Foundation: endocrine system - thyroid and parathyroid hormones

ME-SEM1 20149:15 – 10.15 am.

Tuesday 30 December 2014 Venue 4.02.

…Prof Peter Barling

peter_barling@imu.edu.myExt 2776

DID: 0327317285MOB: 0128398749

Word of advice…• This set of powerpoint slides is far more

extensive than can be covered during the lecture.• Only some will be used.• You are encouraged to look at all of them as the

main means of undertaking your subsequent self-learning and understanding of this topic.

• What you will have to recall for any test or exam will be clearly explained during the lecture.

Objectives of this lecture:

• To introduce you to the thyroid hormones and parathyroid hormone.

• You will receive a very brief introduction to common diseases of the thyroid or of calcium homeostasis.

• This will only brush the surface of the knowledge you will acquire during the organ-specific modules which follow later.

Learning objectives1. To describe the structure of the thyroid gland

and parathyroids.2. To describe the

• structures• biosynthesis• transport• actions• physiological effects• regulation of secretion

of the thyroid hormones and parathyroid hormone.

Thyroid gland• This lies in the anterior neck,

overlying the trachea just inferior to the larynx.

• Consists of two lateral lobes, connected by a medial tissue mass called the isthmus.

• Receives its rich blood supply through the inferior and superior thyroid arteries, which arise from the external carotid & subclavian arteries

• The thyroid two important hormones: thyroxine and tri-iodothyronine.

• Composed of spherical structures (follicles).

• Follicles: formed by cuboidal (or squamous) follicle epithelial cells

• Follicle cells : produce the glycoprotein thyroglobulin

• Thyroglobulin is stored in the follicles

Thyroid gland - histology

Thyroid Follicles

• Parafollicular cells are also located in the follicular epithelium

• They secrete another hormone - calcitonin.

• Calcitonin : inhibits bone resorption & release of ionic Ca from the bony matrix. It has only a minor endocrine function in adult humans.

Thyroid hormones• Derivatives of the amino acid

tyrosine.• Consists of two major types:

– Thyroxine (T4) – has 4 iodine atoms – Triiodothyronine (T3) - has 3 iodine

atoms– Both synthesised from 2 iodotyrosine

amino acids linked together• T4 : the major thyroid hormone

secreted by the thyroid follicles.• T3 : formed mainly at the target

tissues by conversion of T4 to T3. • T3 I is the actual functional thyroid

hormone and its precursor is T4.

Biosynthesis of the thyroid hormones

1. Formation of thyroglobulin

– synthesised on the ribosomes & then transported to the Golgi apparatus, where sugar residues are attached & the molecules packed into vesicles.

– protein-containing vesicles move to the apex of the follicle cell, where their contents are discharged into the lumen, to become part of the storage colloid.

Iodine is essential for thyroid hormone production

• The thyroid hormones are unique biological molecules in incorporating iodine in their structure.

• Adequate iodine intake (diet, water) is required for normal thyroid hormone production.

• Major sources of iodine:- iodized salt

- iodated bread - dairy products

- shellfish• Minimum requirement: 100 micrograms/day• Can be monitored by measuring iodide daily

secretion in urine (iodide in = iodide out)

Iodine attachment to thyrogobulin

– Follicle cells actively accumulate iodide (I-) from the blood.– Inside the cells, iodides are oxidised to iodine– Iodine enters the follicle lumen & attaches to the tyrosine amino acids

of thyroglobulin, forming part of the thyroglobulin colloid.– Attachment of 2 iodines to a tyrosine diiodotyrosine (DIT)– Attachment of 1 iodine to a tyrosine monoiodotyrosine (MIT)

Coupling- Enzymes within the colloid link DIT and MIT together- 2 linked DITs T4

- 1 MIT & 1 DIT T3

At this stage, the hormones are still part of the thyroglobulin colloid

Auto-regulation of thyroid hormone production

• The rate of iodine uptake and incorporation into thyroglobulin is influenced by the amount of iodide available:- low iodide levels increase iodine transport into follicular cells

- high iodide levels decrease iodine transport into follicular cellsThus, there is negative feedback regulation of iodide transport by iodide.

Cleavage of the hormones for release– Follicle cells reclaim iodinated thyroglobulin by endocytosis &

combine it with lysosomes.– The hormones are cleaved out of the colloid by lysosomal

enzymes and diffuse from the follicle cells into the bloodstream.– About 10% of the T4 is converted to T3 before secretion.

• The thyroid gland is unique because of its ability to concentrate iodide and to store and slowly release its hormones.

• The amount of stored iodine as thyroglobulin colloid remains relatively constant & is sufficient to provide normal levels of hormone release for over 3 months

• T3 and T4 are not water-soluble and when they are released from the thyroid gland they are bound to three binding proteins present in human plasma. •These are:

1. thyroxine-binding prealbumin (TBPA)2. thyroxine-binding globulin (TBG)3. plasma albumin

•70-75% of T4 is bound to TBG •15-20% is bound to TBPA •5-10% is bound to albumin.

Transport of thyroid hormones in plasma

Control of thyroid secretion• The highest level of control is in the hypothalamus• This releases TRH (thyrotropin-releasing hormone) • TRH regulates the release of TSH (thyroid stimulating hormone) from the anterior pituitary gland.

• T3 and T4, in turn feed back on the hypothalamus and the anterior pituitary gland when there is sufficient thyroid hormone available .This ‘negative feedback’ decreases the secretion of TRH and TSH.

Mechanism of action of thyroid hormone T3

Biological outcomes of the actions of thyroid hormones

• Thyroid hormones are essential for normal growth of tissues, especially the nervous system.

• Lack of thyroid hormone during development results in short stature and mental deficits (cretinism).

• Thyroid hormone stimulates basal metabolic rate and thereby increases heat production (a calorigenic effect)

Actions of thyroid hormone (T3) on body systems

• Required for GH (and prolactin) production, secretion and action

• Increases intestinal glucose reabsorption (glucose transporter)

• Increases mitochondrial size, number, key enzymes and rate of oxidative phosphorylation (ATP production)

• Increases activity of adrenal medulla and induces sympathetic receptors, speeding heart rate

• Induces enzyme synthesis• Result: stimulation of growth of tissues and

increased metabolic rate.

A major target gene of T3: the Na+/K+ ATPase pump

• Pumps sodium and potassium across cell membranes to maintain the resting membrane potential

• Activity of the Na+/K+ pump uses up energy, in the form of ATP

• About 1/3rd of all ATP in the body is used by the Na+/K+ ATPase

• T3 increases the synthesis of Na+/K+ pumps, markedly increasing ATP consumption.

• T3 also acts on mitochondria to increase ATP synthesis

• The resulting increased metabolic rate increases thermogenesis (heat production).

Thyroid hormone: key points

• Held in storage• Metabolised from an inactive (T4) to an active (T3) form• Acts on mitochondria, thereby increasing ATP production• Bound to receptors activating genes that control energy

utilization and tissue development• Exerts a calorigenic effect

Effects of thyroid hormone on the cardiovascular system

• Increase heart rate• Increase force of cardiac contractions• Increase stroke volume• Increase cardiac output• Up-regulates catecholamine receptors

Hypothyroidism• May result from :

1. thyroid gland defect 2. deficits of TSH or TRH release3. surgical removal of thyroid gland4. deficiency in dietary iodine

• Symptoms:– Low BMR, feeling chilled, constipation, thick, dry skin & puffy eyes,

edema, lethargy & mental sluggishness– if it is due to a lack of iodine, the thyroid gland enlarges from

increased TSH secretion goitre

GOITRE

Hyperthyroidism• The most common hyperthyroid pathology

causing this is Grave disease.• Grave disease is an autoimmune disease caused

by abnormal antibodies that act against the TSH receptorof the follicle cell membrane which then behaves as if TSH levels were very high

• Symptoms : BMR, >> perspiration, rapid, irregular heartbeat, nervousness, weight loss & exophthalmos – protusion of the eyeballs.

Exophthalmos – protusion of the eyeballs due to hyperthyrodism

Parathyroid hormone• Embedded in the posterior aspect of the thyroid gland.• Usually there are four of these glands.• Important in enhancing plasma ionised calcium levels in

the blood.• Release is triggered by falling blood [Ca++] level & inhibited

by hypercalcelmia.

• Effects of PTH:1. Bones - activation of osteoclasts to digest the bony matrix & release

of Ca & phosphate to the blood.2. Kidneys - ↑ reabsorption of Ca (↓ retention of phosphate) 3. Intestinal mucosal cells - ↑ Ca absorption (enhanced indirectly by

PTH’s effect on vit D activation).

At the end of this lecture, you should understand:

• Why and how ionized calcium is regulated very closely

• How parathyroid hormone acts and is regulated• A little about the role of vitamin D in regulating

calcium absorption and turnover• A little about the physiological effects of

hypercalcaemia and hypocalcaemia and some disorders of calcium homeostasis

DIETARY INTAKE

0.3 g

0.5 - 1.0 g

net 0.3-0.4 g

GUT BLOOD

0.3 g1300 g

BONE

0.25 - 2.0 g

FECAL EGESTION0.2 - 0.6 g

URINARY EXCRETION0.1 - 0.4 g

DAILY CALCIUM FLUX RATES

redily exchang- able bone mineral

slowly exchang- able bone mineral

1300 g total

*

*

* controlled

**

Total body calcium:

–99% (1300 g) in bone–0.3% in muscle–0.7% in extracellular fluids–0.05% in plasma

Turnover of calcium in bone

Tetracycline labelling: long bones - 5 - 11% per yearribs - 14 - 44% per yearskull - very low turnover

Calcium kinetic analysis:Overall - 6 - 25% per year, or

- 0.25 - 2 g/day

Calcium in plasma:

• 2.3 - 2.6 mM• * 35-50% bound to albumin• * 50-50% ionized (i.e. Ca++)• * 5-10% organic complexes, e.g.

–citrate–oxalate

Variation in plasma Ca++

• Ionized calcium is maintained at a constant level: 1.03 – 1.23 mM– 18% overall variation

DIETARY INTAKE

0.3 g

0.5 - 1.0 g

net 0.3-0.4 g

GUT BLOOD

0.3 g1300 g

BONE

0.25 - 2.0 g

FECAL EGESTION0.2 - 0.6 g

URINARY EXCRETION0.1 - 0.4 g

DAILY CALCIUM FLUX RATES

redily exchang- able bone mineral

slowly exchang- able bone mineral

1300 g total

*

*

* controlled

**

Yellow arrows = osteoclast-induced pits

Activation of osteoclastogenesis by PTH or PTHrP

The role of the extracellular calcium sensing receptor in PTH

secretion and action

The calcium-sensing receptor (CaSR) • A G-protein coupled receptor which responds to an

increase in the extracellular concentration of calcium ions.

• In parathyroid gland cells, activation of the calcium-sensing receptor on th surface by an increase in extracellular ionised calcium initiates an intracellular cascade which causes activation of a Gqα G protein, which stimulates the phospholipase C pathway, which inhibits the release of parathyroid hormone (PTH).

Hyperparathyroidism• Primary - tumour (usually adenoma) of

parathyroid glands• Hypercalcemia of malignancy - generation

of PTH-related peptide by tumours, e.g. lung carcinoma, some breast tumours etc

• Secondary -– chronic renal disease– pseudohypoparathyroidism– rickets and osteomalacia

Primary hyperparathyroidism• Ca++ elevated - dehydration• Bone disease apparent in advanced

cases - osteitis fibrosa cystica: bone pain, demineralization, cysts

• Treated by removal of 1 or more of the 4 parathyroids

Hypocalcaemia & hypoparathroidism• Defective synthesis or secretion of

parathyroid hormone (PTH). • Sometimes inappropriate activation or

antibody-stimulation of calcium-sensing receptor.

• End-organ resistance to PTH. • Result: severe hypocalcemia - seizures,

stridor, prolonged QT interval (heart) and tetany.

• Can often be treated effectively with vitamin D.

Summary - parathyroid hormone (PTH)• Produced by the parathyroid glands• A peptide with 84 amino acid residues• The first 30 or so are essential for its

biological effects• A central mediator of calcium homeostasis –

it increases ionised calcium levels• Acts on bone to increase osteoclastic bone

resorption and on the kidneys to inhibit calcium excretion by enhancing the renal resorption of Ca2+ from 99% to 99.9% .

Review questions1. Distinguish between T3 and T4 in terms of

their structure and biological activity.2. Explain how the secretion of thyroid

hormones is regulated. 3. What are the effects of thyroid hormones on

protein, carbohydrate and lipid metabolism?4. Explain the role of parathyroid hormone

(PTH) in regulating calcium balance in the blood.

References

1. Marieb, EN. Human Anatomy & Physiology. Chapter 17. The Endocrine System.

2. Johnson LR. Essential Medical Physiology. Chapter 39: Thyroid Gland