Thyroid Hormones

Noor Ullah
noor1.qau@gmail.com

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Biosynthesis of thyroid hormones

• Thyroxine (T4) and tri-iodothyronine (T3)

• Synthesized in the thyroid gland by:
• Iodination
• Coupling of two tyrosine molecules
• Attaching to thyroglobulin protein
• Thyroid gland mostly secretes T4
• Peripheral tissues (liver, kidney, etc.) deiodinate T4 to T3

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 Thyroxin binding
globulin ( TBG or
thyropexin)

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Biosynthesis of thyroid hormones

• T3 is more biologically active form

• T4 can be converted to rT3 (reverse T3) – inactive form
• Most of T4 is transported in plasma as protein-bound
• Thyroglobulin-bound (70%)
• Albumin-bound (25%)
• Transthyretin (TTR or Thyroxin binding prealbumin, TBPA) -bound (5%)
• The unbound (free) form of T4 and T3 are biologically active

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 Plasma level: 100 nmol/L

Plasma level:
2 nmol/L

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 Production of T4 and T3
• T4 is the primary secretory product of the thyroid gland, which is the
only source of T4
• The thyroid secretes approximately 70-90 g of T4 per day
• T3 is derived from 2 processes
• The total daily production rate of T3 is about 15-30 g
• About 80% of circulating T3 comes from deiodination of T4 in peripheral
tissues
• About 20% comes from direct thyroid secretion

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 T4: A Prohormone for T3
• T4 is biologically inactive in target tissues until converted to T3
• Activation occurs with 5' iodination of the outer ring of T4
• T3 then becomes the biologically active hormone responsible for the
majority of thyroid hormone effects

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 Thyroid Hormones actions

• Thyroid hormones (specifically T3) regulate rate of overall

body metabolism
• T3 increases basal metabolic rate
• Calorigenic effects
• T3 increases oxygen consumption by most peripheral tissues
• Increases body heat production

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Metabolic Effects of T3

• Stimulates lipolysis and release of free fatty acids and glycerol

• Induces expression of lipogenic enzymes
• Effects cholesterol metabolism
• Stimulates metabolism of cholesterol to bile acids
• Facilitates rapid removal of LDL from plasma
• Generally stimulates all aspects of carbohydrate metabolism and
the pathway for protein degradation

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Additional Effects of T3
• Initiates or sustains differentiation and growth
• Stimulates formation of proteins, which exert trophic effects on
tissues
• Essential for neural development and maturation and function of the
CNS
• Important for normal reproductive function
• T3 is considered the major regulator of mitochondrial activity

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 Regulation of thyroid hormone secretion
• The hypothalamic-pituitary-thyroid axis regulates thyroid
secretion
• The hypothalamus senses low levels of T3/T4 and releases
thyrotropin releasing hormone (TRH)
• TRH stimulates the pituitary to produce thyroid stimulating
hormone (TSH)
• TSH stimulates the thyroid to produce T3/T4 until levels
return to normal
• T3/T4 exert negative feedback control on the hypothalamus
and pituitary
• Controlling the release of both TRH and TSH

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Regulation of thyroid hormone secretion

• High thyroid levels suppress TRH and

TSH

• Low thyroid levels stimulate TRH and

TSH to produce more hormone

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Goitre
• Enlarged thyroid gland
• May be associated with:
• Hypofunction
• Hyperfunction
• Normal function of thyroid gland
• Causes:
• Iodine deficiency
• Selenium deficiency
• Hashimoto’s thyroiditis
• Congenital hypothyroidism
• Graves' disease (hyperthyroidism)
• Thyroid cancer
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Hypothyroidism
• Deficiency of thyroid hormones
• Primary hypothyroidism:
• Failure of thyroid gland
• Secondary hypothyroidism:
• Failure of the pituitary to secrete TSH (rare)
• Failure of the hypothalamic-pituitary-thyroid axis
• Causes:
• Hashimoto’s disease
• Radioiodine or surgical treatment of hyperthyroidism
• Drug effects
• TSH deficiency
• Congenital defects
• Severe iodine deficiency
• Clinical features
• Tiredness
• Cold intolerance
• Weight gain
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• Dry skin
Hypothyroidism
• Diagnosis
• Elevated TSH level confirms hypothyroidism
• Treatment
• T4 replacement therapy (tablets)
• Monitoring TSH level to determine dosage
• Patient has to continue treatment for life
• Neonatal hypothyroidism
• Due to genetic defect in thyroid gland of newborns
• Diagnosed by TSH screening
• Hormone replacement therapy
• May cause cretinism, if untreated

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Hypothyroidism
• Non-thyroidal illness
• In some diseases, the normal regulation of TSH, T3 and T4 secretion and
metabolism is disturbed
• Most of T4 is converted to rT3 (inactive)
• Causing thyroid hormone deficiency
• TSH secretion is suppressed
• Secretion of T4 and T3 is decreased

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Hypothyroidism
• Failure of thyroid gland to produce adequate level of Hormone
• It is either
1- Congenital
2-Acquired- May be:
• Thyroid (primary hypothyroidism) : 95 %
• Pituitary (secondary hypothyroidism) : 4 %
• Hypothalamus (tertiary hypothyroidism) : < 1%
• In adults called myxedema
• In children called cretinism
Myxedema Coma : The Other Thyroid Emergency

• Represents end stage of improperly treated, neglected, or undiagnosed

primary hypothyroidism
• Occurs in 0.1 % or less of cases of hypothyroidism
• Very rare under age 50
• 50 % of cases become evident after hospital admission
• Mortality is 100 % untreated, 50 % even if treated
• Most cases present in winter (cold exposure)

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Lab findings
• Stat glucose (because of altered mental status)
• Pulse oximetry (ABG usually indicated)
• CBC, Lytes, BUN, creat., calcium
• T4,T3,TSH
• Serum cortisol
• Liver function tests
• Relevant drug / alcohol levels
• Low FT4, TSH high, normal, or low, cholesterol high or N, serum Na
low

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Hyperthyroidism
• Over-activity of the thyroid gland
• Increased secretion of thyroid hormones
• Tissues are exposed to high levels of thyroid hormones (thyrotoxicosis)
• Increased pituitary stimulation of the thyroid gland
• Causes:
• Graves' disease
• Toxic multinodular goitre
• Thyroid adenoma
• Thyroiditis
• Intake of iodine / iodine drugs
• Excessive intake of T4 and T3

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Hyperthyroidism
• Clinical features
• Weight loss with normal appetite
• Sweating / heat intolerance
• Fatigue
• Palpitation / agitation, tremor
• Angina, heart failure
• Diarrhea
• Eyelid retraction and lid lag

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Graves' disease
• Most common cause of hyperthyroidism
• An autoimmune disease
• Antibodies against TSH receptors on thyroid cells mimic the action of
pituitary hormone
• Normal regulation of synthesis/control is disturbed

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Hyperthyroidism
• Diagnosis
• Suppressed TSH level
• Raised thyroid hormone level
• Confirms primary hyperthyroidism
Problems in diagnosis
• Total serum T4 conc. changes due to changes in binding protein levels
• In pregnancy, high estrogens increase TBG synthesis
• Total T4 will be high

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Thyroid function tests

• TSH measurement:
• Indicates thyroid status
• Total T4 or free T4:
• Indicates thyroid status
• Monitors anti-thyroid treatment
• Monitors thyroid supplement treatment
• TSH may take upto 8 weeks to adjust to new level during treatment
• TSH and T4 (total or free) are sensitive, first-line test
• Some labs only measure TSH as first-line test

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Tests for thyroid evaluation

• Blood Tests- TSH

• Key test for diagnosis of hypothyroidism and hyperthyroidism
• TSH assay sensitivity has improved with subsequent test generations
• First generation: RIA
Sensitivity: 1.0 IU/mL
• Second generation: IRMA
Sensitivity: 0.1 IU/mL
• Third generation: ELISA
Sensitivity: 0.03 IU/mL Ladenson PW, et al. Arch Intern Med. 2000;160:1573-1575.
Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text.
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8th ed. 2000. 28
Zophel K, et al. Nuklearmedizin. 1999;38:150-155.
Serum T4 and T3
• Serum total T4 and T3 levels are usually measured by radioimmunoassay
(RIA), chemiluminometric assay, or similar immunometric technique.

• Because more than 99.9% of thyroid hormone is protein bound, alteration

in thyroid hormone–binding proteins, unrelated to thyroid disease,
frequently lead to total T4 and T3 levels outside of the normal range.

• Because of this, assays have been developed to measure free T4 and T3, the
biologically active forms of thyroid hormone.

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Thyroglobulin

• Thyroglobulin is a protein synthesized and secreted exclusively by thyroid

follicular cells.

• This prohormone in the circulation is proof of the presence of thyroid tissue,

either benign or malignant.

• This fact makes thyroglobulin an ideal tumor marker for thyroid cancer patients.

• Thyroglobulin is currently measured by double-antibody RIA, enzyme-linked

immunoassay (ELISA), immunoradiometric assay (IRMA), and
immunochemiluminescent assay (ICMA) methods.

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Thyroid Autoimmunity
• Many diseases of the thyroid gland are related to autoimmune processes.

• The most common cause of hyperthyroidism is an autoimmune disorder called Graves’ disease.

• The antibody in this condition is directed at the TSH receptor and stimulates the receptor,
leading to growth of the thyroid gland and production of excessive amounts of thyroid hormone.

• This condition can be diagnosed with tests that detect antibodies to the TSH receptor.

• Thyroid-stimulating antibodies (TSAb) use a bioassay to determine presence of autoimmune

hyperthyroidism.

• Tests for TSH receptor antibodies (TRAb, TSHR-Ab) can detect antibodies directed against the
TSH receptor.

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Thyroid Autoimmunity

• Chronic lymphocytic thyroiditis—commonly known as Hashimoto’s thyroiditis—

is at the other end of the autoimmune continuum.

• This is the most common cause of hypothyroidism in the developed world.

• In this condition, antibodies lead to decreased thyroid hormone production by

the thyroid gland.

• The best test for this condition is the thyroid peroxidase (TPO) antibody, which is
present in 10%–15% of the general population and 80%–99% of patients with
autoimmune hypothyroidism.

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Possible explanations for various result combinations
High T4 Normal T4 Low T4

High TSH Irregular use of thyroxine Subclinical hypothyroidism Primary hypothyroidism

Amiodarone T4 under replacement
Pituitary hyperthyroidism
(TSH-producing pituitary
tumour - rare)
Thyroid hormone resistance
(very rare)

Normal As above Normal Some drugs

TSH Some drugs (steroids, beta- (anticonvulsants,anti-
blockers, NSAIDS) T3, anti-T4)
Non-thyroidal illness Pituitary or hypothalamic
T4 replacement (sometimes hypothyroidism,
stablises with normal TSH Severe non-thyroidal
and FT4) illness

Low TSH Primary hyperthyroidism Subclinical hyperthyroidism Pituitary or hypothalamic

Subtle T4 over replacement hypothyroidism,
Non-thyroidal illness Severe non-thyroidal
illness

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