THYROID The thyroid gland

below the larynx on each side of and anterior to the trachea15-20 gms in adultssecretes two major hormones:

thyroxine (T4)triiodothyronine (T3)

Also secretes calcitonin (an important hormone for calcium metabolism)

Microscopic Appearance of the Thyroid Gland

Figure 76-1; Guyton & Hall

Thyroid Hormones ↑↑↑BMR Its ↓↓↓ → 40-50% BMR ↓↓ Its ↑↑↑ → 60-100% ↑↑ BMR

secretion is controlled by thyroid-stimulating hormone (TSH) from the anterior pituitary gland.

Synthesis and Secretion of the Thyroid Metabolic Hormones

• 93% T4 & 7% T3

• T4→T3 in tissues• Qualitatively same

• Differ in Rapidity & Intensity of action.

• T3 is 4 times ↑potent than T4, but ↓↓↓conc. In blood & ↓↓↓half life.

Physiologic Anatomy of the Thyroid Gland.

• Composed of large numbers of closed follicles (100-300 micrometers in diameter) filled with colloid (major component Thyroglobulin) and lined with cuboidal epithelial cells that secrete into the interior of the follicles.

• The large glycoprotein Thyroglobulin contains the thyroid hormones within its molecule.

• Secretion enters the follical→absorbed (through epithelium)back into the blood to function.

• Blood flow/min = 5 times its wt.

Iodine Requirement• 50mg/year, 1mg/week

• Common table salt is iodized with 1 part sodium iodide to every 100,000 parts NaCl.

• Iodides (absorbed from GIT)→⅕ removed from the blood by thyroid cells for synthesis of hormones; rest excreted through kidneys.

• Basal membrane of thyroid cells has an active pump to push iodides to interior (Iodine Pump).– Normally 30% more conc. Inside– Max. active 250% more conc. Inside

• The rate of Iodine trapping is influenced by conc. of TSH.

• TSH stimulates and hypophysectomy greatly diminishes the activity of the iodide pump in thyroid cells.

Thyroid cellular mechanisms for iodine transport, thyroxine and triiodothyronine formation, and

thyroxine and triiodothyronine release into the blood.

MIT, monoiodotyrosine; DIT, diiodotyrosine; T3, triiodothyronine;T4, thyroxine; TG, thyroglobulin.

Thyroglobulin and Chemistry of T4 and T3 Formation

Thyroglobulin– formed by ER– secreted by Golgi– mol. wt. 660000– Each mol. has 123-140 tyrosine aminoacids (Tyrosine +

Iodide = Thyroid hormone)

Conversion of Iodides to oxidized form of Iodine– Oxidation is by Peroxidase (enzyme) & H₂O₂– Peroxidase is in apical membrane of the cell or attached to

it.– Thyroglobulin mol. comes out of Golgi & cell membrane at

the same place.– If Peroxidase is not present→Thyroid hormone formation

falls to zero.

Thyroid cellular mechanisms for iodine transport, thyroxine and triiodothyronine formation, and

thyroxine and triiodothyronine release into the blood.

MIT, monoiodotyrosine; DIT, diiodotyrosine; T3, triiodothyronine;T4, thyroxine; TG, thyroglobulin.

Iodinationof Tyrosine & Formation of Thyroid hormones– Binding of oxidized Iodine with Thyroglobulin =

Organification– Enzyme Iodinase speeds up the reaction

– Iodine binds with ⅙ of Tyrosine aminoacids within Thyroglobulin mol.

– Tyrosine→Monoidotyrosine then Diidotyrosine

– Thyroxine=major product, Triidothyroxine=⅕ of that.

Chemistry of thyroxine and triiodothyronine formation.

Storage of Thyroglobulin– Large amount– Thyroglobulin mol. has 30 thyroxine and a few T3.– Storage sufficient for 2-3 months.

Release of Thyroxine and Triiodothyronine in the blood

• Cleavage required for the release.• Pseudopod extensions from the apical surface of the thyroid cells

that close around small portions of the colloid → pinocytic vesicles formed→ enter the apex of thyroid cell digestive vesicles release T4 & T3 in free form→ diffuse through the base of the thyroid cell into the blood.

• ¾ of iodinated tyroxinase never forms hormone, remains as mono or di ido-MIT, DIT released from Thyroglobulin Tyrosine + I⁻.

• 75% MIT, DIT is recycled.• ↓↓↓ of enzyme deiodinase can cause defficiency of hormones due

to lack recycling.• Hormone used by tissues is Triidothyroxine 35 µgm/day.• 99% of T3 & T4 combines with plasma proteins on entering blood.

– Thyroxine binding globulin– Thyroxine binding prealbumins– Thyroxine binding albumin

lysosomesproteases

deiodinase

Transport of Thyroxine andTriiodothyronine to Tissues

• ½ of T4 bound to proteins is released to tissues every 6 days.

• ½ of T3 bound to proteins is released to tissues daily.

• In the target cells, they bind with intracellular protein to be released slowly.

• T4 has more stray binding.

Thyroid Hormones Have Slow Onset and Long Duration of Action

T4• No effect for 2-3 days after injection• Long Latent Period.• Activity peaks in 10-12 days & ↓↓ with a half

life of 15 days.• In some cases it takes 6 weeks-2 months.T3• 4 times rapid• Latent Period 6-12 hours• Peak in 2-3 days

Physiologic Functions of the Thyroid Hormones

Thyroid Hormones Increase the Transcription of Large Numbers of Genes

• Activates Nuclear Transcription→ ↑↑Protein synthesis → Generalised ↑↑ in function.

• More than 90% of Thyroid hormone that binds with cellular receptors is T3. Thyroid Hormone Receptor usually forms a heterodimer with

Retinoid X receptor(RXR) at specific thyroid hormone response element on DNA.

• Receptor+Hormone →Messenger RNA→Translation

Thyroid Hormones Increase Cellular Metabolic Activity

• ↑↑↑ T3 & T4 →BMR ↑ 60-100%.• Utilization of food products ↑↑↑.• Protein formation ↑↑& protein catabolism↑↑ as well.• Growth rate in young ↑↑.• Endocrine gland activity in other ↑↑.• Mental process excited.• Increase in the no. & activity of Mitochondria.• Mitochondria ↑ in size & no.• Total membrane surface area of Mitochondria α ↑ BMR.• Activity of Na⁺-K⁺ ATPase ↑ in response to Thyroid

hormones→↑↑Transport of ions through cell membranes → Energy consumed, heat produced.

Effect of Thyroid Hormone on Growth

• In young growing children, its ↓↓causes great retardation

• ↑↑ causes →↑↑skeletal growth at an early age but fusion also. So, the end height may be shortened.

• Development of brain in fetal life & early childhood.

• ↓↓ release by Fetus → brain remains smaller than normal & retarded.

Effects of Thyroid Hormone on Specific Bodily Mechanisms

o Stimulation of all aspects of Carbohydrate Metabolism

↑Uptake of glucose by cells Enhanced glycolysis Enhanced glyconeogenesis ↑Rate of absorption from GIT ↑Insulin secretion

o Stimulation of Fat Metabolism– Influence of Thyroid hormone→Lipid mobilization from

fat tissues →↓↓in fat stores→ ↑↑free Fatty acids in plasma & ↑↑their oxidation.

↑↑Thyroid hormone →↓↓Plasma conc. of cholesterol, phospholipids & triglycerides + ↑↑↑free Fatty acids.

↓↓Thyriod hormone →↑↑Plasma conc. of cholesterol, phospholipids & triglycerides + excessive deposition of fats in liver.

Metabolic Effects of Thyroid Hormones

Parameter ↓ T3, T4 ↑ T3, T4

Basal metabolic rate ↓ ↑

Carbohydrate metabolism ↓ Gluconeogenesis ↑ Gluconeogenesis ↓ Glycogenolysis ↑ Glycogenolysis Normal serum [glucose] Normal serum [glucose] Protein metabolism ↓ Synthesis ↑ Synthesis ↓ Proteolysis ↑ Proteolysis Muscle wasting

Lipid metabolism ↓ Lipogenesis ↑ Lipogenesis ↓ Lipolysis ↑ Lipolysis ↑ Serum [cholesterol] ↓ Serum [cholesterol]

Thermogenesis ↓ ↑

Table 48-1, Boron & Boulpaep

– The large ↑ in circulating plasma cholesterol in prolonged hypothyroidism is often associated with severe atherosclerosis.

– Mechanisms by which thyroid hormone ↓plasma cholesterol conc. is to ↑rate of cholesterol secretion in the bile & loss in the feces.

– A possible mechanism for ↑ cholesterol secretion is that thyroid hormone induces ↑ no. of LDL receptors on the liver cells→Rapid removal of LDL from the plasma by the liver & secretion of cholesterol in these LDLs by the liver cells.

o Increased Requirement for Vitamins

Thyroid hormone ↑ quantities of hormones i.e ↑in Formation of enzymes & coenzymes→↑need for vit.

A relative vitamin deficiency can occur when excess thyroid hormone is secreted, unless at the same time increased quantities of vitamins are made available.

o Increased Basal Metabolic Rate– Excessive quantities of Thyroid hormone

occasionally ↑ BMR 60-100% above normal. – When no Thyroid hormone is produced, BMR falls

almost to one-half normal.– Extreme amounts of the hormones are required

to cause very high BMR.

o Increased Respiration– ↑Rate of metabolism→ ↑Utilization of O₂→↑CO₂

production →↑Respirationo Decreased Body Weight

– ↑ Thyroid hormone almost always ↓ body weight.– Greatly ↓ Thyroid hormone almost always ↑ body

weight.• These effects do not always occur, because thyroid

hormone also ↑ appetite which may counterbalance the change in the metabolic rate.

o Increased Gastrointestinal Motility

– ↑Appetite→↑Rate of gastric secretions + ↑Motility of GIT.

– Hyperthyroidism often results in diarrhea. – Lack of thyroid hormone can cause constipation.

o Effect of Thyroid Hormones on CVS Increased metabolism in tissues → Rapid utilization of O₂

& metabolites → need for heat elimination + Vasodilation →↑blood flow→↑Cardiac Output(sometimes ↑ 60 % or more when excessive thyroid hormone is present & ↓50% in very severe hypothyroidism).

Direct effect on the excitability of the heart → ↑ heart rate.

Moderate ↑in Thyroid hormone →↑ Heart strength

Large ↑ in Thyroid hormone→↓ strength of heart muscle (due to long term excessive protein catabolism).

Some severely thyrotoxic patients die of cardiac decompensation secondary to myocardial failure and to increased cardiac load imposed by the increase in cardiac output.

The mean arterial pressure remains normal after administration of thyroid hormone. (↑blood flow through the tissues between heartbeats→↑pulse pressure; e.g in hyperthyroidism 10-15 mm Hg ↑ systolic pressure & corresponding↓ diastolic pressure.)

o Excitatory Effects on the Central Nervous System– Thyroid hormone ↑ rapidity of cerebration but also

often dissociates this. – Lack of thyroid hormone decreases this function.– Hyperthyroidism → extreme nervousness &

psychoneurotic tendencies e.g anxiety complexes, extreme worry & paranoia.

o Effect on the Function of the Muscles

– Slight ↑in thyroid hormone→ muscles react with vigor.– Excessive quantity of Thyroid hormone→ muscles become weakened

(due to excess protein catabolism).– Lack of thyroid hormone→ muscles become sluggish & relax slowly

after a contraction.– Hyperthyroidism→ ↑ reactivity of the neuronal synapses in the areas

of the spinal cord that control muscle tone → Fine muscle tremor (occurs 10- 15 times/sec).

This tremor is an important means for assessing the degree of thyroid hormone effect on the central nervous system.

o Effect on Sleep– In hyperthyroidism

• the exhausting effect of thyroid hormone on the musculature and on the central nervous system →a feeling of constant tiredness.

• excitable effects on synapses do not let person sleep.

– Hypothyroidism →Extreme somnolence with sleep sometimes lasting 12-14 hrs/day.

o Effect on Other Endocrine Glands– ↑Glucose metabolism→↑Insulin by the pancreas– ↑Bone formation→↑Parathyroid– ↑Rate at which adrenal glucocorticoids are

inactivated by the liver→ feedback ↑ in adrenocorticotropic hormone production by the anterior pituitary→ increased rate of glucocorticoid secretion by the adrenal glands.

o Effect of Thyroid Hormone on Sexual Function– In men

• Lack of Thyroid hormone→Loss of libido• Great excess of Thyroid hormone→Impotence

– In women• lack of thyroid hormone→ Loss of libido• Hypothyroidism often causes menorrhagia and polymenorrhea

but strangely enough, in some women it may cause irregular periods and occasionally even amenorrhea.

• hyperthyroidism→ oligomenorrhea and occasionally amenorrhea

• The action of thyroid hormone on the gonads cannot be pinpointed to a specific function but probably results from a combination of direct metabolic effects on the gonads as well as excitatory and inhibitory feedback effects operating through the anterior pituitary hormones that control the sexual functions.

Regulation of Thyroid Hormone Secretion

Specific feedback mechanisms operate through the hypothalamus and anterior pituitary gland → control the rate of thyroid secretion→ maintain normal levels of metabolic activity in the body.

TSH (from the Anterior Pituitary Gland) Increases Thyroid Secretion.

Thiocyanate, Propylthiouracil, and high concentrations of inorganic Iodides are Antithyroid Substances.

Hypothalamohypophyseal-Thyroid Axis

HypothalamusHypothalamus

ThyrotropeThyrotrope

ThyroidThyroid

TT33, T, T44

TRH TRH

TSHTSH

__

__

+

+

TSH (thyrotropin)– is an anterior pituitary hormone– a glycoprotein (mol. wt. 28,000)– increases all the known secretory activities of the

thyroid glandular cells.

Specific effects of TSH on the thyroid gland are• ↑Proteolysis of Thyroglobulin to release

stored T3 &T4. (most imp. early effect).• ↑Activity of Iodine Pump→↑Iodide trapping.

(Intracellular:Extracellular Ratio ↑8 times)• ↑Iodination of Tyrosine to form Thyroid

hormone• ↑size & ↑secretory activity of Thyroid cells• ↑no. of Thyroid cells.

Mechanism of ActionActivation of the “second

messenger” cyclic adenosine monophosphate (cAMP) system of the cell

• Binding of hormone with specific TSH receptors to basal membrane of Follicular cell → Activation of Adenylyl cyclase in membrane → Formation of cAMP in the cell → Activation of Protein Kinase → Multiple phosphorylation →immediate ↑ in secretion of thyroid hormones + prolonged growth of the thyroid glandular tissue itself.

Regulation of TSH• Anterior pituitary secretion of TSH is controlled by a

hypothalamic hormone, thyrotropin-releasing hormone (TRH), which is secreted by nerve endings in the median eminence of the hypothalamus.

• TRH is – is a tripeptide amide—pyroglutamyl-histidylproline-

amide– is transported to the anterior pituitary by way of the

hypothalamichypophysial portal blood.– directly affects the anterior pituitary gland cells to

increase their output of TSH.

• Blockage of blood portal system ↓↓↓↓TSH from ant. pit. The molecular mechanism by which TRH causes the TSH-secreting cells of

the anterior pituitary to produce TSH is– first to bind with TRH receptors in the pituitary cell membrane.– This in turn activates the phospholipase second messenger system

inside the pituitary cells to produce large amounts of phospholipase C,– followed by a cascade of other second messengers, including calcium

ions and diacyl glycerol,– which eventually leads to TSH release

• Effects of Cold and Other Neurogenic Stimuli on TRH and TSH Secretion

Feedback Effect of Thyroid Hormoneto Decrease Anterior Pituitary

Secretion of TSH• ↑Thyroid → ↓ of TSH by ant. Pit.• At 1.75 times normal the TSH ↓↓

to zero.• Even when ant. Pit. Is seperated

from Hypothalamus; direct effect on ant. Pit.

Regulation of thyroid secretion.

Antithyroid Substances

• Thiocyanate Ions Decrease Iodide Trapping• Propylthiouracil Decreases Thyroid Hormone

Formation.• Iodides in High Concentrations Decrease Thyroid

Activity and Thyroid Gland Size.

Diseases of the ThyroidHyperthyroidism• Causes of Hyperthyroidism:

o Toxic Goiter, Thyrotoxicosis, Graves’ Disease– Autoimmunity against Thyroid tissue– Thyroid Stimulating Immunoglobulino Thyroid Adenoma

• Symptoms:– (1) a high state of excitability– (2) intolerance to heat– (3) increased sweating– (4) mild to extreme weight loss (sometimes as much as 100 pounds)– (5) varying degrees of diarrhea– (6) muscle weakness– (7) nervousness or other psychic disorders– (8) extreme fatigue but inability to sleep– (9) tremor of the hands. Exophthalmos

• Physiology of Treatment in Hyperthyroidism (Surgery)• Treatment of the Hyperplastic Thyroid Gland with Radioactive Iodine

Hypothyroidism• Causes:

– Autoimmunity destroys the gland (Autoimmune Thyroiditis in most cases) → Progressive deterioration & fibrosis of gland → No secretion.

– Endemic Colloid Goiter caused by Dietary Iodide Deficiency– Idiopathic Nontoxic Colloid Goiter

• Physiologic Characteristics of Hypothyroidism:– fatigue – extreme somnolence with sleeping up to 12 to 14 hours a day– extreme muscular sluggishness – slowed heart rate– decreased cardiac output– decreased blood volume– sometimes increased body weight– constipation– mental sluggishness– failure of many trophic functions in the body evidenced by depressed growth of hair and

scaliness of the skin– development of a froglike husky voice– in severe cases, development of an edematous appearance throughout the body called

myxedema.– Atherosclerosis in Hypothyroidism.– Cretinism (caused by extreme hypothyroidism during fetal life, infancy, or childhood

Myxedema– Total lack of Thyroid functions– Bagginess under the eyes and swelling of the face– Non pitting edema due to gel nature of excess

fluid(greatly increased quantities of hyaluronic acid + chondroitin sulfate bound with protein form excessive tissue gel in the interstitial spaces→↑ total quantity of interstitial fluid)

Atherosclerosis in Hypothyroidism– Lack of thyroid hormone →altered fat and cholesterol

metabolism + diminished liver excretion of cholesterol in the bile→↑ blood cholesterol (associated with increased atherosclerosis) →peripheral vascular disease, deafness, & coronary artery disease with consequent early death.

Pathophysiology of Thyroid Hormones

• Pathophysiology of Thyroid Hormones:

• Graves’ disease – autoimmune disorder; immune complex mimics TSH – stimulates continual production of thyroid hormone – leads to hyperthyroidism and goiter formation.

• Cretinism – deficiency of thyroid hormones in childhood – results in severe growth retardation and mental retardation.

Cretinism– Congenital Cretinism– Endemic Cretinism– Caused by extreme hypothyroidism during fetal life, infancy, or

childhood.– Characterized by failure of body growth & by mental retardation.

Hypothalamohypophyseal-Thyroid Axis in GraveHhs’ Disease

HypothalamusHypothalamus

ThyrotropeThyrotrope

ThyroidThyroid

TT33, T, T44

TRHTRH

TSHTSH

__

+

__

+

TSI

+

– Unless the cretinism is treated within a few weeks after birth, mental growth remains permanently retarded due to retardation of the growth, branching, andmyelination of the neuronal cells of the central nervous system at this critical time in the normal development of the mental powers.

– Skeletal growth in the child with Cretinism is characteristically more inhibited than is soft tissue growth→ disproportionate rate of growth (the soft tissues are likely to enlarge excessively, giving the child with cretinism an obese, stocky, and short appearance).

– Occasionally the tongue becomes very large in relation to the skeletal growth → obstructs swallowing and breathing→ guttural breathing that sometimes chokes the child.

• Treatment of Hypothyroidism– daily oral ingestion of a tablet or more containing

Thyroxine.– Proper treatment of the hypothyroid patient →complete

normality (formerly myxedematous patients have lived into their 90s after treatment for more than 50 years).

Overview of ECF Ca⁺⁺

• ECF Ca⁺⁺= q.n mg / dL• Precise control muscle contraction, blood

clotting, nerve impulses• ↑↑ Ca⁺⁺ depression of CNS while ↓ CNS

more excited • 0.1 % is in ECF , 1% in cells and 99% in bones

Overview of PHOSPHATE

• 85 % in bones • 14 – 15 % in cells and less than 1% ECF• Deposition and absorption of Bone• Osteoblasts on the surface and cavities• Osteoclasts

PARATHYROID• Poly peptide; mol. wt. 2500; 84 a.a• Controls ECF Ca⁺⁺ & Phosphate conc. by

– Intestinal reabsorption– Renal excretion– Exchange between ECF & bone

• ↑Ca⁺⁺ & Phosphate absorption from bone• ↓ Ca⁺⁺ excretion & ↑ Phosphate excretion by

kidneys

4 Parathyroid glands– Removal of 2 doesnot affect much– but removal of 3→hypoparathyroidism

Anatomy of the Parathyroid Glands & Microscopic Appearance of Chief Cells

Figure 79-9;Guyton & Hall

Mechanism of Action• cAMP acts as a 2nd messenger to carry out the

effects of hormone.

Regulation• Slightest ↓↓ in Ca⁺⁺ion concentration

→↑↑↑parathyroid• ↑↑ In Ca⁺⁺ →↓↓ Parathyroid Hormone

• Bone– resorption ( osteoclasts) – osteocytic osteolysis

• Kidney– Ca2+ reabsorption– phosphate reabsorption– Na+ reabsorption (weak effect)– 1,25-(OH)2-D3

• Intestine– Ca2+ absorption – phosphate absorption

PTH Actions

• Plasma Calcium concentration and PTH secretion

PlasPpma Calcium Concentration & PTH Secretion

06 8 10 12 14

50

100

PT

H s

ecre

tion

(%

max

imal

rat

e)

Total plasma [Ca2+] (mg/dL)

Plasma Calcium Concentration & PTH Secretion

Hypocalcemia

DisorderPlasma [PTH]

Plasma [1,25-(OH)2-D3] UrineBone

Plasma [Ca2+]

Plasma [Phosphate]

Vitamin D deficiency

Chronic renal failure

(2°)

*

*

Phosphate

cAMP

Phosphate ( GFR)*

Osteomalacia

Resorption

Resorption

* Primary events or disturbances

Surgical hypoparathyroidism

(2°)*

Osteomalacia

Resorption cAMP

Phosphate

Castanzo, Table 9-17

Primary Hyperparathyroidism

Primary Hyperparathyroidism

Plasma[PTH]

*

Plasma [1,25-(OH)2-D3] Urine

Phosphate

Ca2+

cAMP

Bone

Resorption

Plasma [Ca2+]

Plasma [Phosphate]

* Primary disturbance

Castanzo, Table 9-17

CALCITONIN

• Peptide hormone • Mol. Wt. 3400• From thyroid gland (C cells in the interstitium

between follicles)• Actions opposite to Parathyroid • ↑↑ Ca⁺⁺ concentration↑↑ Calcitonin• ↓↓ Ca⁺⁺ concentration in Plasma • PTH overrides its effects.

VITAMIN D

• Increases Ca⁺⁺ absorption from GIT • Bone deposition and bone absorption • ↑ Intestinal Ca⁺⁺ absorption • ↑ Intestinal phosphate absorption • ↓ Renal Ca⁺⁺ & phosphate excretion • In large quantities it causes bone absorption • In ↓↓ quantities it causes bone deposition

Activation of vitamin D3 to form 1,25-dihydroxycholecalciferol and the role of vitamin D in controlling the plasma calcium concentration

Pathophysiology

• Decreased – Osteoclasts inactive- ca decreases- tetany