does thyroid hormone have any effect?
Does Hypothyroidism Affect Gastrointestinal Motility?
A case of Hirschsprung disease: does thyroid hormone have any effect?
Does Hypothyroidism Affect Gastrointestinal Motility?
Growth
Metabolism
Immune System
Skin & Hair
An Intimate Relationship between Thyroid Hormone and Skin: Regulation of Gene Expression
Carotenemia. A review.
Beta-carotene, vitamin A and carrier proteins in thyroid diseases
An Intimate Relationship between Thyroid Hormone and Skin: Regulation of Gene Expression
Carotenemia. A review.
Beta-carotene, vitamin A and carrier proteins in thyroid diseases
Eyes
Labs Altered by Aberrant Thyroid Hormone Function
The effect of subclinical hypothyroidism on platelet parameters.
Hypothyroidism leads to more small-sized platelets in circulation.
Haemostasis in hypothyroidism
The effect of subclinical hypothyroidism on platelet parameters.
Hypothyroidism leads to more small-sized platelets in circulation.
Haemostasis in hypothyroidism
Autism
Are thyroid hormone concentrations at birth associated with subsequent autism diagnosis?
Familial autoimmune thyroid disease as a risk factor for regression in children with Autism Spectrum Disorder: a CPEA Study.
Autism: transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents.
Lower cortisol and higher ACTH levels in individuals with autism
Parental Autoimmune Diseases Associated With Autism Spectrum Disorders in Offspring
AUTISM: MATERNALLY DERIVED ANTIBODIES SPECIFIC FOR FETAL BRAIN PROTEINS
Are thyroid hormone concentrations at birth associated with subsequent autism diagnosis?
Familial autoimmune thyroid disease as a risk factor for regression in children with Autism Spectrum Disorder: a CPEA Study.
Autism: transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents.
Lower cortisol and higher ACTH levels in individuals with autism
Parental Autoimmune Diseases Associated With Autism Spectrum Disorders in Offspring
AUTISM: MATERNALLY DERIVED ANTIBODIES SPECIFIC FOR FETAL BRAIN PROTEINS
© Down Syndrome Treatment Center of Oregon 2014