Understanding Thyroid Hormones: Biosynthesis, Functions, and Clinical Implications

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Thyroid Hormones and
Thermogenesis
 
ENDOCRINE BLOCK
 
DR. USMAN GHANI
 
Objectives:
 
 
By the end of this lecture, the students are expected to:
1.
Describe types and steps of biosynthesis of thyroid hormones
2.
Discuss the thyroid hormone actions
3.
Determine different levels for the regulation of thyroid hormones
4.
List the thyroid function tests
5.
Define goiter
6.
Differentiate between hypo and hyperthyroidism based on:
1.
Causes
2.
Diagnosis
3.
Treatment
7.
Discuss the role of thyroid hormone in thermogenesis
Types and Biosynthesis of
Thyroid Hormones
 
Thyroxine (T
4
) and tri-iodothyronine (T
3
)
Synthesized in the thyroid gland by:
Iodination
Coupling of two tyrosine molecules
Binding to thyroglobulin protein
Thyroid gland mostly secretes T
4
Peripheral tissues (liver, kidney, etc.) de-iodinate T
4
to T
3
Deiodination is catatalyzed by deiodinase enzymes
 
 
Plasma
[T
3
]:
2 nmol/L
 
Thyroxine (T
4
)
Tri-iodothyronine (T
3
)
Reverse T
3
 (rR
3
)
 
Plasma
[T
4
]:
100
nmol/L
Types and Biosynthesis of
Thyroid Hormones
 
T
3
 is the more biologically active form
T
4
 can be converted to rT
3
 (reverse T
3
) – inactive
form
Most of T
4
 is transported in plasma as protein-bound
Thyroxin Binding globulin (TBG)-bound (70%)
Albumin-bound (25%)
Transthyretin (prealbumin)-bound (5%)
The unbound (free) form of T
4
 and T
3
 are biologically
active
Thyroid hormone action
 
Plays an essential role in 
maturation of 
all
 body tissues,
coordinating development and specific cell functions
Involved in thermogenesis 
and metabolic regulation
Increases cellular oxygen consumption and stimulates the
metabolic rate
Affects the rate of protein, carbohydrate and lipid
metabolis
m
Thyroid Hormone Action
 
Clinical evidence of the wide spectrum of thyroid hormone action:
 
Untreated congenital hypothyroidism 
permanent
brain damage
 
Hypothyroid children have:
Delayed skeletal maturation 
short stature
Delayed puberty
 
Hypothyroid patients have high serum cholesterol due
to:
Down regulation of LDL receptors on liver cells
Failure of sterol excretion via the gut
Regulation of Thyroid
Hormone Secretion
 
The hypothalamic-pituitary-thyroid axis regulates
thyroid secretion
 
The hypothalamus senses low levels of  T
3
/T
4
 and
releases thyrotropin releasing hormone (TRH)
 
TRH stimulates the pituitary to produce thyroid
stimulating hormone (TSH)
Regulation of Thyroid
Hormone Secretion
 
TSH stimulates the thyroid to produce T
3
/T
4
 until
levels return to normal
 
T
3
/T
4
 exert negative feed back control on the
hypothalamus and pituitary
 
Controlling the release of both TRH and TSH
 
Regulation of Thyroid
Hormone Secretion
 
High thyroid hormone levels
suppress TRH & TSH
 
Low thyroid hormone levels
stimulate TRH & TSH to produce
more hormone
 
1.
Hypothalamus nuclei
Regulation of 
Trh
 gene transcription and processing
Regulation in response to nutrient status
2.
Pituitary:
Regulation of TRH degradation
Regulation of TSH synthesis and activation
3.
 
Thyroid:
Synthesis, release, regulation of T
4 
and its conversion to T
3 
by
deiodinase 2 (D2) enzyme
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Elements involved in
Hypothalamic-Pituitary-Thyroid
regulation
Thyroid Function Tests
 
I.
TSH measurement:
Indicates thyroid status
Sensitive, first-line test
II.
Total T
4
 or free T
4
:
Indicates thyroid status
Monitors thyroid treatment (both anti-thyroid and
thyroid supplement treatment)
TSH may take up to 8 weeks to adjust to new level
during treatment
Thyroid Function Tests
 
III.
Total T
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 or free T
3
:
Rise in T
3
 is independent of T
4
In some patients only T
3
 rises (T
4
 is normal): T
3
 toxicosis
For earlier identification of thyrotoxicosis
IV.
Antibodies:
Diagnosis and monitoring of autoimmune thyroid disease
(Hashimoto’s thyroiditis); anti-thyroid peroxidase in
hypothyroidism
Diagnosis of Graves’ disease: antibodies against TSH
receptors on thyroid cells
Goitre, Hypo and Hyperthyroidism
 
 
Enlarged thyroid gland
 
Goitre may be associated with:
Hypofunction
Hyperfunction
Normal concentration of thyroid hormones
(euthyroid)
 
Causes
:
Iodine, selenium deficiency
Hashimoto’s thyroiditis
Graves’ disease (hyperthyroidism)
Congenital hypothyroidism / thyroid cancer
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
Hypothyroidism
 
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 / dry skin
Hypothyroidism
 
 
Non-thyroidal illness
In some diseases, the normal regulation of
TSH, T
3
 and T
4
 secretion and metabolism is
disturbed
Most of T
4
 is converted to rT
3
 (inactive)
Causing thyroid hormone deficiency
Secretion of T
4
 and T
3
 is decreased
Hyperthyroidism
 
Over-activity of the thyroid gland
Hyper-secretion of thyroid hormones
Tissues are exposed to high levels of thyroid hormones
(thyrotoxicosis)
Hyper-stimulation of the thyroid gland by pituitary
 
Causes
:
Graves’ disease
Toxic multinodular goitre
Thyroid adenoma
Thyroiditis
Intake of iodine / iodine drugs
Excessive intake of T
4
 and T
3
Hyperthyroidism
 
Clinical features:
Weight loss with normal appetite
Sweating / heat intolerance
Fatigue
Palpitation / agitation, tremor
Angina, heart failure
Diarrhea
Eyelid retraction and lid lag
Graves’ Disease
 
Most common cause of hyperthyroidism
 
An 
autoimmune
 disease
 
Antibodies
 against TSH receptors on
thyroid cells mimic the action of pituitary
hormone
Hyperthyroidism
 
Diagnosis
Suppressed TSH level
Raised thyroid hormones levels
Confirms primary hyperthyroidism
 
Problems in diagnosis
Total serum T
4 
varies due to changes in binding protein levels
High estrogens in pregnancy increase TBG synthesis
Total T
4
 will be high, free T
4
 will be normal
Hyperthyroidism
 
Congenital TBG deficiency can also influence results
Free T
4
 and TSH are first-line tests for thyroid dysfunction
 
Treatment
Antithyroid drugs: carbimazole, propylthiouracil
Radioiodine: sodium 
131
I inhibits T
4
/T
3
 synthesis
Surgery: thyroidectomy
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Humans are 
homeothermic
 (keep constant body temp.)
Tightly controlled 
temperature homeostasis
Thermogenesis is of two types:
Obligatory
: Basic heat production due to basal metabolic rate
Facultative
: On-demand extra heat production from metabolic activity in
brown adipose tissue (BAT), skeletal muscle, etc.
In BAT, the facultative thermogenesis is stimulated by
sympathetic nervous system in response to cold temperature
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Mullur et al, Physiol Rev. 2014 “
Thyroid Hormone Regulation of Metabolism
Sites of thyroid hormone
regulation of metabolism
Thyroid Hormone and Thermogenesis
 
 
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The Mechanisms by which Thyroid
Hormone Regulates Thermogenesis
Silva, Ann Intern Med. 2003;139:205-213: The Thermogenic Effect of Thyroid Hormone and Its Clinical
Implications
 
The energy released
from substrate
oxidation is captured
in ATP
 
The energy is then
transferred from ATP to
provide energy for
biological processes
 
A fraction of the energy is lost as heat without ATP production/consumption
Thyroid hormone increases heat production by:
I
ncreasing
 ATP utilization
 / 
R
educing
 the thermodynamic efficiency of
ATP synthesis
A
B
 
The energy released in the oxidation of substrates in the
mitochondria 
proton gradient
 
The energy accumulated in this gradient is used the ATP
Synthase to produce ATP i.e. oxidation is coupled to
phosphorylation
 
UCPs reduce the proton gradient, bypassing the ATP synthase 
 
exothermic
movement of protons down the gradient
 heat (because oxidation is
uncoupled
 to phosphorylation)
Mechanism of action of uncoupling proteins (UCPs):
 
Example: UCP1
 is
present in 
the inner
mitochondrial
membrane 
of 
BAT.
Other UCPs are
ubiquitous
 
Transport of protons
 
Take home message
 
Thyroid hormones include T4 , T3, and rT3 (which is inactive), they are synthesized
by iodination, coupling and attaching to thyroglobulin protein.
T3 is the active form of thyroid hormone and is synthesized by deiodinase in
peripheral and central tissues.
Thyroid hormone has wide spectrum of actions, for instance 
maturation of all body
tissues, 
coordinating development and specific cell functions, metabolic regulation,
and t
hermogenesis.
Thyroid hormone is regulated by feed back mechanism. Several elements are
involved in the regulation at the 
 level of the hypothalamic nuclei, pituitary gland,
thyroid, and peripheral tissues.
TFT include measurement of 
TSH, total and free T4, 
total 
and free 
T3, and  thyroid
antibodies.
 
Take home message
 
Goiter is and enlarged thyroid gland, that can be associated with: Hypo-, Hyper,
or Eu (normal) thyroid function
H
ypo and hyperthyroidism are differentiated based on their clinical picture,
causes, diagnostic criteria, and treatment
Thyroid hormone regulates both obligatory and facultative thermogenesis.
It increases obligatory thermogenesis, by accelerating ATP turnover and
reducing the efficiency of ATP synthesis
It increases facultative thermogenesis: Thyroid hormone is necessary for an
efficient response of BAT to cold
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This educational material delves into the types and biosynthesis of thyroid hormones, the physiological actions of thyroid hormones, regulation levels, thyroid function tests, goiter, and the distinction between hypo- and hyperthyroidism. It covers the role of thyroid hormones in thermogenesis, metabolic rate regulation, and cellular metabolism. Clinical manifestations of thyroid hormone imbalances and their impact on growth, development, and metabolic functions are also discussed.


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  1. Thyroid Hormones and Thermogenesis ENDOCRINE BLOCK DR. USMAN GHANI

  2. Objectives: By the end of this lecture, the students are expected to: 1. Describe types and steps of biosynthesis of thyroid hormones 2. Discuss the thyroid hormone actions 3. Determine different levels for the regulation of thyroid hormones 4. List the thyroid function tests 5. Define goiter 6. Differentiate between hypo and hyperthyroidism based on: 1. Causes 2. Diagnosis 3. Treatment 7. Discuss the role of thyroid hormone in thermogenesis

  3. Types and Biosynthesis of Thyroid Hormones Thyroxine (T4) and tri-iodothyronine (T3) Synthesized in the thyroid gland by: Iodination Coupling of two tyrosine molecules Binding to thyroglobulin protein Thyroid gland mostly secretes T4 Peripheral tissues (liver, kidney, etc.) de-iodinate T4 to T3 Deiodination is catatalyzed by deiodinase enzymes

  4. Thyroxine (T4) Tri-iodothyronine (T3) Reverse T3 (rR3) Plasma [T4]: 100 nmol/L Plasma [T3]: 2 nmol/L

  5. Types and Biosynthesis of Thyroid Hormones T3 is the more biologically active form T4 can be converted to rT3 (reverse T3) inactive form Most of T4 is transported in plasma as protein-bound Thyroxin Binding globulin (TBG)-bound (70%) Albumin-bound (25%) Transthyretin (prealbumin)-bound (5%) The unbound (free) form of T4 and T3 are biologically active

  6. Thyroid hormone action Plays an essential role in maturation of all body tissues, coordinating development and specific cell functions Involved in thermogenesis and metabolic regulation Increases cellular oxygen consumption and stimulates the metabolic rate Affects the rate of protein, carbohydrate and lipid metabolism

  7. Thyroid Hormone Action Clinical evidence of the wide spectrum of thyroid hormone action: Untreated congenital hypothyroidism permanent brain damage Hypothyroid children have: Delayed skeletal maturation short stature Delayed puberty Hypothyroid patients have high serum cholesterol due to: Down regulation of LDL receptors on liver cells Failure of sterol excretion via the gut

  8. 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)

  9. Regulation of Thyroid Hormone Secretion TSH stimulates the thyroid to produce T3/T4 until levels return to normal T3/T4 exert negative feed back control on the hypothalamus and pituitary Controlling the release of both TRH and TSH

  10. Regulation of Thyroid Hormone Secretion High thyroid hormone levels suppress TRH & TSH Low thyroid hormone levels stimulate TRH & TSH to produce more hormone

  11. Elements involved in Hypothalamic-Pituitary-Thyroid regulation 1. Hypothalamus nuclei Regulation of Trh gene transcription and processing Regulation in response to nutrient status 2. Pituitary: Regulation of TRH degradation Regulation of TSH synthesis and activation 3. Thyroid: Synthesis, release, regulation of T4 and its conversion to T3 by deiodinase 2 (D2) enzyme Patricia Joseph-Bravo et al. J Endocrinol 2015;226:T85-T100

  12. Thyroid Function Tests I. TSH measurement: Indicates thyroid status Sensitive, first-line test II. Total T4 or free T4: Indicates thyroid status Monitors thyroid treatment (both anti-thyroid and thyroid supplement treatment) TSH may take up to 8 weeks to adjust to new level during treatment

  13. Thyroid Function Tests III. Total T3 or free T3: Rise in T3 is independent of T4 In some patients only T3 rises (T4 is normal): T3 toxicosis For earlier identification of thyrotoxicosis IV. Antibodies: Diagnosis and monitoring of autoimmune thyroid disease (Hashimoto s thyroiditis); anti-thyroid peroxidase in hypothyroidism Diagnosis of Graves disease: antibodies against TSH receptors on thyroid cells

  14. Goitre, Hypo and Hyperthyroidism Enlarged thyroid gland Goitre may be associated with: Hypofunction Hyperfunction Normal concentration of thyroid hormones (euthyroid) Causes: Iodine, selenium deficiency Hashimoto s thyroiditis Graves disease (hyperthyroidism) Congenital hypothyroidism / thyroid cancer

  15. 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

  16. Hypothyroidism 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 / dry skin

  17. 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 Secretion of T4 and T3 is decreased

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

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

  20. Graves Disease Most common cause of hyperthyroidism An autoimmune disease Antibodies against TSH receptors on thyroid cells mimic the action of pituitary hormone

  21. Hyperthyroidism Diagnosis Suppressed TSH level Raised thyroid hormones levels Confirms primary hyperthyroidism Problems in diagnosis Total serum T4 varies due to changes in binding protein levels High estrogens in pregnancy increase TBG synthesis Total T4 will be high, free T4 will be normal

  22. Hyperthyroidism Congenital TBG deficiency can also influence results Free T4 and TSH are first-line tests for thyroid dysfunction Treatment Antithyroid drugs: carbimazole, propylthiouracil Radioiodine: sodium 131I inhibits T4/T3 synthesis Surgery: thyroidectomy

  23. Thermogenesis (Heat production) Thermogenesis (Heat production) Humans are homeothermic (keep constant body temp.) Tightly controlled temperature homeostasis Thermogenesis is of two types: Obligatory: Basic heat production due to basal metabolic rate Facultative: On-demand extra heat production from metabolic activity in brown adipose tissue (BAT), skeletal muscle, etc. In BAT, the facultative thermogenesis is stimulated by sympathetic nervous system in response to cold temperature

  24. Sites of thyroid hormone regulation of metabolism 1 2 Hypothalamus-Pituitary- Thyroid Axis In response to feedback regulation, nutrition status and stress level regulation of TRH, TSH, and T4 release and central conversion of T4 toT3 4 Brown adipose tissue In response to sympathetic nervous system and bile acids D2 T3 UCP1 & thermogenesis and body weight 6 Pancreas In response T4 T3 effect on cell function & proliferation local 3 Liver 5 White adipose tissue In response to sympathetic nervous system T3 lipolysis & body fat In response to lipolysis in WAT effect on cholesterol and lipid metabolism and synthesis and release of bile acid Muscle In response T4 and to bile acid D2 & local T3 energy expenditure Mullur et al, Physiol Rev. 2014 Thyroid Hormone Regulation of Metabolism

  25. Thyroid Hormone and Thermogenesis Thyroid hormone has an essential role in thermogenesis: 1- Obligatory thermogenesis: ~ 30% of obligatory thermogenesis depends on thyroid hormone which is essential for temperature homeostasis 2- Facultative thermogenesis: in the absence of thyroid hormone, the thermogenic response of brown adipose tissue is substantially reduced

  26. The Mechanisms by which Thyroid Hormone Regulates Thermogenesis B The energy is then transferred from ATP to provide energy for biological processes A The energy released from substrate oxidation is captured in ATP A fraction of the energy is lost as heat without ATP production/consumption Thyroid hormone increases heat production by: Increasing ATP utilization / Reducing the thermodynamic efficiency of ATP synthesis Silva, Ann Intern Med. 2003;139:205-213: The Thermogenic Effect of Thyroid Hormone and Its Clinical Implications

  27. Mechanism of action of uncoupling proteins (UCPs): Example: UCP1 is present in the inner mitochondrial membrane of BAT. Other UCPs are ubiquitous The energy released in the oxidation of substrates in the mitochondria proton gradient The energy accumulated in this gradient is used the ATP Synthase to produce ATP i.e. oxidation is coupled to phosphorylation UCPs reduce the proton gradient, bypassing the ATP synthase exothermic movement of protons down the gradient heat (because oxidation is uncoupled to phosphorylation)

  28. Transport of protons

  29. Take home message Thyroid hormones include T4 , T3, and rT3 (which is inactive), they are synthesized by iodination, coupling and attaching to thyroglobulin protein. T3 is the active form of thyroid hormone and is synthesized by deiodinase in peripheral and central tissues. Thyroid hormone has wide spectrum of actions, for instance maturation of all body tissues, coordinating development and specific cell functions, metabolic regulation, and thermogenesis. Thyroid hormone is regulated by feed back mechanism. Several elements are involved in the regulation at the level of the hypothalamic nuclei, pituitary gland, thyroid, and peripheral tissues. TFT include measurement of TSH, total and free T4, total and free T3, and thyroid antibodies.

  30. Take home message Goiter is and enlarged thyroid gland, that can be associated with: Hypo-, Hyper, or Eu (normal) thyroid function Hypo and hyperthyroidism are differentiated based on their clinical picture, causes, diagnostic criteria, and treatment Thyroid hormone regulates both obligatory and facultative thermogenesis. It increases obligatory thermogenesis, by accelerating ATP turnover and reducing the efficiency of ATP synthesis It increases facultative thermogenesis: Thyroid hormone is necessary for an efficient response of BAT to cold

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