Production of Thyroid Hormones.
Transport of T3 and T4.
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Regulation of Thyroid Hormones.
Actions of Thyroid Hormones.
Thyroid Hormone
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. There are two biological y active thyroid hormones:
Tetraiodothyronine (T4)- also k/a thyroxine.
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Triiodothyronine (T3)- Derived from modification of tyrosine.. Thyroid secretes-
. 80mg of T4 per day
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. 5mg of T3 per day. Additional 25mg/day of T3 is produced by peripheral conversion of T4.
. T3 has a much greater biological activity about 10 folds than T4.
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Production of Thyroid Hormones
IODINE Metabolism:
. Dietary iodine is absorbed in the GI tract.
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Taken up by the thyroid gland
Or removed from the body by the kidneys.
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. 80% of the iodine is lost in urine.. 20 % is taken up by the Thyroid follicular cells.
Production of Thyroid Hormones.......
IODINE Metabolism:
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. Transport of iodide into follicular cel s is dependent
upon a Na+/I- co-transport system.
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. Iodide(I?) taken up by the thyroid gland is oxidized byperoxide in the lumen of the follicle.
. Oxidized iodine(I) can then be used in production of
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thyroid hormones.
Production of Thyroid Hormones...........
Production Of Thyroglobulin:
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Pituitary produces TSH, which binds to follicle cell
receptors.
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Follicle cells produce thyroglobulin (glycoprotein).Thyroglobulin is released into the colloid space.
It 's tyrosine residues are iodinated by I.
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This results in formation of monoiodotyrosine or
diiodotyrosine.
Production of Thyroid Hormones...........
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. Thyroid hormone production and
release:
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T4 is approximately 95%.T3 is 5%.
Transport of Thyroid Hormones
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. Thyroid hormones are lipid-soluble.
. Found in the circulation associated with binding proteins:
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Thyroid Hormone-Binding Globulin(TBG) (~70% of hormone)Pre-albumin(Transthyretin) (~15%)
Albumin (~15%)
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. Less than 1% of thyroid hormone is found free in the circulation.
. Only free and albumin-bound thyroid hormone is biologically available to tissues.
Conversion of T4 to T3
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. T4 is converted to T3 in peripheral tissues by the
enzyme 5'monodeiodinase.
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. Large amount of T4 (25%) is converted to T3 inperipheral tissues.
. Conversion takes place mainly in the Liver and
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Kidneys.
T3 formed is then released to the blood stream.
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Equal amount of "Reverse T3" may also be formed(no biological activity).
Regulation of Thyroid Hormones
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. Thyroid hormone synthesis and secretion is
regulated by two main mechanisms:
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Regulation by the Hypothalamus and AnteriorPituitary.
"Auto Regulation" mechanism, which reflects
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the available levels of iodine.
Regulation of Thyroid Hormones........
Auto Regulation of Thyroid Hormone production.
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. Rate of iodine uptake and incorporation into thyroglobulin is influenced by theamount of iodide available: -
Low iodide levels increase iodine transport into follicular cells
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High iodide levels decrease iodine transport into follicular cells
Thus, there is negative feedback regulation of iodide transport by iodide.
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Regulation of Thyroid Hormones........ Neuroendocrine Regulation of Thyroid
hormones:
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Hypothalamo-pituitary-thyroid axis.
Regulation of Thyroid Hormones.......
. Influence of TRH:
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TRH is a hypothalamic releasing factor.
Travels through the pituitary portal system
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Act on Anterior Pituitary Thyrotrophic cells.TRH acts through G protein-coupled receptors
Activates the IP3 (Ca2+) and DAG (PKC) pathways
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Cause increased production and release of TSH.
Regulation of Thyroid Hormones.......
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. Role of TSH-TSH (glycoprotein) composed of two subunits:
Alpha subunit (common to LH, FSH, TSH, hCG)
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Beta subunit- specific for receptor binding and biological activity.
Action of TSH on Thyroid:
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TSH acts on fol icular cel s of the thyroid.Increases iodide transport into fol icular cel s
Increases production and iodination of thyroglobulin
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Increases endocytosis of col oid from lumen into fol icular cel s
Regulation of Thyroid Hormones.......
.Regulation of TSH release from the anterior
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pituitary:
TSH release is influenced by-
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Hypothalamic TRH.Thyroid hormones themselves.
Thyroid hormones exert NEGATIVE FEEDBACK on TSH
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release:
Inhibition of TSH synthesis.
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Decrease in pituitary receptors for TRH.Regulation of Thyroid Hormones.......
.Other Factors Regulating Thyroid Hormone levels:
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Diet:
High carbohydrate diet- increases T3 levels, resulting in increased metabolic rate (diet-induced thermogenesis).
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Low carbohydrate diet- decrease T3 levels, resulting in decreased metabolic rate.Cold Stress: increases T3 levels in other animals, but not in humans.
Any condition that increases body energy requirements (e.g., pregnancy, prolonged cold) stimulates
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hypothalamus.
Actions of Thyroid Hormones
1. Essential for normal growth of tissues, including the nervous system.
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Lack of TH during development results in short stature and mental deficits (cretinism).
2. Thyroid hormone stimulates or increase Basal Metabolic Rate(BMR).
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3. Required for GH and prolactin production and secretion4. Required for GH action
5. Increases intestinal glucose reabsorption (glucose transporter)
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6. Increases mitochondrial oxidative phosphorylation (ATP production)
7. Increases activity of adrenal medulla (sympathetic; glucose production)
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8. Induces enzyme synthesisResult: stimulation of growth of tissues/increased metabolic rate/Increased heat production (calorigenic effect)
Actions of Thyroid Hormones.....
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.Effects of Thyroid Hormone On Nutrient sources:
Effects on PROTEIN synthesis and degradation:
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Low level of TH- increased protein synthesis (low metabolic rate; growth)High level- increased protein degradation (high metabolic rate; energy)
Effects on CARBOHYDRATES:
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low doses of TH- increase glycogen synthesis (low metabolic rate; storage of energy)
high doses- increase glycogen breakdown (high metabolic rate; glucose production
Actions of Thyroid Hormones.....
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.One Major Target Gene Of T3:
Na+/K+ ATPase Pump:
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o Pumps sodium and potassium across cel membranes to maintain resting membrane potentialo Activity of the Na+/K+ pump uses up energy, in the form of ATP
o About 1/3rd of al ATP in the body is used by the Na+/K+ ATPase
T3 increases the synthesis of Na+/K+ pumps, markedly increasing ATP consumption (BMR increases).
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T3 also acts on mitochondria to increase AT P synthesis (size and number of mitochondria wil increase).
The resulting increased metabolic rate increases thermogenesis (heat production).
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Actions of Thyroid Hormones......Thyroid hormone actions which increase oxygen consumption
Increase mitochondrial size, number and key enzymes.
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Increase plasma membrane Na-K ATPase activity.
Increase futile(ineffective) thermogenic energy cycles.
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Decrease superoxide dismutase activity..Effects of thyroid hormones on the cardiovascular system
Increase heart rate
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Increase force of cardiac contractions
Increase stroke volume
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Increase Cardiac outputUp-regulate catecholamine receptors
Actions of Thyroid Hormones.....
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.Effects of thyroid hormones on the Respiratory System:Increase resting respiratory rate
Increase minute ventilation
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Increase ventilatory response to hypercapnia and hypoxia
.Effects of thyroid hormones on the Renal System:
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Increase blood flowIncrease glomerular filtration rate(GFR)
.Effects of thyroid hormones on Oxygen-carrying Capacity:
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Increase RBC mass
Increase oxygen dissociation from hemoglobin
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Actions of Thyroid Hormones...... Effects of thyroid hormones on intermediary metabolism
Increase glucose absorption from the GI tract
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Increase carbohydrate, lipid and protein turnover
Down-regulate insulin receptors
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Increase substrate availability. Effects thyroid hormones in growth and tissue development:
Increase growth and maturation of bone.
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Increase tooth development and eruption.
Increase growth and maturation of epidermis, hair fol icles and nails.
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Increase rate and force of skeletal muscle contraction.Inhibits synthesis and increases degradation of mucopolysaccharides in subcutaneous tissue.
Thyroid function test
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Thyroid function tests.Biochemical tests used to investigate thyroid function:
Tests that establish whether there is thyroid dysfunction-
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TSH
T4
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T3Tests to know the cause of thyroid dysfunction-
Thyroid auto-antibody
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Serum thyroglobulin measurements
Thyroid enzyme activities
Thyroid function tests......
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. TSH:
The single most sensitive, specific and reliable test of thyroid status.
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. Total T4 and Total T3:More than 99% of T4 and T3 circulate in plasma bound to protein.
Both change if [TBG] alters (e.g. in pregnancy).
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. Free T4 and Free T3:
Free thyroid hormone concentrations are independent of changes in TBGs.
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More reliable for diagnosis of thyroid dysfunction.Thyroid function tests......
.Indications of TFT:
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Diagnosing thyroid disorder in symptomatic person
Screening new-born for hypothyroidism
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Monitoring thyroid replacement therapy in hypothyroidism patientsDiagnosis & monitoring female infertility patients
Screening adults for thyroid disorders
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Thyroid function tests....... TSH:
First line test in Thyroid function tests
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Normal TSH level excludes thyroid dysfunction
Uses:
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Screening for euthyroidismScreening of hypothyroidism in newborns
Diagnosis of 1 & 2 hypothyroidism
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Diagnosis of clinical & subclinical hyperthyroidism
Follow up of T3 & T4 replacement therapy in hypothyroidism
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Methods of TSH estimationRadioimmunoassay/ Immunometric assay/ Chemiluminiscent & flourescent techniques.
Normal values: TSH 0.4 to 4mU/L
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Thyroid function tests......
. Total thyroxine:
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Total thyroxine includes free as well as protein bound thyroxine.Normal levels: 5 to 12.5ug/dL, largely bound to transport protein espTBG.
. Free T4:
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Small fraction of total T4 unbound to protein
Metabolically active form and (0.05%) of total T4
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Do not get affected by TBG levels.Measurement useful in conditions where TBG levels are affected
Normal levels: 0.89- 1.76ng/dL
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Thyroid function tests....... Free and Total T3
Normal plasma level T3 are very low.
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Metabolical y more active, shorter half life, faster turn over.
Free T3 ? (0.5%) of total and useful with altered protein level.
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T3 level: 80 to 180ng/dl and fT3 level: 1.5 ? 4.1pg/mL.Measured by immunoassays.
Uses:
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Diagnosis of T3 thyrotoxicosis
Early diagnosis of hyperthyroidism
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Thyroid function tests....... Thyroglobulin:
Synthesised & secreted by thyroid follicles(30ng/ml)
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Reflects thyroid mass, thyroid injury & TSH receptor stimulation
Raised level- Grave`s disease/ Thyroiditis/ Nodular goitre
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Indications:Monitoring recurrence of certain variants of thyroid Ca
Thyroid dysgenesis in Congenital hypothyroidism
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Follow up of patients with thyroid malignancy
Thyroid function tests......
. Thyroid Autoantibodies:
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Diagnosing autoimmune diseases
Autoantibodies-
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Anti-Tg antibodyAnti-microsomal antibody
TSH-Receptor antibody (inhibitory or stimulatory)
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non Tg colloid antigen
Thyroid function tests......
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. Anti-Tg antibodies:Methods:
Agar gel diffusion precipitation test
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Tanned red cell haem agglutination tests(TRCH test)
ELISA/ Immunofluorescence of tissue section/ RIA
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Positive:Hashimoto`s thyroiditis
Grave`s disease
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Myxoedema
Nontoxic goitre
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Thyroid caPernicious anaemia
Thyroid function tests......
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. Anti-microsomal Abs (also k/a Anti-TPO Abs):Methods:
CFT
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Immunofluorescence tests
TRCH assay/ ELISA/ RIA
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Positive:Grave`s disease
Hashimoto`s thyroiditis
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More frequently positive for autoimmune diseases than Tg Ab.
Thyroid function tests......
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. Thyroid receptor antibody:2-Types:
TBI- Grave`s disease.
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TSIgs- Grave`s disease/ Predicting relapse or remission in hyperthyroidism/ development of neonatal
hyperthyroidism.
Thyroid function tests......
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. Thyroid scan
Advantages:
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Distinguishes diffuse glandular activity from patchy pattern seen in goitreFunctional classification of nodules: Warm, Hot, Cold
In association with thyroid suppression regimes, TSH dependent or autonomous nature of hot nodules
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Information regarding size, shape, position of gland
Identification & localisation of functioning thyroid tissue in ectopic or metastatic sites
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Helps on differentiating various causes of thyrotoxicosisThyroid function tests......
. Thyroid scan
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Indications:
Thyroid nodule
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Diffuse or multinodular goitreClinical hyper- or hypothyroidism
Evaluation of substernal mass
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R/O Ectopic thyroid tissue
Subacute thyroiditis, early phase
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Contraindications:Pregnancy
Lactation
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Thyroid function tests....... Whole body scan I-131:
Post-operative evaluation for thyroid remnant or functioning metastasis
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Follow up patients after I-131 ablation or I-131 treatment
Serum Tg rising
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Suspected tumour recurrenceSuspected functioning metastases (either local or distant metastases)
Radiological imaging
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. Ultrasound
Scoring-
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five categories of ultrasound findings.Higher the score
Higher the TR (TI-RADS) level
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and likelihood of malignancy.
Cytology of thyroid
. FNAC thyroid:
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Indications:
Diagnosis of diffuse non toxic goitre
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Diagnosis of solitary or dominant thyroid noduleConfirmation of clinically obvious malignancy
Complications:
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Local haemorrhage & haematoma.
Transient laryngeal nerve paresis.
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Tracheal punctureRarely, needling causes formation of a hot nodule
Main limitation: Inability to distinguish between follicular adenoma & carcinoma.
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Cytology of thyroid....
.FNAC thyroid
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Procedure:Materials-
? Syringes & syringe holder(pistol)
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? 22-25 gauge needle
? Cotton Swabs
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? Alcohol bottles for wet fixationCytology of thyroid....
. FNAC thyroid:
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Smearing, fixation & stainingRapid smearing
Air dried stained with giemsa
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Alcohol fixed smears stained with Pap
Sample adequacy
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Six groups of fol icular cel sEach containing 10 to 20 cel s on two separate slides