Thyroid Hormone – Types and Functions

Iodine is an essential trace element absorbed in the small intestine. It is an integral part of T3 and T4. Sources of iodine include iodized table salt, seafood, seaweed, and vegetables. Decreased iodine intake can cause iodine deficiency and decreased thyroid hormone synthesis. Iodine deficiency can cause cretinism, goiter, myxedema coma, and hypothyroidism. [1][2][3]

TSH is released into the blood and binds to the thyroid-releasing hormone receptor (TSH-R) on the basolateral aspect of the thyroid follicular cell. The TSH-R is a Gs-protein coupled receptor, and its activation leads to the activation of adenylyl cyclase and intracellular levels of cAMP.  The increased cAMP activates protein kinase A (PKA). PKA phosphorylates different proteins to modify their functions. The five steps of thyroid synthesis are below:

• Synthesis of Thyroglobulin: Thyrocytes in the thyroid follicles produce a protein called thyroglobulin (TG). TG does not contain any iodine, and it is a precursor protein stored in the lumen of follicles. It is produced in the rough endoplasmic reticulum. Golgi apparatus pack it into the vesicles, and then it enters the follicular lumen through exocytosis.
• Iodide uptake: Protein kinase A phosphorylation causes increased activity of basolateral Na+-I- symporters, driven by Na+-K+-ATPase, to bring iodide from the circulation into the thyrocytes. Iodide then diffuses from basolateral side to the apex of the cell, where it is transported into the colloid through Pendrin transporter.
• Storage: thyroid hormones are bound to thyroglobulin for stored in the follicular lumen.
• Release: thyroid hormones are released into the fenestrated capillary network by thyrocytes in the following steps:

  1. Thyrocytes uptake iodinated thyroglobulin via endocytosis
  2. Lysosome fuse with the endosome containing iodinated thyroglobulin
  3. Proteolytic enzymes in the endolysosome cleave thyroglobulin into MIT, DIT, T3, and T4.
  4. T3 (20%) and T4 (80%) are released into the fenestrated capillaries via MCT8 transporter. [5]
  5. Deiodinase enzymes remove iodine molecules from DIT and MIT. Iodine can be salvaged and redistributed to an intracellular iodide pool. [1][6][4][6

Iodination of thyroglobulin: Protein kinase A also phosphorylates and activates the enzyme thyroid peroxidase (TPO). TPO has three functions: oxidation, organification, and coupling reaction.

• Oxidation: TPO uses hydrogen peroxide to oxidize iodide (I-) to iodine (I2). NADPH-oxidase, apical enzyme, generates hydrogen peroxide for TPO.
• Organification: TPO links tyrosine residues of thyroglobulin protein with I2. It generates monoiodotyrosine (MIT) and diiodotyrosine (DIT). MIT has a single tyrosine residue with iodine, and DIT has two tyrosine residues with iodine.
• Coupling reaction: TPO combines iodinated tyrosine residues to make triiodothyronine (T3) and tetraiodothyronine (T4). MIT and DIT join to form T3, and two DIT molecules form T4.

Organ Systems Involved

Thyroid hormone affects virtually every organ system in the body, including the heart, CNS, autonomic nervous system, bone, GI, and metabolism. In general, when the thyroid hormone binds to its intranuclear receptor, it activates the genes for increasing metabolic rate and thermogenesis. Increasing metabolic rate involves increased oxygen and energy consumption.

Heart: thyroid hormones have a permissive effect on catecholamines. It increases the expression of beta-receptors to increase heart rate, stroke volume, cardiac output, and contractility.

Lungs: thyroid hormones stimulate the respiratory centers and lead to increased oxygenation because of increased perfusion.

Skeletal muscles: thyroid hormones cause increased development of type II muscle fibers. These are fast-twitch muscle fibers capable of fast and powerful contractions.

Metabolism: thyroid hormone increases the basal metabolic rate. It increases the gene expression of Na+/K+ ATPase in different tissues leading to increased oxygen consumption, respiration rate, and body temperature. Depending on the metabolic status, it can induce lipolysis or lipid synthesis. Thyroid hormones stimulate the metabolism of carbohydrates and anabolism of proteins. Thyroid hormones can also induce catabolism of proteins in high doses. Thyroid hormones do not change the blood glucose level, but they can cause increased glucose reabsorption, gluconeogenesis, glycogen synthesis, and glucose oxidation.

Growth during childhood: In children, thyroid hormones act synergistically with growth hormone to stimulate bone growth. It induces chondrocytes, osteoblasts, and osteoclasts. Thyroid hormone also helps with brain maturation by axonal growth and the formation of the myelin sheath.[7]

Function

Physiological effects of thyroid hormones are listed below:

• Increases the basal metabolic rate
• Depending on the metabolic status it can induce lipolysis or lipid synthesis
• Stimulate the metabolism of carbohydrates
• Anabolism of proteins. Thyroid hormones can also induce catabolism of proteins in high doses
• Permissive effect on catecholamines
• In children, thyroid hormones act synergistically with growth hormone to stimulate bone growth
• The impact of thyroid hormone in CNS is important. During the prenatal period, it is needed for the maturation of the brain. In adults, it can affect mood. Hyperthyroidism can lead to hyperexcitability and irritability. Hypothyroidism can cause impaired memory, slowed speech, and sleepiness.
• Thyroid hormone affects fertility, ovulation, and menstruation

Mechanism

Thyroid hormones are lipophilic and circulate bound to the transport proteins. Only a fraction (~0.2%) of the thyroid hormone (free T4) is unbound and active. Transporter proteins include thyroxine-binding globulin (TBG), transthyretin, and albumin. TBG transports the majority (two-thirds) of the T4, and transthyretin transports thyroxine and retinol. When it reaches its target site, T3 and T4 can dissociate from their binding protein to enter cells either by diffusion or carrier-mediated transport. Receptors for T3 bind are already bound to the DNA in the nucleus before the ligand binding. T3 or T4 then bind to nuclear alpha or beta receptors in the respective tissue and cause activation of transcription factors leading to the activation of certain genes and cell-specific responses. Thyroid hormones are degraded in the liver via sulfation and glucuronidation and excreted in the bile. [8]

Thyroid receptors are transcription factors that can bind to both T3 and T4. However, they have a much higher affinity for T3. As a result, T4 is relatively inactive. Deiodinases convert T4 to active T3 or inactive reverse T3 (rT3). There are three types of deiodinases: type I, II, and III. Type I (DIO1) and II (DIO2) are located in the liver, kidneys, muscles, and thyroid glands. Type III (DIO3) deiodinases are located in the CNS and placenta. DIO1 and DIO2 convert T4 to active form T3, and DIO3 converts T4 into inactive form rT3. [8]

Symptoms of Hypothyroidism

Generalized decreased basal metabolic rate can present as apathy, slowed cognition, skin dryness, alopecia, increased low-density lipoproteins, and increased triglycerides. Hypothyroidism must be ruled out in psychiatry patients presenting with apathy and slowed cognition. Hypothyroidism can decrease sympathetic activity leading to decreased sweating, bradycardia, and constipation. Patients can present with myopathy and decreased cardiac output because of decreased transcription of sarcolemmal genes.

Hyperprolactinemia can be caused by hypothyroidism. Thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates prolactin and TSH release. Prolactin release can suppress testosterone, LH, FSH, and GnRH release. Prolactin can also cause breast tissue growth.

Patients with hypothyroidism may present with myxedema caused by decreased clearance of complex glycosaminoglycans and hyaluronic acids from the reticular layer of the dermis. Initially, the nonpitting edema is pretibial. As the state of hypothyroidism continues, patients can develop generalized edema.

Symptoms related to decreased metabolic rate:

• Bradycardia
• Fatigue
• Cold intolerance
• Weight gain
• Poor appetite
• Hair loss
• Cold and dry skin
• Constipation
• Myopathy, stiffness, cramps, entrapment syndromes
• Delayed deep tendon reflex relaxation

Symptoms from generalized myxedema:

• Myxedematous heart disease
• Puffy appearance with doughy skin texture
• Hoarse voice with difficulty articulate words
• Pretibial and periorbital edema

Symptoms of hyperprolactinemia:

• Amenorrhea or menorrhagia
• Galactorrhea
• Erectile dysfunction, infertility in men
• Decreased libido

Other symptoms:

• Depression
• Impaired concentration and memory
• Goiter
• Hypertension

Congenital hypothyroidism:

• Umbilical hernia
• Hypotonia
• Prolonged neonatal jaundice
• Poor feeding, absence of thirst (adipsia)
• Decreased activity
• Pot-belly, puffy-face, protuberant tongue
• Poor brain development

Symptoms of Hyperthyroidism

Generalized hypermetabolism from hyperthyroidism causes increased Na+/K+-ATPase to promote thermogenesis. There is increased catecholamine secretion and, beta-adrenergic receptors are also upregulated in various tissues. As a result of the hyperadrenergic state, peripheral vascular resistance is decreased. In the heart, hyperthyroidism causes a decreased amount of phospholamban, a protein that normally decreases the affinity of calcium-ATPase for calcium in the sarcoplasmic reticulum. As a result of decreased phospholamban, there is increased Ca+ movement between the sarcoplasmic reticulum and cytosol, leading to increased contractility. Increased beta-receptors on the heart also leads to increased cardiac output.

General

• Heat intolerance
• Weight loss
• Increased appetite
• Increased sweating from cutaneous blood flow increase
• Weakness
• Fatigue
• Onycholysis (separation of nails from nail beds)
• Pretibial myxedema

Eyes

• Lid lag (when looking down, sclera visible above cornea)
• Lid retraction (when looking straight, sclera visible above the cornea)
• Graves ophthalmopathy

Goiter

• Diffuse, smooth, non-tender goiter
• The audible bruit can be heard at the superior poles

Cardiovascular

• Tachycardia (can be masked by patients taking beta-blockers)
• Palpitations
• An irregular pulse from atrial fibrillation
• Hypertension
• Widened pulse pressure because systolic pressure increases and diastolic pressure decreases
• Heart failure (elderly patients)
• Chest pain
• Abnormal heart rhythms

Musculoskeletal

• Fine tremors of the outstretched fingers. Face, tongue, and head can also be involved. Tremors respond well to treatment with beta-blockers.
• Myopathy affecting proximal muscles. Serum creatine kinase levels can be normal
• Osteoporosis caused by the direct effects of T3. Elderly patients can present with fractures.

Neuropsychiatric system

• Restlessness
• Anxiety
• Depression
• Emotional instability
• Insomnia
• Tremoulousness
• Hyperreflexia

Conditions associated with hypothyroidism

• Iodine deficiency [11]
• Cretinism [12]
• Wolff-Chaikoff effect [13]
• Subacute thyroiditis [14]
• Postpartum thyroiditis [15]
• Riedel thyroiditis [16]
• Hashimoto thyroiditis [17]
• Drug-induced [18]

Conditions associated with hyperthyroidism

• Graves disease [19]
• Iodine excess [20]
• Struma ovarii [21]
• Thyrotropic pituitary adenoma [22]
• Jod-Basedow phenomenon [23]
• Drug-induced: amiodarone, lithium [24]
• Thyrotoxicosis and thyroid storm [25]
• Toxic multinodular goiter [26]
• Thyroid adenoma [27]

Antithyroid drugs that work in the thyroid gland [28]

• Perchlorate – inhibits Na+/I- symporter – blocks iodide uptake
• Thionamides – inhibits TPO – block thyroid hormone synthesis
• Iodide > 5mg – inhibits Na+/I- symporter and TPO – blocks iodide uptake and thyroid hormone synthesis
• Lithium – inhibits thyroid hormone release (off-label use for thyroid storm)

Antithyroid drugs that work in peripheral tissue – all these drugs inhibit the deiodinase enzymes. Deiodinase enzymes normally convert T4 into the active form T3. These drugs inhibit the conversion of T4 to T3 and reduce its activity.

• Propylthiouracil (thionamide)
• Dexamethasone
• Amiodarone
• Propranolol

• https://www.ncbi.nlm.nih.gov/books/NBK470452/
• https://www.ncbi.nlm.nih.gov/books/NBK285554/
• https://www.ncbi.nlm.nih.gov/books/NBK28/
• https://www.ncbi.nlm.nih.gov/books/NBK537039/
• https://www.ncbi.nlm.nih.gov/books/NBK500006/
• https://www.ncbi.nlm.nih.gov/books/NBK241/
• https://www.ncbi.nlm.nih.gov/books/NBK519566/
• https://www.ncbi.nlm.nih.gov/books/NBK519536/
• https://www.ncbi.nlm.nih.gov/books/NBK500006/