Thyroid HormonesThyroid Hormones

ENDO412ENDO412

Objectives of the LectureObjectives of the Lecture

• Identification of the regulatory mechanism regulatory mechanism controlling thyroid hormone secretion.

• Identification of the biosynthesis, storage & secretion biosynthesis, storage & secretion of thyroid hormones.

• Explaining the significance of the conversion of T4 to T3 & reverse T3 conversion of T4 to T3 & reverse T3 in extra thyroid tissue.

• Describing in brief the different actions of the thyroid hormones.actions of the thyroid hormones.• Identifying causes & consequences of over secretion & under secretionover secretion & under secretion

of the thyroid hormones.• Listing & applications of thyroid function teststhyroid function tests.

Thyroid HormonesThyroid Hormones

• Thyroid hormones that are synthesized Thyroid hormones that are synthesized & secreted by the thyroid glands are & secreted by the thyroid glands are

essential for normal growth, essential for normal growth, development & metabolism of human development & metabolism of human

body. body.

• Hormone production by the thyroid Hormone production by the thyroid gland is tightly regulated through gland is tightly regulated through

hypothalamic-pituitary-thyroid axis. hypothalamic-pituitary-thyroid axis.

Biosynthesis & Secretion of thyroid hormonesBiosynthesis & Secretion of thyroid hormones

• All T4 & T4 & small amount of T3T3 are synthesized in the thyroid gland.

Process of biosynthesis of thyroid hormonesProcess of biosynthesis of thyroid hormones:

1- Trapping of iodide from plasma by thyroid gland.

2- Oxidation of iodide to iodine by thyroid peroxidase.

3- Incorporation of iodine into tyrosine amino acids residues on thyroglobulin of the colloid of

thyroid follicles to form monoiodotyrosine (MIT) & diiodotyrosine (DIT).

4- Coupling of DIT & DIT to form tetraiodothyronine (Thyroxine or T4) & Coupling of DIT & MIT to form triiodothyronine (T3).

5- T4 & T3 are splitted from the thyroglobulin & reabsorbed into cells to be released into

plasma.

IodideIodide

IodideIodide IodineIodineMIT

ThyroglobulinThyroglobulin

DIT T3 T4

T4 T3

Blood

Thyroid Cell

Colloid

T4 T34 T3

Thyroid peroxidase

Active uptake

Thyroid Follicle

BiosynthesisBiosynthesis & &SecretionSecretion

of Thyroidof Thyroid HormonesHormones

What are thyroid hormones in the bodyWhat are thyroid hormones in the body??

1- 1- Thyroxine (T4):Thyroxine (T4):

produced exclusively by the thyroid gland

2- T3:2- T3:

- 15% is produced in the thyroid gland - 85% is produced from T4 in the liver, kidney & muscles by deiodination of outer

ring (as 80% of T4 is converted to T3 in extrathyroid tissues) - T3 is the biologically activeactive form of thyroid hormones (as it is has 10 times more

affinity more than T4 for thyroid receptors)

3- Reverse T3 (rT3): 3- Reverse T3 (rT3):

- Produced outside thyroid from T4 by deiodination of inner ring. - rT3 is biologically inactiveinactive.

Transport of thyroid hormones in bloodTransport of thyroid hormones in blood

Thyroid hormones are transported in blood in two formsThyroid hormones are transported in blood in two forms

1-1-Bound formsBound forms::

• Thyroid hormones are transported in plasma bound to plasma proteins: - Thyroid Binding Globulin Thyroid Binding Globulin (TBG) binds 70% of plasma T4 & 80% of plasma T3

- Others: Pre-albuminPre-albumin & Albumin Albumin

2- 2- Free formFree form::

• 0.05% of plasma T4 & 0.02% of plasma T3 are free (notnot bound to plasma proteins)

Only the Only the freefree fraction can cross the cell membrane & affect intracellular fraction can cross the cell membrane & affect intracellular metabolismmetabolism

Thyroid Binding Globulin (TBG)Thyroid Binding Globulin (TBG)

- produced by the liverliver

- Synthesis of TBG is increasedincreased by estrogens (in cases of pregnancy & intake of contraceptive pills) & is decreaseddecreased by androgens, glucocorticoids & liver disease. - In these casesIn these cases, total T4 & total 3 are changed without changes in the free forms

- Some medications Some medications as salicylates compete with T3 & T4 for binding sites on TBG causing decreasedecrease in total T3 & total T4 without decreasing free T3 or free T4.

Transport of thyroid hormones in blood Transport of thyroid hormones in blood (cont.)(cont.)

Mechanism of action of thyroid hormonesMechanism of action of thyroid hormones

• Thyroid hormones belong to group Igroup I hormones that are bound to intracellular receptors (mainly nuclear receptors).

• Hormone-Receptor complexcomplex binds to hormone sensitive element (HREHRE) of certain genes (T3 responsive genes) affecting their transcriptiontranscription.

• Products (proteins as enzymes) exert a number of effects on growthgrowth, developmentdevelopment & cell metabolismcell metabolism.

General actions of thyroid hormonesGeneral actions of thyroid hormones

1- Major effect of T3 & T4 is to enhance general protein synthesis essential Major effect of T3 & T4 is to enhance general protein synthesis essential for for growthgrowth.. for example: T3 enhances transcription of growth hormone (GH) itself. (anabolic effects of T3) However, very high T3 levels in blood causes inhibition of protein synthesis.

2- Thyroid hormones are essential for normal physical, mental &2- Thyroid hormones are essential for normal physical, mental & reproductive reproductive developmentdevelopment in humans. in humans.

Intrauterine or neonatal hypothyroidism causes cretinismcretinism in which there is physical & mental retardation.

3- Thyroid hormones have 3- Thyroid hormones have metabolicmetabolic actions that regulates metabolism of actions that regulates metabolism of carbohydrates, lipids & proteins. carbohydrates, lipids & proteins.

basal Metabolic rate (BMR) is increased.

Regulation of thyroid functionRegulation of thyroid function

• Thyroid stimulating hormone (TSHTSH) or thyrotropin of the anterior pituitary gland enhances synthesissynthesis & secretionsecretion of thyroid hormones by the thyroid gland.

• Production of TSH by the pituitary is controlled by a stimulatory effect of thyrotropin-releasing hormone (TRHTRH) of the hypothalamus by negative feedback from circulating free T3 & free T4.

• Accordingly, the hypothalamus (via TRH), sets the level of thyroid Accordingly, the hypothalamus (via TRH), sets the level of thyroid

hormones production required physiologically by the body. hormones production required physiologically by the body.

HypothalamusHypothalamus

AntAnt. Pituitary Pituitary

glandgland

Plasma T3 & T4lasma T3 & T4

ThyroidThyroid glandgland

Peripheral tissuesPeripheral tissues

Negative FeedbackRegulation ofRegulation of

thyroid hormonesthyroid hormones synthesis & secretionsynthesis & secretion

TRH

TSH

Over secretion of thyroid hormonesOver secretion of thyroid hormones(Hyperthyroidism)(Hyperthyroidism)

1- 1- Primary Hyperthyroidism (thyrotoxicosis)Primary Hyperthyroidism (thyrotoxicosis)

Thyroid hormones elevation in blood due to causes in the thyroid thyroid

gland itself.

Most importantMost important: Graves` disease.

2- 2- Secondary hyperthyroidism Secondary hyperthyroidism

Thyroid hormones elevation due to TSH- secreting tumor of the

pituitarypituitary.

Graves` diseaseGraves` disease

EtiologyEtiology:

• A primary hyperthyroid disease which results from production of a thyroid-stimulating immunoglobulin IgG that activates TSH thyroid-stimulating immunoglobulin IgG that activates TSH receptors on thyroid gland receptors on thyroid gland resulting in over production & secretion of thyroid hormones (T3 & T4) by thyroid gland.

ClinicallyClinically:

• Thyroid gland is diffusely enlarged • Thyrotoxic manifestations:

Increased heart rate & hypertension Nervousness & inability to sleep (insomnia) Sensitivity to heat (increased BMR), flushed skin & excessive sweat weight loss with increased appetite Exophalmos of the eye in some cases

Diagnostic Laboratory Investigations:Diagnostic Laboratory Investigations:

Plasma Free T3 & free T4 Free T3 & free T4 are elevated Serum TSHTSH is markedly reduced

TreatmentTreatment:

1- blocking hormone production by antithyroid drugs

2- Surgical removal of the thyroid gland (subtotal thyroidectomy)

Under secretion of thyroid hormonesUnder secretion of thyroid hormones(Hypothyroidism)(Hypothyroidism)

Defined as low free T4 level with a normal or high TSH.

Types of hypothyroidismTypes of hypothyroidism:

1 -PrimaryPrimary: Thyroid gland dysfunction Most common :

1 -Congenital hypothyroidism (in neonates)Congenital hypothyroidism (in neonates) 2 -Chronic lymphocytic thyroiditis (Hashimoto`s thyroiditis)Chronic lymphocytic thyroiditis (Hashimoto`s thyroiditis)

Autoimmune disease of thyroid Thyroid gland is enlarged

3 -Iodine deficiencyIodine deficiency 4 -Thyroid surgeryThyroid surgery

5 -Radioactive iodine treatmentRadioactive iodine treatment

2 -SecondarySecondary: Pituitary dysfunction (hypopitutarismhypopitutarism due to radiation therapy or destruction of the pituitary)

Important clinical manifestations of hypothyroidism:Important clinical manifestations of hypothyroidism:

SymptomsSymptoms::

Cold intoleranceDepressionMental retardation (infants)Growth failure (children)Dry skinConstipationDyspnoea on exersion

SignsSigns:

BradycardiaPeriorbital edemaSlowed movement & speechDelayed relaxation phase of deep tendon reflex tendonsLabLab: Hypercholesterolemia

Laboratory InvestigationLaboratory Investigation::

1- Low plasma freefree T4T42- Plasma TSHTSH is normal or high in primary hypothyroidism & low in secondary hypothyroidism2- Neonatal screening Neonatal screening for congenital hypothyroidism (plasma TSHTSH is elevated in affected neonates)

Under secretion of thyroid hormonesUnder secretion of thyroid hormones(Hypothyroidism) (Hypothyroidism) cont.

Thyroid Function TestsThyroid Function Tests

Investigations to determine thyroid statusInvestigations to determine thyroid status

1- 1- Tests to establish whether there is thyroid dysfunctionTests to establish whether there is thyroid dysfunction Thyroid hormone Thyroid hormone (free & total ) concentrations in plasma (T3 & T4) TSHTSH

2- 2- Tests to elucidate the cause of the thyroid dysfunction:Tests to elucidate the cause of the thyroid dysfunction: as for examples:

Thyroid autoanibodies Serum thyroglobulin Thyroid enzyme activity Biopsy of the thyroid Ultrasonography (sonar) of the thyroid Isotope scanning of the thyroid

Tests to determine thyroid statusTests to determine thyroid status

1- Thyroid hormones concentrations in plasmaThyroid hormones concentrations in plasma: :

Free thyroid hormones (free T3 & free T4)Free thyroid hormones (free T3 & free T4) concentrations in plasma are independent of changes in the concentration of thyroid binding proteins as TBG, prealbumin & albumin.

So, they provide more reliable means of diagnosing thyroid dysfunction So, they provide more reliable means of diagnosing thyroid dysfunction than measurement of total thyroid hormone concentrationsthan measurement of total thyroid hormone concentrations

Total thyroid hormones (total T3 & total T4Total thyroid hormones (total T3 & total T4) ) concentrations in plasma are greatly influenced by TBG which is increased in cases of oral contraceptives intake & in pregnancy.

In these cases, total T3 & T4 are increased while free t3 & T4 remain normal.

Tests to determine thyroid status Tests to determine thyroid status (cont.)(cont.)

2- 2- Plasma TSH (Thyrotropin)Plasma TSH (Thyrotropin):: TSH concentration in plasma is TSH concentration in plasma is elevatedelevated in cases of : in cases of :

1- Primary hypothyroidism : Primary hypothyroidism : under secretion of the thyroid hormones due to causes in the thyroid2- Secondary hyperthyroidism: Secondary hyperthyroidism: over secretion of the thyroid hormones due to hperfunction of the anterior pituitary that secretes TSH

TSH concentration in plasma is TSH concentration in plasma is reducedreduced in cases of : in cases of :

1- Primary hyperthyroidism: Primary hyperthyroidism: over secretion of the thyroid hormones due to causes in the thyroid itself 2- Secondary hypothyroidism : Secondary hypothyroidism : under secretion of the thyroid hormones due to hypofunction of the anterior pituitary

Measurement of TSH concentration in plasma is helpful in Measurement of TSH concentration in plasma is helpful in cases ofcases of::

Normal thyroid hormones in blood with clinical manifestation of Normal thyroid hormones in blood with clinical manifestation of hyperthyroidismhyperthyroidism:

In these cases patient is clinically hyperthyroid (enlarged gland, thyrotoxic manifestationsclinically hyperthyroid (enlarged gland, thyrotoxic manifestations)BUT his thyroid hormones thyroid hormones in blood are normal (or upper normal). TSHTSH is reduced (to below 0.1mU/L)

Subclinical hyperthyroidismSubclinical hyperthyroidism::

In these cases, patient are clinically normal for thyroid illness clinically normal for thyroid illness (or have mild hyperthyroid)& Thyroid hormones & Thyroid hormones are normal.BUT: BUT: TSHTSH is reduced

Tests to determine thyroid status Tests to determine thyroid status (cont.)(cont.)

TSH may be misleading in:TSH may be misleading in:

1- First trimester of pregnancy:First trimester of pregnancy: TSH may be very low (less than 0.1 mU/L) in 3% of cases due to the weak thyrotrophic effect of human chorionic gonadotrophins(hCG) which is high in this period.

2- 50% of patients with pituitary hypothyroidism50% of patients with pituitary hypothyroidism: Show normal TSH BUT: circulating TSH may show reduced bioactivity

3- First 4-6 months of treatment of hyperthyroidismFirst 4-6 months of treatment of hyperthyroidism: TSH may be still low even T3 & T4 are normal (or even below normal ). So, follow up of patients during this period by TSH is notnot reliable.

Tests to determine thyroid status Tests to determine thyroid status (cont.)(cont.)

Nonthyroidal illness (NTIs):Nonthyroidal illness (NTIs):

Patients with a wide range of chronic & acute non-thyroidal illness (NTIs) may show abnormal thyroid function tests abnormal thyroid function tests (particularly low T3) & even though patients are euthyroideuthyroid (not show clinical manifestations of hyper- or hpothyroidism). This is called sick euthyroid syndromesick euthyroid syndrome. It may result from the effects of the chronic disease on the circulating thyroid hormones (as change in thyroid hormones binding proteins etc..). Accordingly, thyroid function tests should be onlyonly requested if the reason of hospital admission is related to a thyroid problem

Tests to determine thyroid status Tests to determine thyroid status (cont.)(cont.)