2. O Acts by binding to a specific nuclear thyroid
hormone receptor (TR).
O T3 has a 15-fold higher binding affinity for TRs than
does T4.
O The hormone-receptor complex binds to DNA via
zinc fingers and increases/decreases the
expression of a variety of different genes that
code for proteins that regulate cell function.
O In humans, there are two TR genes, α and β.
O By alternative splicing, each forms at least two
different mRNAs and therefore two different
receptor proteins.

3. Schematic diagram of thyroid hormone mechanism of action.
The interaction of T3 with the TR that is bound as a heterodimer with
retinoid X receptor (RXR) to the thyroid hormone response element
(TRE), often in the 5′ flanking region of a T3-responsive gene, causes
either an increase or a decrease in the transcription of that gene.
coactivator proteins
corepressor proteins

4. O The active proteins are TRα1, TRβ1, TRβ2, and
TRβ3.
O There are tissue-specific preferences in
expression of the various TRs.
O TRβ2 is found only in the brain
O TRα, particularly TRα2, is thought to be important in the
hypothalamus and pituitary.
O TRα1 is expressed in all tissues, although its mRNA is
especially highly expressed in the kidney, liver.
O TRβ3 mRNA is expressed at very low levels but is more
abundant in the liver, kidneys, and lungs than in other
tissues.

5. O Experiments with inactivation of TRα and TRβ
have illuminated their different physiologic roles
O Feedback regulation of thyroid hormone effects
and cochlear development are functions of TRβ.
O Cardiac function and energy metabolism are
more likely to be regulated by TRα.
β
β
β β
β

7. Calorigenic Action
O T4 and T3 increase the O2 consumption of almost
all metabolically active tissues.
O Some of the calorigenic effect of thyroid
hormones is due to metabolism of the fatty acids
they mobilize.
O Thyroid hormones increase the activity of the
membrane-bound Na, K ATPase in many tissues
O The resulting increased metabolic rate increases
thermogenesis.
O Most of the effect of thyroid hormone are
secondary to its calorigenic effects.

8. Effects Secondary to Calorigenesis
O Increase in metabolic rate by T4 and T3 in
pharmacological dose increases N2 excretion; if
food intake is not increased, endogenous protein
and fat stores are catabolized and weight is lost.(
Catabolic action)
O In small doses causes positive N2 balance and
stimulate growth (Anabolic action).
O Excess catabolic effect along with marked
creatinuria leads to muscle fatiguability
(Thyrotoxic Myopathy)

9. O The potassium liberated during protein
catabolism appears in the urine, and there is also
an increase in urinary hexosamine and uric acid
excretion
O Bone protein mobilization Osteoporosis,
hypercalcemia and subsequent hypercalciuria.
O Hypothyroidism protein catabolism
accumulation of osmotically active
protein
conjugates under skin/subcutaneous tissue
coarse puffy skin (Myxoedema)

10. O Increased BMR increased use of co-
factors and vitamins Vitamin deficiency
in hyperthyroid state.
O Thyroid hormone is necessary for hepatic
conversion of β carotene to vitamin A.
O Decreased thyroid hormone increased
accumulation of β carotene in blood
(Carotenemia)
yellowish discoloration of skin.

11. Typical appearance of
patients with moderately
severe primary
hypothyroidism or
myxedema.
Carotenemia
versus
Jaundice

12. O T4 is essential for maintenance of lactation.
O Milk secretion is decreased in hypothyroidism and
stimulated by thyroid hormones.
O Thyroid hormone is involved in gonadal
development and secondary sexual
characteristics.
O In adult women, severe hypothyroidism may be
associated with diminished libido and failure of
ovulation.
O Secretion of progesterone is inadequate, and
endometrial proliferation persists, resulting in
excessive and irregular breakthrough menstrual
bleeding.

13. O In hyperthyroidism menstrual flow is initially
diminished and ultimately ceases reducing
fertility.
O Likely mechanism for menstrual changes:
O disruption in amplitude and frequency of LH/FSH
pulses caused by thyroid hormone influences on
GnRH signaling..
O “spillover” of elevated TSH stimulating the luteinizing
hormone (LH) receptor48 and elevated TRH initiating
excess prolactin release.
O A significant fraction of men with hypothyroidism
or hyperthyroidism have moderate to severe
erectile dysfunction that improves with treatment
of the thyroid disease

14. Effects on the Cardiovascular System

15. O Circulatory T3 enters the myocytes, combines with its
receptors, and enters the nucleus, where it promotes
the expression of some genes and inhibits the
expression of others.
O Those that are enhanced include the genes for a -
myosin heavy chain, sarcoplasmic reticulum Ca2+
ATPase, b-adrenergic receptors, G proteins, Na-K
ATPase, and certain K+ channels.
O Those that are inhibited include the genes for b-
myosin heavy chain, phospholamban, adenylyl
cyclase, T3 nuclear receptors, and NCX, the Na+–
Ca2+ exchanger.
O The net result is increased heart rate and force of
contraction

17. O The myosin containing β-MHC has less ATPase
activity than the myosin containing α -MHC.
O α -MHC predominates in the atria in adults, and
its level is increased by treatment with thyroid
hormone. This increases the speed of cardiac
contraction.
O Conversely, expression of the α -MHC gene is
depressed and that of the β -MHC gene is
enhanced in hypothyroidism.

18. Effects on the Nervous System
O Thyroid hormone is essential for the development of
the central nervous system.
O T4 deficiency in fetus or in infants causes:
O Defective myelination of axons of cortical region
O Defective branching of dendrites leading to defective
synapses
O Marked reduction in vascularity of brain
Net Result Infantile brain/mental retardation
O Thyroid hormone therapy must be given to a thyroid
hormone-deficient child during the first few months of
postnatal life to prevent mental retardation.(critical
period- 1 year of life)

19. O The parts of the central nervous system (CNS) most
affected are the cerebral cortex, the basal ganglia and
the cochlea .(mental retardation, motor rigidity, and
deafness).
O T4 deficiency in adults cause:
O Loss of all intellectual function
O Memory loss
O Decrease electrical activity of brain
O Slow, delayed and husky voice
O Eventually Psychosis (Myxoedema
Madness)
O T4 excess increases response to
catecholamines and stimulation of RAS
anxiety, nervousness, irritability, insomnia , rythmic
tremors etc

20. Effects on growth and development
O Thyroid hormone is essential for normal growth and
maturation of the skeleton.
O Growth failure in thyroid deficiency is caused by
impaired general protein synthesis, reduced growth
hormone, and especially reduced insulin-like growth
factor 1.
O A major way thyroid hormones promote normal body
growth is by stimulating the expression of the gene
for growth hormone (GH) in the somatotrophs of the
anterior pituitary gland.

21. O Impairment of linear growth leads to dwarfism
(cretinism) in which the limbs are disproportionately
short in relation to the trunk but cartilage growth is
unaffected.
O Children with prolonged hypothyroidism, even after
adequate treatment, do not reach predicted height
The consequences of untreated
congenital hypothyroidism are
demonstrated in this 17-year-old
girl.
Her tongue is enlarged, and her
extremities are inappropriately short
in relation to her trunk.

22. Effect on carbohydrate metabolism
O Dual and opposite effects
O Increases peripheral utilization of glucose can
cause hypoglycemia
O Can also cause hyperglycemia by :
O Increase absorption from GI tract
O Increase glycogenolysis in the liver
O Increase gluconeogenesis from pyruvate
O Increase breakdown of insulin
O Decrese secretion of insulin
O In hyperthyroidism, therefore, the plasma glucose
level rises rapidly after a carbohydrate meal,
sometimes exceeding the renal threshold.

23. Effects on lipid metabolism
O Thyroid hormones lower circulating cholesterol levels.
O The decrease in plasma cholesterol concentration is
due to increased formation of low-density lipoprotein
(LDL) receptors in the liver, resulting in increased
hepatic removal of cholesterol from the circulation.
O Thyroid decreases the stores of triglycerides and
phospholipids by increasing the activity of lipases i.e
increasing lipolysis
O Dextro –thyroxine (D-T4) and TETRAC are used
clinically as serum cholestrol lowering agents in
atherosclerosis

24. Effects on Hematopoietic System
O T4 deficiency leads to anaemia due to:
O In response to the diminished oxygen requirements and
decreased production of erythropoietin causing mild
normocytic, normochromic anemia.
O Decreased absorption ov vitamin B12,Folate deficiency from
malabsorption or dietary inadequacy may cause macrocytic
anemia.
O The frequent menorrhagia and the defective absorption of iron
resulting from achlorhydria may contribute to a microcytic,
hypochromic anemia.
O T4 excess stimulates erythropoiesis,increase production of
2,3 DPG in RBC shifting O2 dissociation curve to right.
O A parallel increase in plasma volume also occurs, with the
result that the hematocrit is normal.

25. Relation to Catecholamines
O The actions of thyroid hormones and the
catecholamines norepinephrine and epinephrine are
intimately interrelated.
O The functional synergism observed between
catecholamines and thyroid hormones,arises from the
ability of thyroid hormones to increase expression of
catecholamine receptors and the signaling effectors to
which they are linked.
O The reduced adrenergic responsiveness associated with
hypothyroidism has been linked to all steps of
catecholamine signaling, including receptor and
postreceptor actions, resulting in an impaired cAMP
response.

26. Catecholamines T4
• Epinephrine and nor epinephrine
increases BMR,stimulates
CNS,increases heart rate and
force of contraction
• T4 also has the same action but
is prolonged and slow
• Cannot increase BMR in absence
of T4
• T4 potentiate the action of
catecholamine and in their
presence increase in BMR by T4
is more
• Cause stimulation of Reticular
Activating System
• Same effect but :
T4 action on CNS and CVS can
be decreased after
sympathectomy
or by β blockers

28. Hypothyroidism
O Reduced circulating levels of free T4 and T3.
O The syndrome of adult hypothyroidism is generally
called myxedema.
O Children who are hypothyroid from birth or before are
called cretins.
O Hypothyroidism may be the end result of a number of
diseases of the thyroid gland, or it may be secondary
to pituitary or hypothalamic failure.
O Treatment is almost always with levothyroxine

29. Causes of Hypothyroidism
Primary Hypothyroidism
Acquired
• Hashimoto’s thyroiditis
• Iodine deficiency (endemic goiter)
• Drugs blocking synthesis or release of T4 (e.g., lithium, ethionamide,
sulfonamides, iodide)
• Goitrogens in foodstuffs or as endemic substances or pollutants
• Cytokines (interferon-γ, interleukin-2)
• Thyroid infiltration (amyloidosis, hemochromatosis, sarcoidosis,
• Postablative thyroiditis due to 131I surgery or therapeutic irradiation for
nonthyroidal malignancy
Congenital
• Maternal iodine deficiency
• Fetal thyroid dysgenesis
• Inborn errors of thyroid hormone synthesis
• Maternal antithyroid antibodies that cross the placenta
• Fetal hypopituitary hypothyroidism
Transient (Post-Thyroiditis) Hypothyroidism
Following subacute, painless, or postpartum thyroiditis
Consumptive Hypothyroidism
Rapid destruction of thyroid hormone due to D3 expression in large hemangiomas or hemangioendotheliomas
Defects of Thyroxine-to-Triiodothyronine Conversion
Selenocysteine insertion sequence–binding protein 2 (SBP2) defect
Drug-Induced Thyroid Destruction
Tyrosine kinase inhibitor (e.g., sunitinib)
Central Hypothyroidism
Acquired
Pituitary origin (secondary) Hypothalamic disorders (tertiary)
Bexarotene (retinoid X receptor agonist) Dopamine and/or severe illness
Congenital TSH deficiency or structural abnormality
TSH receptor defect

30. Signs and Symptoms of Adult
Hypothyroidism
Tiredness
Forgetfulness/Slower Thinking
Moodiness/ Irritability
Depression
Inability to Concentrate
Thinning Hair/Hair Loss
Loss of Body Hair
Dry, Patchy Skin
Weight Gain
Cold Intolerance
Elevated Cholesterol
Family History of Thyroid
Disease or Diabetes
Muscle Weakness/
Cramps
Constipation
Infertility
Menstrual Irregularities/
Heavy Period
Slower Heartbeat
Difficulty Swallowing
Persistent Dry or Sore Throat
Hoarseness/
Deepening of Voice
Enlarged Thyroid (Goiter)
Puffy Eyes

31. Various manifestations of
Hypothyroidism

32. Hyperthyroidism
O It is the condition resulting from increased circulating
levels of free T4 and T3.
O The term thyrotoxicosis, rather than hyperthyroidism,
should be used for this disorder because it need not be
associated with hyperfunction of the thyroid gland. The
term hyperthyroidism is reserved for disorders that result
from sustained overproduction and release of hormone by
the thyroid itself.
O It has various causes,the most common cause is Graves
disease (Graves hyperthyroidism), which accounts for
60–80% of the cases

33. Causes of Hyperthyroidism
Sustained Hormone Overproduction (Hyperthyroidism)
Graves’ disease (von Basedow’s disease)
Toxic multinodular goiter
Toxic adenoma
Chorionic gonadotropin-induced Gestational hyperthyroidism
Physiologic hyperthyroidism of pregnancy
Familial gestational hyperthyroidism due to TSH receptor mutations
Trophoblastic tumors
Amiodarone-associated hyperthyroidism due to iodide release
Metastatic functioning thyroid carcinoma
TSH-secreting pituitary tumors
Thyroid hormone resistance with pituitary predominance
Transient Hormone Excess (Thyrotoxicosis)
Thyroiditis
Autoimmune
Lymphocytic thyroiditis (silent thyroiditis, painless thyroiditis,
postpartum thyroiditis)
Acute exacerbation of Hashimoto’s disease
Viral or postviral
Subacute (granulomatous, painful, postviral) thyroiditis
Drug-induced or associated thyroiditis (Amiodarone,Lithium, interferon-α, interleukin-2,
GM-CSF)
Infectious thyroiditis
Exogenous Thyroid Hormone
Iatrogenic overreplacement
Ingestion of natural products containing thyroid hormone
Natural foodstuffs
Thyromimetic compounds (e.g., tiratricol PLB)
Occupational exposure to thyroid hormone (e.g., pill manufacturing,veterinary occupations

34. Nervousness/Tremor
Mental Disturbances/
Irritability
Difficulty Sleeping
Bulging Eyes/
Unblinking Stare/ Vision Changes
Enlarged Thyroid (Goiter)
Menstrual Irregularities/
Light Period
Frequent Bowel Movements
Warm, Moist Palms
First-Trimester Miscarriage/
Excessive Vomiting in Pregnancy
Persistent Dry or Sore Throat
Difficulty Swallowing
Palpitations/
Tachycardia
Impaired Fertility
Weight Loss or Gain
Heat Intolerance
Increased Sweating
Family History of
Thyroid Disease
or Diabetes
Sudden Paralysis
Hoarseness/
Deepening of Voice
Signs and Symptoms of Hyperthyroidism

35. Computed tomographic scans of orbits in two patients with Graves’ orbitopathy.
Rare thyroid acropachy in a patient with Graves’disease.
The hypermetabolic state leads to axial bone destruction

36. Test Hypothyroidism Hyperthyroidism
A. Based on metabolic Function
• BMR (Normal: ±10%) Decreases to – 30% to -40% Increases from +10% to
+100%
• S.Creatinine (0.2 to 0.6 mg/dl) decreases increases
• Fasting blood sugar decreases increases
• S.Cholestrol (120-200mg/dl) increases decreases
B. Based on handling of
Iodine
• Total S.T4(3-8µg/dl):S.T3( 0.15µg/dl) decreases increases
• Free S.T4(2ng/dl); S.T3(0.3ng/dl) decreases increases
• Protein bound Iodine (3.5-7.5µg/dl) decreases increases
• RAI123 uptake (normal: 20-40%) decreases <20% Increases>60%
• Serum TSH level (normal 2.3
µU/ml)
• Primary hypothyroidism-
decreases
• Secondary
hypothyroidism-
decreases
Decreases or
undetectable
C.Urine Calcium Loss decreases increases
T h y r o i d F u n c t i o n Te s t C o m p a r e d

37. Thank You…………..