Thyroid Gland

Introduction

The thyroid gland plays a central role in regulating metabolism and energy balance. Thyroxine is crucial for early brain development, while its excess accelerates metabolic activity and heart rate, and deficiency leads to reduced metabolic function and impaired growth.

• The thyroid gland regulates cellular metabolic rate and energy expenditure.
• Thyroid hormones are essential for normal growth and physical development. They play a critical role in brain maturation during infancy and early childhood.
• Deficiency leads to impaired growth and reduced metabolic activity.
• The gland also secretes calcitonin, which contributes to regulation of calcium homeostasis.

Functional Anatomy

General Aspects

Development

• The thyroid gland develops from the floor of the primitive pharynx during the third week of gestation. It descends to the neck through the thyroglossal duct; remnants may form a lingual thyroid.
• Hormone synthesis begins around the eleventh week of fetal life.

Location

• The gland is located in the anterior neck, in front of the trachea. It extends from the cricoid cartilage to the suprasternal notch. It has two lateral lobes connected by an isthmus.
• A pyramidal lobe may be present as a normal anatomical variation.
• The average weight in adults is about 15 to 20 grams.
• Parathyroid glands are situated on its posterior surface and regulate calcium metabolism.

Blood Supply

• The thyroid gland has a highly vascular supply, with blood flow exceeding that of many organs. It receives arterial blood from the superior and inferior thyroid arteries.
• Venous drainage occurs through thyroid veins into major cervical veins.

Innervation

• The gland is innervated by autonomic nerves.
• Sympathetic fibers arise from cervical ganglia, while parasympathetic fibers travel via the vagus nerve. This innervation regulates vascular tone and influences hormone delivery and glandular activity.

Histology

• The thyroid gland is composed of numerous spherical follicles forming its basic structural units.
• Each follicle is lined by a single layer of epithelial cells surrounding colloid, which contains thyroglobulin.
• The apical surface of follicular cells has microvilli and is rich in organelles for hormone synthesis.
• The basal surface is closely associated with a dense network of capillaries for efficient hormone exchange.
• Parafollicular cells are located near follicles and secrete calcitonin.
• Follicle size and colloid content vary with functional activity.
• In inactive states, follicles are large with abundant colloid.
• In active states, follicles are smaller with reduced colloid and increased cellular activity.

Synthesis, Secretion And Metabolism Of Thyroid Hormones

• The thyroid gland secretes thyroxine, triiodothyronine, and small amounts of reverse triiodothyronine.
• Calcitonin is produced by parafollicular cells.
• Thyroxine is released in larger quantities, but triiodothyronine is more biologically active.
• Thyroxine is converted to triiodothyronine in peripheral tissues, acting as a prohormone.
• Reverse triiodothyronine is inactive.
• Iodine is essential for hormone synthesis.
• Both deficiency and excess iodine can impair thyroid function.

Iodine Metabolism

• Iodine metabolism is essential for synthesis of thyroid hormones.
• Dietary iodine is converted to iodide and absorbed efficiently from the gastrointestinal tract.
• Approximately 150 micrograms per day is required for normal thyroid function.
• The normal plasma iodide concentration is about 0.3 micrograms per deciliter.
• The thyroid gland actively concentrates iodide for hormone synthesis.
• Around 120 micrograms of iodide is taken up daily by the gland.
• Iodine circulates bound to proteins such as albumin, while excess is excreted.
• The kidneys are the primary route for iodide elimination in urine.
• Thyroid hormones release iodine into circulation during metabolism.
• The liver plays a major role in degradation of hormones and recycling of iodine.
• Some iodine is excreted in bile and eliminated through feces.
• Adequate intake maintains hormonal balance, while deficiency impairs synthesis.
• Low iodine intake leads to increased thyroid stimulating hormone secretion. This results in gland enlargement, known as goiter, and reduced hormone production.
• Severe deficiency during early life can cause developmental disorders such as cretinism.
• Iodine deficiency remains a public health concern in many regions worldwide.

Thyroid Hormone Synthesis

Steps of Thyroid Hormone Synthesis

• Thyroid hormone synthesis occurs within follicular cells and involves sequential biochemical steps.
• The major steps include iodide trapping, oxidation, thyroglobulin formation, coupling, proteolysis, and hormone release.

Iodide Trapping

• Iodide trapping is the initial and essential step.
• Iodide is actively transported from blood into follicular cells by the sodium iodide symporter. This is a secondary active transport driven by the sodium gradient.
• The sodium potassium pump maintains this gradient using energy.
• The transporter concentrates iodide up to 20 to 40 times higher than plasma levels.
• Thyroid stimulating hormone increases synthesis and activity of this transporter.
• Iodide enters against both electrical and concentration gradients, requiring metabolic energy. It is then transported into the follicular lumen where hormone synthesis proceeds.
• High iodide concentration in the colloid is necessary for efficient hormone production.
• Certain other tissues can accumulate iodide, but they do not synthesize thyroid hormones.
• Proper iodide uptake is crucial for maintaining normal thyroid function.
• Impairment of this step can reduce hormone production and lead to clinical disorders.

Conversion of Iodide into Iodine

• Iodide oxidation occurs after iodide enters the follicular lumen. It is converted to iodine by thyroid peroxidase.
• This step, called organification, is essential for subsequent hormone synthesis.

Thyroglobulin Synthesis

• Thyroglobulin is a large glycoprotein synthesized in thyroid follicular cells. It is produced in the endoplasmic reticulum and processed in the Golgi apparatus.
• The protein is secreted into the colloid by exocytosis. It contains multiple tyrosine residues that serve as sites for hormone formation.
• Thyroid hormones are synthesized while attached to this molecule.

Binding of Iodine to Thyroglobulin

• Iodine binding occurs after iodide is oxidized to reactive iodine.
• Iodine binds to tyrosine residues on thyroglobulin with the help of thyroid peroxidase. This step forms iodinated intermediates essential for hormone production.

Coupling Reaction

• Iodination of tyrosine forms monoiodotyrosine and diiodotyrosine within thyroglobulin.
• Further iodination converts monoiodotyrosine to diiodotyrosine.
• The coupling reaction combines iodinated tyrosine residues to form thyroid hormones.
• Two diiodotyrosine molecules combine to produce thyroxine.
• Combination of monoiodotyrosine with diiodotyrosine forms triiodothyronine.
• The reaction is catalyzed by thyroid peroxidase.
• Coupling may occur within the same thyroglobulin molecule or between different molecules.
• Small amounts of reverse triiodothyronine are also formed.
• Diiodotyrosine is most abundant, followed by thyroxine, monoiodotyrosine, and triiodothyronine.

Secretion of Thyroid Hormones

• Thyroid hormone secretion begins with endocytosis of colloid by follicular cells.
• The internalized colloid fuses with lysosomes, where proteolytic enzymes act.
• Proteolysis of thyroglobulin releases iodinated compounds into the cytoplasm.
• Free thyroxine and triiodothyronine are generated along with monoiodotyrosine and diiodotyrosine.
• Monoiodotyrosine and diiodotyrosine are deiodinated by specific enzymes.
• The released iodine is efficiently recycled for new hormone synthesis.
• Only thyroxine and triiodothyronine are secreted into the bloodstream.
• Monoiodotyrosine and diiodotyrosine are not released into circulation. This recycling mechanism conserves iodine within the gland.
• Thyroid follicular cells perform three major functions.
  • They actively uptake iodide from blood for hormone synthesis.
  • They synthesize and secrete thyroglobulin into the colloid.
  • They process stored colloid to release active hormones into circulation.

Structure of T3 and T4

• Thyroxine contains four iodine atoms at specific positions on the thyronine ring.
• Triiodothyronine contains three iodine atoms.
• The number of iodine atoms determines their names as T4 and T3. These structural differences influence their biological activity and potency.

Metabolism of Thyroid Hormones

Normal Concentration

• Normal plasma concentration of thyroxine is about eight micrograms per deciliter.
• Plasma triiodothyronine is approximately 0.15 micrograms per deciliter.
• Most circulating hormones are protein bound. About 99.9 percent of thyroxine and 99.8 percent of triiodothyronine are bound.
• Only small free fractions are biologically active and regulate metabolic effects.

Protein Binding

• Thyroid hormones circulate bound to plasma proteins, which regulate their availability.
• The main binding proteins are thyroxine binding globulin, transthyretin, and albumin.
• Thyroxine binds predominantly to thyroxine binding globulin and transthyretin.
• Triiodothyronine binds mainly to albumin and thyroxine binding globulin.

TBG

• Thyroxine binding globulin is synthesized in the liver and has a high affinity for thyroid hormones.
• About 70 percent of thyroxine and 45 percent of triiodothyronine are bound to it. Its levels increase during pregnancy and with estrogen therapy.
• Levels decrease with glucocorticoids, androgens, and certain drugs.
• Some medications reduce hormone binding, altering circulating hormone distribution.

TBPA

• Transthyretin is a plasma protein that binds thyroid hormones with moderate affinity.
• It binds about 20 percent of thyroxine and less than 1 percent of triiodothyronine.

Albumin

• Albumin binds a large proportion of triiodothyronine and a smaller fraction of thyroxine.
• Approximately 55 percent of triiodothyronine and 10 percent of thyroxine are albumin bound.
• The concentration of binding proteins influences the free hormone fraction.
• Increased binding proteins reduce free hormone levels temporarily. This stimulates thyroid stimulating hormone secretion, restoring normal levels.
• Reduced binding proteins increase free hormone levels transiently.
• Feedback mechanisms then decrease hormone production. These adjustments maintain a stable euthyroid state despite variations in binding proteins.

Importance of protein binding:

• Protein binding creates a circulating reservoir of thyroid hormones.
• Bound hormones can replenish free hormone levels during temporary deficiency.
• Binding protects hormones from rapid metabolic degradation. This contributes to longer half lives, about one day for triiodothyronine and seven days for thyroxine.
• Only the free hormone fraction exerts biological effects.
• Free hormones regulate feedback control of hormone secretion.

Peripheral Conversion

• The thyroid gland mainly secretes thyroxine, which is converted in peripheral tissues.
• About 35 percent of thyroxine is converted to triiodothyronine by deiodinase enzymes in liver and kidney. This conversion accounts for most of the circulating active hormone.
• Triiodothyronine is the biologically active form that acts on target cells.
• A significant portion of thyroxine is also converted to reverse triiodothyronine, which is inactive.
• Deiodinase enzymes are abundant in brain and pituitary, increasing local hormone activity.
• Remaining hormone undergoes conjugation and is prepared for excretion.
• Dietary status influences peripheral conversion.

Effect of Diet

• Fasting reduces conversion of thyroxine to triiodothyronine. This leads to decreased active hormone levels and increased inactive reverse triiodothyronine.
• In prolonged starvation, reverse triiodothyronine normalizes, but active hormone remains low.
• Overnutrition produces the opposite effect, increasing active hormone and reducing inactive forms. These adjustments help conserve energy during nutrient deficiency and support metabolism during excess intake.

Effect of Drugs

Certain drugs inhibit deiodinase enzymes, reducing triiodothyronine formation and increasing reverse triiodothyronine levels.

Effects of Diseases

• In nonthyroidal illnesses such as trauma, infections, organ failure, and severe malnutrition, deiodinase activity decreases. This leads to reduced active hormone levels.
• Hormone levels usually normalize after recovery from the illness.

Peripheral Degradation

• Peripheral degradation of thyroid hormones occurs mainly through deiodinase enzymes.
• Three types are present: type one, type two, and type three deiodinases. These enzymes contain selenocysteine, which is essential for their catalytic activity.
• Selenium deficiency can impair hormone metabolism.
• Type one deiodinase is found in liver, kidney, thyroid, and pituitary.
• Type two deiodinase is present in brain, skeletal muscle, placenta, and brown adipose tissue.
• Type three deiodinase is mainly present in brain and reproductive tissues.
• Type one and type two enzymes convert thyroxine into triiodothyronine, maintaining active hormone levels.
• Type three enzyme converts thyroxine into inactive reverse triiodothyronine.
• In the brain, type two deiodinase ensures adequate hormone supply to neurons.
• Further degradation produces inactive metabolites.
• In the liver, hormones undergo conjugation with sulfate and glucuronic acid. These conjugates enter bile and may undergo enterohepatic circulation.
• Only a small fraction of iodine is lost in feces.
• Additional metabolites such as tetraiodoacetic acid are also formed.

Regulation of Secretion

• Thyroid hormone secretion is controlled by a negative feedback mechanism involving hypothalamus and pituitary.
• The hypothalamus releases thyrotropin releasing hormone, which stimulates pituitary thyrotrophs.
• The pituitary secretes thyroid stimulating hormone, which acts on the thyroid gland.
• The thyroid gland then releases triiodothyronine and thyroxine into circulation.
• Levels of free thyroid hormones regulate this axis through feedback control.
• Low hormone levels increase thyroid stimulating hormone secretion.
• High hormone levels suppress both hypothalamic and pituitary activity.
• Feedback inhibition occurs directly at the pituitary and indirectly via the hypothalamus.
• Therefore, thyroid stimulating hormone is a sensitive indicator of thyroid function.
• Dopamine, somatostatin, and glucocorticoids inhibit thyroid stimulating hormone release.

TSH

Structure and Secretion

• Thyroid-stimulating hormone is a glycoprotein composed of 211 amino acids and is secreted by anterior pituitary cells. It consists of two subunits, namely an alpha subunit and a beta subunit, which are non-covalently linked.
• The alpha subunit is structurally similar to those of luteinizing hormone, follicle-stimulating hormone, and human chorionic gonadotropin.
• The beta subunit provides biological specificity by enabling selective binding to thyroid cell receptors.
• The average secretion rate is approximately 110 micrograms per day, and the plasma concentration is around 2 micro units per milliliter.
• Secretion follows a pulsatile rhythm with a circadian pattern that increases in the evening, peaks around midnight, and declines during daytime.

Functions of TSH

• Thyroid-stimulating hormone regulates nearly all stages of thyroid hormone production and release.
• It enhances iodide trapping by increasing sodium-iodide symporter activity in thyroid follicular cells.
• It promotes oxidation and organification of iodide, leading to synthesis of triiodothyronine and thyroxine.
• It stimulates coupling reactions and facilitates thyroglobulin synthesis and storage within the colloid.
• It increases endocytosis of colloid and release of active thyroid hormones into circulation.
• It augments thyroid gland vascularity, thereby improving nutrient and iodide delivery.
• It induces follicular cell hypertrophy and hyperplasia, and prolonged elevation may result in goiter formation.

TSH Receptor and Other Receptors

• The thyroid-stimulating hormone receptor is a G protein-coupled receptor with seven transmembrane domains and a glycosylated extracellular region.
• It primarily activates adenylyl cyclase through stimulatory G protein, increasing cyclic adenosine monophosphate levels.
• It can also signal through the phospholipase C pathway, contributing to intracellular calcium mobilization.
• Thyroid cells also express receptors for growth factors and cytokines that modulate their activity.
• Insulin-like growth factor one and epidermal growth factor promote thyroid cell growth and functional activity.
• Tumor necrosis factor alpha and gamma interferon inhibit thyroid function and cellular proliferation.
• In chronic inflammatory states, these cytokines may suppress thyroid activity, contributing to reduced metabolic function.

Physiological Effects Of Thyroid Hormones

Mechanism of Action

• Thyroid hormones act mainly through intracellular receptors and produce genomic effects similar to steroid hormones.
• Receptors are widely distributed in most tissues, except for limited responsiveness in adult brain and gonads.
• Developing neurons are highly sensitive, indicating a crucial role in growth and maturation.
• Triiodothyronine and thyroxine enter target cells by carrier-mediated, energy-dependent transport.
• Within the cytoplasm, most thyroxine is converted to the more active triiodothyronine.
• Triiodothyronine binds to nuclear thyroid hormone receptors that interact with specific DNA response elements. This hormone-receptor complex regulates gene expression by increasing transcription of messenger ribonucleic acid.
• Enhanced transcription leads to increased synthesis of structural and enzymatic proteins. These proteins promote cellular growth, differentiation, and metabolic activity.
• Thyroid hormones increase mitochondrial biogenesis and the synthesis of respiratory enzymes. They also enhance sodium-potassium adenosine triphosphatase activity in cell membranes.
• Increased enzyme activity raises cellular oxygen consumption and heat production.
• Overall, these actions elevate basal metabolic rate and support normal tissue function.
• The effects are essential for development, energy metabolism, and maintenance of physiological homeostasis.

Thyroid-Hormone Receptors (TR)

• Thyroid hormone receptors are nuclear proteins encoded by two genes, alpha on chromosome 17 and beta on chromosome 3.
• Each gene produces multiple messenger ribonucleic acids, forming receptor isoforms such as TR alpha one, TR alpha two, TR beta one, and TR beta two.
• TR alpha one, TR beta one, and TR beta two bind triiodothyronine, whereas TR alpha two does not bind hormone.
• TR alpha one and TR beta one are widely distributed across tissues and regulate metabolic activity.
• TR beta two is mainly expressed in the brain and contributes to neuroendocrine regulation.
• The function of TR alpha two remains uncertain despite its wide distribution.
• Coactivators and corepressors modify receptor activity, producing tissue-specific responses to thyroid hormones.
• Triiodothyronine binds receptors with higher affinity, making it more biologically potent than thyroxine.
• In cardiac muscle cells, triiodothyronine enters directly and regulates gene expression without significant local conversion from thyroxine.

Physiological Actions

Thyroid hormones regulate basal energy metabolism, central nervous system development, and normal growth during childhood.

General Effects on Basal Metabolism

• Cellular metabolism depends on oxygen utilization for oxidative phosphorylation and adenosine triphosphate production in mitochondria.
• Thyroid hormones increase the basal rate of oxygen consumption, thereby enhancing overall metabolic activity. This rise in metabolism increases heat production, producing a calorigenic or thermogenic effect. They stimulate sodium–potassium adenosine triphosphatase activity, which increases cellular energy expenditure.
• Increased oxygen consumption closely parallels enhanced activity of this membrane enzyme.
• Triiodothyronine promotes gene expression for sodium–potassium pump subunits, further amplifying metabolic effects. These metabolic actions occur in most tissues, especially skeletal muscle, liver, heart, kidney, and connective tissue.
• Certain tissues such as the anterior pituitary, adult brain, gonads, uterus, lymph nodes, and spleen show minimal thermogenic response.
• In a resting adult, oxygen consumption is approximately 250 milliliters per minute.
• In hyperthyroidism, oxygen consumption may rise to about 400 milliliters per minute. This results in an increase in basal metabolic rate up to approximately 80 percent above normal.
• In hypothyroidism, basal metabolic rate may decrease to nearly 40 percent below normal.
• Alterations in metabolic rate directly influence body temperature and energy balance.
• Thyroid hormones also enhance mitochondrial activity by increasing synthesis of cytochromes and oxidative enzymes. They improve the efficiency and number of mitochondrial respiratory units. This leads to increased capacity for oxidative phosphorylation and energy generation.
• Additionally, thyroid hormones stimulate production of uncoupling proteins, especially uncoupling protein one. These proteins facilitate heat generation by uncoupling oxidation from adenosine triphosphate synthesis. Expression of uncoupling protein two and three is also increased, further contributing to metabolic regulation.

Effects Secondary to Metabolic or Thermogenic Actions

• Increased metabolic rate enhances nitrogen excretion, reflecting accelerated protein breakdown.
• Adequate nutritional intake is required to prevent loss of body protein and fat in hypermetabolic states.
• Excess thyroid activity leads to rapid weight loss when intake is insufficient.
• Heat production rises, causing an increase in body temperature.
• Peripheral vasodilation occurs, reducing vascular resistance and altering hemodynamics.
• Increased metabolism raises vitamin requirements, and deficiencies may develop if intake is inadequate.

Effects on Nervous System

• Thyroid hormones are essential for central nervous system development, particularly during late fetal life and early infancy.
• Brain maturation is most rapid during the last six months of gestation and the first six months after birth.
• These hormones promote differentiation and maturation of neurons and supporting cells.
• They support growth of the cerebral cortex, cerebellum, and basal ganglia.
• They stimulate axonal elongation and dendritic branching, improving neural connectivity.
• They enhance formation of synaptic connections and organization of neural circuits.
• Thyroid hormones regulate synthesis of enzymes required for neurotransmitter production.
• They increase the number and sensitivity of neurotransmitter receptors in brain tissue.
• They promote myelination by stimulating enzymes necessary for myelin formation.
• They enhance neuronal energy metabolism by increasing synthesis of mitochondrial enzymes.
• They also facilitate neuronal migration during early brain development.
• Functionally, they maintain alertness, responsiveness to stimuli, and normal reflex activity.
• They support memory, learning capacity, and intellectual performance.
• Deficiency during infancy leads to irreversible impairment of central nervous system development.
• Early detection and prompt treatment in newborns are therefore essential.
• In adults, cerebral blood flow and oxygen utilization remain relatively stable despite thyroid dysfunction.
• Thyroxine is converted to triiodothyronine in the brain by astrocytes.
• After removal of the thyroid gland, local enzyme activity increases to maintain hormone availability.

Effects on Growth and Development

• Thyroid hormones are essential for normal body growth and musculoskeletal maturation.
• They stimulate gene expression of growth hormone in anterior pituitary cells.
• They enhance the action of growth hormone on peripheral tissues.
• They promote linear bone growth and endochondral ossification at epiphyseal plates.
• They increase chondrocyte activity and support cartilage development.
• They stimulate bone remodeling by enhancing osteoblastic activity.
• They facilitate tooth eruption and proper dental development.
• They support growth of skin, hair, and nails.
• They increase synthesis of structural and enzymatic proteins.
• In hypothyroid children, growth is delayed and epiphyseal closure is prolonged.
• They reduce accumulation of glycosaminoglycans in subcutaneous tissue by increasing their degradation.

Cardiovascular Effects

• Thyroid hormones exert significant effects on the cardiovascular system by increasing heart rate, contractility, and cardiac output.
• They enhance the number and sensitivity of beta adrenergic receptors in sinoatrial and atrioventricular nodes. This leads to increased heart rate, and tachycardia is a common feature in excess hormone states.
• Myocardial contractility is increased through multiple cellular mechanisms.

• They stimulate expression of alpha myosin heavy chains, which possess high adenosine triphosphatase activity.
• They suppress beta myosin heavy chains, which have lower enzymatic activity.
• They increase beta receptor density, G protein activity, and sodium–potassium adenosine triphosphatase activity in cardiac cells.
• They enhance calcium handling by increasing sarcoplasmic reticulum calcium adenosine triphosphatase activity. These changes improve calcium reuptake and strengthen the force of contraction.
• Increased contractility raises stroke volume, contributing to elevated cardiac output.
• Systolic blood pressure rises due to increased cardiac output and forceful ventricular contraction.
• Thyroid hormones also produce thermogenic effects that increase body temperature. This causes peripheral vasodilation, which reduces systemic vascular resistance. As a result, diastolic blood pressure decreases.
• The combined effect leads to a widened pulse pressure, which is characteristic of hyperthyroid states.
• Circulation becomes hyperdynamic due to increased cardiac output and reduced vascular resistance. Circulation time is shortened, reflecting rapid blood flow through tissues.
• Overall, these effects improve tissue perfusion but may impose increased workload on the heart in prolonged excess states.

Effects on Intermediary Metabolism

• Thyroid hormones increase tissue oxygen consumption and enhance overall oxidation of metabolic substrates.
• They also increase absorption of nutrients from the gastrointestinal tract, ensuring adequate substrate supply.
• By regulating gene expression of metabolic enzymes, they amplify intermediary metabolism across tissues.

On Carbohydrate Metabolism

• In carbohydrate metabolism, they increase intestinal glucose absorption.
• They stimulate hepatic gluconeogenesis and glycogenolysis, increasing glucose release into circulation.
• They also enhance glucose uptake and utilization by peripheral tissues. Therefore, plasma glucose concentration usually remains near normal despite increased turnover.
• In hyperthyroidism, glucose rises rapidly after meals but declines quickly.
• Persistent hyperglycemia is uncommon, although prolonged excess may contribute to glucose intolerance.

On Fat Metabolism

• In fat metabolism, thyroid hormones stimulate lipolysis in adipose tissue. This increases release of free fatty acids and glycerol, which supports energy production and gluconeogenesis.
• They increase lipid turnover by enhancing fatty acid oxidation.
• They stimulate both synthesis and breakdown of cholesterol.
• Hepatic uptake of cholesterol increases due to upregulation of low-density lipoprotein receptors.
• The net effect is a reduction in plasma cholesterol and total lipid levels.

On Protein Metabolism

• In protein metabolism, thyroid hormones increase protein turnover.
• They promote proteolysis in skeletal muscle, releasing amino acids for metabolic use.

On Metabolic Actions of Other Hormones

• Thyroid hormones potentiate the actions of other hormones such as catecholamines, glucagon, cortisol, and growth hormone.
• These interactions enhance gluconeogenesis and lipid mobilization, further increasing metabolic activity.

Effects on Sympathetic Nervous Systems

• Thyroid hormones enhance metabolic rate, heat production, heart rate, and neuromuscular activity, mimicking sympathetic effects.
• They do not increase catecholamine secretion but increase beta receptor sensitivity in tissues such as heart, muscle, and adipose tissue. This potentiates actions like lipolysis, glycogenolysis, and gluconeogenesis.
• Triiodothyronine stimulates production of thermogenin in brown adipose tissue.
• Thermogenin contributes to thermogenesis by enhancing heat production in response to catecholamines.

Effects on Respiratory System

• Thyroid hormones increase tissue oxygen utilization, thereby raising overall oxygen demand.
• They stimulate respiratory rate, minute ventilation, and ventilatory responses to hypoxia and hypercapnia.
• Improved ventilation enhances arterial oxygen levels and tissue oxygen delivery.
• They also increase erythropoietin synthesis, promoting erythropoiesis and improving oxygen-carrying capacity.

Effects on GI Tract

• In the gastrointestinal system, thyroid hormones increase motility and secretion.
• Hyperthyroidism is associated with increased bowel frequency, whereas hypothyroidism causes constipation.
• They enhance appetite and facilitate intestinal absorption of nutrients, including glucose.

Effects on Skeletal Muscle

• In skeletal muscle, thyroid hormones regulate expression of myosin proteins.
• Hypothyroidism leads to muscle stiffness, cramps, and reduced strength.
• In hyperthyroidism, increased protein breakdown may cause muscle weakness.
• Chronic excess results in thyrotoxic myopathy, characterized by muscle wasting and fatigue.

Effects on Reproductive System

• In the reproductive system, thyroid hormones support normal endocrine function.
• In females, they regulate follicular development and ovulation.
• Thyroid imbalance may cause menstrual disturbances such as heavy bleeding or reduced menstrual flow.
• In males, they support spermatogenesis and maturation of Sertoli cells.

Effects on Kidney

• In the kidneys, thyroid hormones increase renal size and tubular cell activity.
• They enhance renal blood flow and glomerular filtration rate.
• Tubular reabsorption of electrolytes, glucose, and water is increased.
• Increased water reabsorption contributes to expansion of blood volume.
• Overall, thyroid hormones exert widespread effects on respiration, digestion, muscle function, reproduction, and renal physiology.

Table 57.1: Summary of physiologic effects of thyroid hormones.

System	Key Effects
Metabolism	↑ Basal metabolic rate, oxygen use (most tissues)
Cardiovascular	↑ heart rate, ↑ contractility, ↑ systolic pressure, ↓ diastolic pressure
Central nervous system	Brain development and maturation
Bone	Skeletal growth and maturation
Muscle	↑ myosin expression, ↑ protein breakdown
Adipose	↑ lipolysis
Gastrointestinal	↑ motility, ↑ appetite, ↑ absorption
Reproductive	Follicular maturation and ovulation

Applied Physiology

Hyperthyroidism

• Hyperthyroidism is a state of excessive thyroid hormone activity arising from thyroidal or extrathyroidal sources.
• It is classified into primary and secondary forms based on the site of pathology.

Primary Hyperthyroidism

• Primary hyperthyroidism results from intrinsic thyroid gland disorders.
• Common causes include toxic adenoma, multinodular goiter, Graves disease, activating receptor mutations, functioning carcinoma, and iodine excess.

Secondary Hyperthyroidism

Secondary hyperthyroidism occurs due to causes outside the thyroid gland.

Pituitary Causes

Pituitary tumors secreting excess thyroid-stimulating hormone are important causes.

Extrathyroidal Causes

Extrathyroidal sources include excessive hormone administration and ectopic or hormone-secreting tumors such as choriocarcinoma.

Features of Hyperthyroidism

• Clinical features reflect increased metabolic and sympathetic activity.
• Common symptoms include heat intolerance, sweating, irritability, fatigue, tremor, and palpitations.
• Increased appetite with weight loss and frequent bowel movements are characteristic.
• Reproductive effects include reduced libido and menstrual irregularities.
• Important signs include tachycardia, atrial fibrillation, and increased systolic blood pressure with wide pulse pressure.
• Patients may have warm, moist skin and fine tremors.
• Thyroid enlargement may be present depending on the cause.
• Eye signs such as exophthalmos and periorbital edema are characteristic of autoimmune disease.
• Proximal muscle weakness and, occasionally, gynecomastia may occur.
• Basal metabolic rate is markedly elevated and may reach up to 100 percent above normal, supporting diagnosis.

Diagnosis of Hyperthyroidism

• Diagnosis relies on measuring triiodothyronine, thyroxine, and thyroid-stimulating hormone in plasma.
• In primary hyperthyroidism, triiodothyronine and thyroxine are elevated, while thyroid-stimulating hormone is suppressed.
• In secondary hyperthyroidism, all three hormones are elevated due to pituitary overactivity.

Physiological Basis of Treatment

• Treatment of hyperthyroidism aims to reduce excessive hormone synthesis, release, or peripheral effects.
• Antithyroid drugs act by interfering with iodide handling and hormone formation in the thyroid gland.

Thionamides

• Thionamides such as propylthiouracil, carbimazole, and methimazole inhibit thyroid peroxidase activity.
• They block oxidation and organification of iodide and prevent coupling reactions required for hormone synthesis.
• They may reduce autoimmune stimulation of the thyroid gland.
• Propylthiouracil additionally inhibits peripheral conversion of thyroxine to triiodothyronine, lowering active hormone levels.

Anions

• Anions such as perchlorate and thiocyanate compete with iodide for transport through the sodium–iodide symporter.
• This reduces iodide uptake and limits substrate availability for hormone production.

High Dose of Iodide

• High doses of iodide transiently inhibit hormone synthesis by blocking organification, known as the Wolff–Chaikoff effect.
• They also reduce hormone release by inhibiting proteolysis of thyroglobulin and decreasing cyclic adenosine monophosphate activity.

Propranolol

• Beta blockers such as propranolol provide symptomatic relief.
• They reduce heart rate, cardiac output, tremors, and anxiety by blocking beta adrenergic receptors.
• They also mildly decrease peripheral conversion of thyroxine to triiodothyronine.

Radioiodine

• Radioiodine therapy destroys thyroid follicular cells and gradually reduces hormone production.
• Dose adjustment is essential to achieve normal thyroid function and avoid hypothyroidism.
• Overall, these treatments target hormone synthesis, release, and peripheral actions to restore physiological balance.

Special States of Hyperthyroidism

Thyrotoxicosis

• Thyrotoxicosis refers to the clinical state caused by excess circulating thyroid hormones. It is not always identical to hyperthyroidism.
• Hyperthyroidism specifically means increased synthesis and release of thyroid hormones by the thyroid gland.
• Thyrotoxicosis may occur with hyperthyroidism, such as in Graves’ disease, toxic multinodular goiter, and toxic adenoma. It may also occur without increased hormone production, as seen in thyroiditis or after excessive intake of thyroid hormone medication.

Graves’ Disease

• Graves’ disease is the most common cause of hyperthyroidism and usually presents with diffuse enlargement of the thyroid gland. It is an autoimmune disorder in which antibodies stimulate thyroid-stimulating hormone receptors.
• Continuous receptor stimulation causes thyroid enlargement and overproduction of triiodothyronine and thyroxine.
• Blood levels of thyroid hormones become elevated, while pituitary thyroid-stimulating hormone becomes suppressed through negative feedback.
• Common features include weight loss, heat intolerance, tremor, palpitations, anxiety, and increased appetite.
• Exophthalmos may occur due to inflammation, swelling of extraocular muscles, and expansion of orbital connective tissue, pushing the eyeballs forward.
• Treatment includes antithyroid drugs such as carbimazole or methimazole, radioactive iodine therapy, or surgical thyroid removal when indicated.

Thyroid Storm

• Thyroid storm is a rare but life-threatening extreme form of thyrotoxicosis. It may be triggered by surgery, trauma, severe infection, uncontrolled hyperthyroidism, or acute illness.
• Clinical features include high fever, marked tachycardia, agitation, delirium, vomiting, diarrhea, dehydration, and possible heart failure or shock. It is a medical emergency requiring intensive care management.
• Treatment includes rapid fluid replacement, cooling measures, beta-blockers, corticosteroids, and antithyroid medications.
• Early diagnosis and prompt treatment significantly reduce mortality.

Hypothyroidism

Hypothyroidism in Adult

Hypothyroidism in adults is commonly referred to as myxedema, a state of reduced thyroid hormone activity.

Etiology

• It causes slowing of metabolic processes and affects multiple organ systems.
• Based on the site of dysfunction, hypothyroidism is classified as primary or secondary.

Primary Hypothyroidism

• Primary hypothyroidism occurs when the thyroid gland itself is unable to produce sufficient hormones.
• Autoimmune thyroiditis, especially Hashimoto thyroiditis, is a common cause.
• Iodine deficiency remains an important cause in some regions.
• Medical causes include thyroid surgery, radioactive iodine therapy, or damage after treatment.
• Certain drugs may reduce thyroid function, such as lithium, excess iodine, and prolonged use of antithyroid medicines.
• Some individuals are born with congenital thyroid defects that later persist into adult life if untreated.

Secondary Hypothyroidism

• Secondary hypothyroidism results from disorders outside the thyroid gland. It commonly develops due to pituitary disease causing reduced secretion of thyroid-stimulating hormone.
• Causes include pituitary tumors, pituitary surgery, infarction, or postpartum pituitary necrosis.
• It may also arise from hypothalamic disorders that reduce thyrotropin-releasing hormone secretion.
• Brain injury, tumors, or infiltrative diseases may damage the hypothalamus.

Features of Hypothyroidism

Symptoms

• Hypothyroidism causes generalized slowing of metabolism and reduced tissue activity.
• Common symptoms include cold intolerance, fatigue, weakness, and reduced exercise tolerance.
• Patients may develop dry, coarse skin and thinning or loss of hair.
• Memory impairment, poor concentration, and slowed thinking are frequent complaints.
• Constipation occurs due to decreased gastrointestinal motility.
• Weight gain may occur despite poor appetite.
• The voice often becomes hoarse, deep, and husky.
• Yellowish skin discoloration may occur because carotene conversion to vitamin A is reduced.
• Women may develop menstrual irregularities, menorrhagia, infertility, or galactorrhea.
• Severe untreated disease may rarely cause psychosis.

Signs

• Signs include bradycardia, cool extremities, puffy face, and non-pitting edema of hands and feet (myxedema).
• Periorbital edema and diffuse goiter may be present.
• Tendon reflex relaxation is delayed, especially at the Achilles tendon.
• Serum cholesterol is often elevated, and basal metabolic rate is reduced.

Diagnosis of Hypothyroidism

• Primary hypothyroidism shows low triiodothyronine and thyroxine with elevated thyroid-stimulating hormone due to feedback stimulation.
• Pituitary or hypothalamic hypothyroidism shows low thyroid hormones with low or inappropriately normal thyroid-stimulating hormone.
• Thyrotropin-releasing hormone testing may help localize central causes when required.

Treatment of Hypothyroidism

• Thyroid hormone replacement is the standard treatment for hypothyroidism.
• Levothyroxine is preferred and adjusted individually, usually about 1.6 micrograms/kg/day in healthy adults, guided by thyroid-stimulating hormone levels.

Hashimoto’s Thyroiditis

• Hashimoto thyroiditis is a chronic autoimmune inflammation of the thyroid gland.
• Antibodies against thyroglobulin and thyroid peroxidase gradually destroy thyroid tissue, causing hypothyroidism.
• Fine-needle aspiration may show Hürthle cells with prominent lymphocytic infiltration.

Hypothyroidism in Children (Cretinism)

Congenital hypothyroidism is thyroid hormone deficiency present at or before birth. The older term “cretinism” is now avoided in clinical practice.

Causes

Common causes include maternal iodine deficiency, thyroid gland agenesis or maldevelopment, inherited defects of hormone synthesis, maternal blocking antibodies, and fetal pituitary insufficiency.

Features

• Thyroid hormones are essential for brain development, skeletal growth, and normal metabolism during infancy.
• Untreated infants may develop prolonged jaundice, poor feeding, lethargy, constipation, large tongue, umbilical hernia, and delayed milestones.
• Severe untreated disease can cause short stature and permanent intellectual disability.
• A protuberant abdomen and coarse facial features may appear later.

Treatment

• Newborn screening with thyroid-stimulating hormone and thyroxine is crucial for early detection.
• Prompt treatment with levothyroxine started within the first weeks of life greatly improves growth and neurodevelopment outcomes.

Thyroid Function Tests

• Thyroid function tests assess hormone production, pituitary response, thyroid structure, and autoimmune disease.
• Core blood tests include serum thyroid-stimulating hormone, free thyroxine, and sometimes free triiodothyronine.
• Measurement of thyroid-binding proteins may help in selected cases affecting total hormone levels.
• Thyrotropin-releasing hormone stimulation testing is now rarely required.
• Nuclear medicine tests include radioactive iodine uptake and thyroid scan to evaluate gland activity and nodules.
• Older suppression or stimulation tests are seldom used today.
• Non-isotopic investigations include thyroid autoantibody testing.
• Imaging methods include ultrasonography, computed tomography, and magnetic resonance imaging.
• Fine-needle aspiration cytology helps evaluate suspicious thyroid nodules.

Measurement of Thyroid Hormones

• Thyroid hormones are measured in blood using immunoassays such as radioimmunoassay or enzyme-linked methods.
• Primary hyperthyroidism shows raised thyroxine or triiodothyronine with suppressed thyroid-stimulating hormone.
• Primary hypothyroidism shows low hormone levels with elevated thyroid-stimulating hormone.
• Pituitary hypothyroidism shows low hormones with low thyroid-stimulating hormone.

Table 57.2: Thyroid function tests in primary thyroid dysfunctions.

Test Parameter	Primary Hyperthyroidism	Primary Hypothyroidism
Thyroid-binding proteins	Normal	Normal
Total T3/T4	High	Low
Free T3/T4	High	Low
Thyroid-stimulating hormone	Low	High

Plasma TSH Estimation

• Measurement of thyroid-stimulating hormone is one of the most sensitive tests for thyroid dysfunction. It reflects pituitary response to circulating thyroid hormone levels.
• In primary hypothyroidism, thyroid hormone production is reduced, so thyroid-stimulating hormone rises due to loss of negative feedback.
• In secondary hypothyroidism caused by pituitary disease, thyroid-stimulating hormone is low or inappropriately normal, with low thyroxine.
• In primary hyperthyroidism, thyroid-stimulating hormone is suppressed.
• In rare pituitary-mediated hyperthyroidism, thyroid-stimulating hormone, thyroxine, and triiodothyronine may all be elevated.

Measurement of Binding Proteins

• Most thyroid hormones circulate bound to proteins, mainly thyroxine-binding globulin.
• Older tests estimated protein binding indirectly by the triiodothyronine resin uptake method.
• In this test, labeled triiodothyronine is added to serum and binds available protein-binding sites.
• Resin then binds the unbound labeled hormone.
• Greater resin uptake suggests fewer free protein-binding sites, often seen when endogenous hormone levels are high.
• Lower resin uptake suggests more unoccupied binding sites, often associated with hypothyroidism or increased binding proteins.
• This test is now largely replaced by direct free hormone assays

TRH Response Test

• The thyrotropin-releasing hormone test evaluates pituitary secretion of thyroid-stimulating hormone after administered releasing hormone.
• In healthy individuals, thyroid-stimulating hormone rises after stimulation.
• In primary hypothyroidism, the response may be exaggerated because baseline thyroid hormone feedback is reduced.
• In hyperthyroidism, the response is blunted or absent because high thyroid hormone levels suppress pituitary thyrotrophs.
• In pituitary failure, little or no thyroid-stimulating hormone rise occurs.
• In hypothalamic disease, a delayed or prolonged response may occur.
• This test is now rarely required because modern hormone assays and imaging provide faster diagnosis.

Detection of Thyroid Antibodies

• Testing for thyroid antibodies helps diagnose autoimmune thyroid disorders.
• In Graves disease, antibodies stimulate thyroid-stimulating hormone receptors and increase hormone production. These antibodies are commonly called thyroid-stimulating immunoglobulins.
• Hormone secretion becomes partly independent of normal pituitary feedback regulation.
• In Hashimoto thyroiditis, antibodies against thyroid peroxidase and thyroglobulin are frequently detected.
• Positive antibody tests support diagnosis but should be interpreted with clinical findings and hormone levels.

Plasma Cholesterol Estimation

• Thyroid hormones influence lipid metabolism and cholesterol clearance.
• Hypothyroidism commonly causes elevated total cholesterol and low-density lipoprotein cholesterol.
• Hyperthyroidism may lower cholesterol levels.
• Cholesterol testing is not diagnostic because many conditions alter lipid values.
• It is useful for monitoring treatment response, especially in hypothyroidism.
• Untreated hypothyroidism increases risk of atherosclerosis and coronary artery disease.

Estimation of BMR

• Basal metabolic rate reflects resting energy expenditure.
• It is usually increased in hyperthyroidism because metabolism is accelerated.
• It is reduced in hypothyroidism because cellular activity declines.
• Direct basal metabolic rate testing is rarely used now because hormone assays are more accurate and practical.
• Historical changes in basal metabolic rate strongly correlated with thyroid status.

Thyroid Scintiscanning

• Thyroid scintiscanning provides an image of thyroid size, shape, and functional activity using radioactive tracers. It helps assess gland morphology and detect nodules.
• Nodules may appear hot when functioning autonomously or cold when uptake is reduced.
• Cold nodules require further evaluation because some may be malignant.
• Scanning can identify ectopic thyroid tissue, including lingual or mediastinal thyroid tissue. It is useful in evaluating retrosternal goiter and some neck masses.
• Selected scans may detect functioning metastases from differentiated thyroid carcinoma.
• Technetium pertechnetate and radioiodine are commonly used tracers in modern practice.

Fine-Needle Aspiration Cytology

• Fine-needle aspiration cytology is an important preoperative test for thyroid nodules. It helps distinguish benign lesions from malignancy with high diagnostic accuracy.
• False-negative results are more common than false-positive results, so suspicious nodules may need repeat evaluation.

Ultrasound/CT/MRI

• Ultrasonography accurately measures thyroid size and differentiates cystic from solid nodules. It also detects small nodules and guides needle aspiration procedures.
• Computed tomography and magnetic resonance imaging are useful for retrosternal extension, airway compression, and spread to nearby structures.
• Magnetic resonance imaging better defines soft tissue and nerve involvement.

Achilles Tendon Reflex

Delayed relaxation of the Achilles tendon reflex is a classical bedside sign suggesting hypothyroidism.