2. Thyroid gland
– serves a cosmetic function of giving grace to
the contour of the neck ”
- Wharton (1656)
3. History
• Described by Galen
• Wharton (1656) - glandulae thyroideae
• Hyperthyroidism – Parry 1825
- Graves 1835
- Basedow 1840
• Murray (1891) - treated case of hypothyroidism
• Magnus Levy (1895) – effect of thyroid on metabolic rate
• Kendell(1915) – isolated thyroxine in crystalline form
• Harrington and Barger (1927) - synthesized thyroxine
4. Introduction
• Thyroid gland – a large gland in neck, secrete hormones that regulate
growth and metabolism.
• Weight – 25 -35 gm.
• Basic unit of thyroid gland – thyroid follicle
• Follicular cells secrete T3 and T4 & Parafollicular cells (C- cells)
secrete Calcitonin under TSH influence.
5. Chemistry and Synthesis
• T3 & T4 – iodine containing derivatives of thyronine
• Thyroxine (T4) – 3,5,3’,5’ tetroidothyronine
(T3) – 3,5,3’ tridothyronine
• Thyroid hormones are stored in thyroid follicle as part of TGB
molecule
6.
7.
8. Steps involved in Synthesis
1) Iodide trap by follicular cells
Trap with help of N+/I- Symporter in to follicular cells
2) Oxidation & Iodination
Pendrin transport Iodide into cytosol
Iodide oxidized Thyroid peroxidase Iodinium(I+)
H2O2 Hypoiodus acid (HOI)
Enzyme linked hypoiodate
(E-OI)
These combine with tyrosil residues of TGB to form MIT & DIT.
9. 3) Coupling
Iodinated tyrosil residues couple together under thyroid peroxidase
enzyme influence.
MIT + DIT – T3
DIT + DIT – T4
Oxidation and coupling both under TSH influence
4) Storage & Release
Iodinated Tyrosil & Thyronil reisdues remain as colloid & later
transported into interior of cells by endocytosis. Lysosomes engulf
colloid and acted upon by proteolytic enzymes. TSH influence present.
Free T3 & T4 released, MIT & DIT deiodinated.
10. 5) Transport of T3 & T4 into plasma & their protein binding
TBG – 75 % T3,T4 TBPA – 15 – 20 % TBA – 12 – 15 %
Free T3 – 0.5% Free T4 – 0.05%
6) Peripheral conversion of T4 to T3
Liver & kidney convert T4 T3
Target tissue need T3 for metabolic action
T4 DID – 1 T3 (Active) Propylthiouracil inhibit DID -1
DID – 2
Amiodarone inhibit DID – 1 & 2
T4 DID – 1 rT3 (Inactive)
DID – 3
11. Transport, Metabolism & Excretion
• Same as discussed
• Glucoronide / sulfate conjugation of hormones & deiodinated
products.
• Liver (primary), kidney & salivary glands are other metabolic sites.
• Conjugated metabolites excrete in bile followed by deconjugation in
intestines & again reabsorbed (Enterohepatic circulation).
• T ½ T4 – 6-7 days
T3 – 1-2 days
15. • T3, T4 penetrate by active transport in cell & bind to thyroid hormone
receptor (TR).
• Usually TR is in inactivated state & is bound to thyroid response
element (TRE) along with corepressors keeping gene transcription
suppressed.
• T3 bind to TR binding leads to heterodimerization with Retionoid X
Receptor (RXR). Conformational change releasing corepressor and
binding co-activator.
• Induces gene transcription, pattern specific mRNA, protein synthesis
& metabolic effects.
16. Physiological Actions
1. Growth & development
Mainly Milestone & CNS development
2. Intermediary metabolism
Lipids – enhance lipolysis (catecholamine's, lipolytic hormones)
Carbohydrate – Increased glucose utilization by cells
Glycogenolysis & Gluconeogenesis
Increased absorption
Diabetic like state
Proteins – Prolong action of T3 results in – ve nitrogen balance & tissue
wasting (Weight loss).
17. 3. Calorigeneis
Uncoupling of oxidative phosphorylation release excess energy & heat.
4. CVS
Increased peripheral demand, contractility & CO (Hyper dynamic state).
Up regulate Beta receptors.
5. Nervous system
Behavioural & functional effects.
6. Skeletal Muscle
Low – Weak & flabby muscles, High - tone, tremor
18. 7. GIT
Low - GI motility – Constipation
High - GI motility – Diarrhoea
8. Kidney
Increased urine frequency
9. Haemopoesis
Facilitate erythropoiesis. If low – anemia occurs.
10. Reproduction
Normal pregnancy & lactation. If Low – fertility impaired.
19. Thyroid Disorders
Hypothyroidism
a syndrome due to deficiency of thyroid hormones.
Irreversible mental retardation in children
More common in women.
20. 1. Cretinism
Hypothyroidism during foetal life
Mental retardation, pot bellied, yellow skin dwarfs (Cretins).
More weight due to decreased BMR
Due to Iodine deficiency OR presence of TSH receptor – blocking
antibodies.
Insulin resistance
Endemic cretinism – mother is iodine deficient
21. Rx
• Initial daily dose - L-T4 10–15 mcg/kg
• Doses adjusted at
4–6-week intervals during first 6 months,
2-month intervals during the 6–18-month,
then 3–6-month intervals
• Goal - maintain serum free T4 levels in the upper half of the
normal range, or slightly above the normal range, with a normal
TSH.
22. 2. Myxoedema
Hypothyroidism during adult years.
Antibodies against thyroid peroxidase or thyroglobulin
Severe hypothyroidism in which there is accumulation of
hydrophilic mucopolysaccharides in the skin and other tissues
making face to swell and look puffy.
Increased deposition of glycosamino glycan's.
Common in women.
23. Rx
• Supportive care and treatment of the precipitating cause
L-T4 - loading dose 200–300 mcg
- 24 hours later 100 mcg
IV daily maintenance dose
• Add - L-T3 - 10 mcg IV 8 hourly ( in young pts.)
• Overly aggressive treatment – may be associated with increased
mortality
24. 3. Myxoedema Coma
Medical emergency
Uncommon but life threatening form of untreated hypothyroidism
with physiological decompensation.
Occurs in patients with long standing hypothyroidism.
Precipitated by a climate induced hypothermia, infection, drug
therapy and other systemic conditions
Progressive mental deterioration
Increased mortality risk
25. Rapid Rx required
Ventilate pt. if respiratory acidosis is significant.
Immediate IV levothyroxine given
Loading dose of 500 - 800mcg followed by 50 – 100mcg daily.
Hydrocortisone 100 mg IV
Treatment of associated infection.
Correction of hyponatremia with saline.
Correction of hypoglycemia with IV dextrose.
27. 5. Non – toxic goitre
Endemic or Sporadic
Endemic – deficiency of iodine
Sporadic – Defect in hormone synthesis
Low T3, T4 Increased TSH Thyroid gland enlargement
more iodide trapped increased T3 synthesis
demands met patient euthyroid.
Rx – 150 – 200 µg of iodine daily ( iodized edible salt)
28. 6. Thyroid nodule
Excess TSH release causes a thyroid nodule
Rx – T4 therapy 2.6 µg/kg single oral daily dose
Stop Rx if no reduction in 6 months
7. Papillary Carcinoma of Thyroid
Excess TSH
Rx – T4 therapy 2.5 – 3.5 µg/kg/day
8. Hypothyroidism during pregnancy
Maternal TBG levels, so less free T4. Rx – L – thyroxine on
demand
29. Hyperthyroidism
Hyperthyroidism - T3, T4 production
Thyrotoxicosis - ingestion of thyroid hormones
1. Grave’s disease
Most common
Autoimmune disorder
Pt. produce TSH receptor stimulating Ab’s mimicking action of TSH,
no negative feedback.
T3, T4, TSH – R Ab’s & TSH is low.
30. Enlarged thyroid, exophthalmos are evident.
Rx
• Immediate control: Propranolol 40mg/6hr orally.
• Long term control: Anti thyroid drugs – Carbimazole 15mg TDS
initially and then reducing it to 5mg TDS for 12-18 months.
• Radio iodine ablation – Postmenopausal women and elderly
men.
• Thyroidectomy – If presence of large goitre and poor drug
compliance.
31. 2. Toxic – nodular goitre
Single adenoma – Plummer’s disease
Multiple adenoma – Multinodular goitre
Usually disease progress from non-toxic to toxic phase
Excess T3, T4
Rx - same as that of Grave’s disease but surgery is preferred.
32. 3. Subacute thyroiditis
Viral infection Enlarged & tender thyroid
Resolve over weeks or months.
If non – tender – called silent thyroiditis
Initially, T4 & T3 are elevated and TSH is low, but as the disease
progresses T4 & T3 will drop and TSH will rise
Rx
• In most cases only symptomatic Rx is necessary e.g.
acetaminophen 0.5 g four times daily
33. • If pain, fever, and malaise, a short course of NSAID or a
glucocorticoid such as prednisone 20mg three times daily for 7-
10 days may be necessary to reduce the inflammation.
• L-thyroxine is indicated during the hypothyroid phase of the
illness. 10% of the patients will require L-thyroxine long term.
34. 4. Thyroid storm
Extreme manifestation of thyrotoxicosis
Fatal & occurs in association with Grave’s or Toxic Nodular Goitre.
More common in pts. who are incompletely / not treated for
thyrotoxicosis.
Due to cytokine release & acute immunological disturbance.
If pt. not rendered euthyroid before surgery, increased risk.
CF – Fever, sweating, tachycardia, arrhythmias, diarrhoea, delirum,
Pul. Edema, stupor, coma & death.
35. Rx Aim
• To decrease both synthesis & release of thyroid hormones
• Block increased adrenergic activity
• Supportive measures
Propylthiouracil – 250 µg QID orally
Collosal Iodine (saturated KI solution) > 6 mg daily orally
OR
Sodium ipodate 1 g orally daily
Propranolol 1 – 2 mg slow IV f/b 40 – 80 mg oral
Hydrocortisone 100 mg IV f/b oral prednisolone
Diltiazem ( if propranolol CI) 60 – 120 mg BD oral
37. 5. Neonatal Hyperthyroidism
Some neonates born to mothers with Graves’ disease will be
hyperthyroid at delivery
Antithyroid drug therapy up to 12 weeks
• Propylthiouracil 5–10 mg/kg per day or
• Methimazole 0.5–1 mg/kg per day
One drop per day of SSKI (Saturated Solution of Potassium Iodide)
in the first few days.
38.
39. Thyroid Drugs
1. Levo-thyroxine (T4) Sodium
Preferred over Liothyronine (T3)
Sustained & uniform action
Low arrhythmic risk
Easily deiodinated to T3
Good oral BA
Long t ½ - once daily dose.
Sucralfate, iron, Ca+ & PPI reduce absorption (empty stomach).
40. 2. Liothyronine (T3) Sodium
Not freely available
Occasionally used IV along with L-thyroxine in myxoedema coma.
Costly, short t ½ .
Used in short term suppression of TSH in pts. undergoing thyroid
cancer surgery & in case of DID deficiency who fail to convert T4 to
T3.
41. Adverse effects
Tachycardia, palpitation, weight loss, diarrhoea, insomnia, heat
intolerance.
Rapid correction of hypothyroidism in IHD pts. can precipitate
angina.
Drug Interactions
TH therapy increase insulin requirement in diabetic pts.
Pts. on TH therapy need large doses of digoxin.
During concomitant therapy, doses of anticoagulants need to be
reduced.
43. Goitre may occur with treatment.
Methimazole – active metabolite of Carbimazole & 10 times more
potent than Propylthiouracil.
Orally absorbed, wide distribution, metabolized/excreted in urine.
Adverse effects
Reversible hypothyroidism & goitre ( TSH ) - overtreatment.
GI intolerance, skin rash, joint pain.
Loss of hair & taste, fever, cholestatic jaundice, lupus like reaction.
Rare important S/E – Agranulocytosis.
44. Doses
• Propylthiouracil – 50 – 150 mg TDS (MD: 25 – 50 mg TDS)
• Methimazole – 5 – 10 mg TDS (MD: 5 – 15 mg OD)
• Carbimazole – 5 – 15 mg TDS (MD: 2.5 – 10 mg OD)
Uses
Grave’s disease, Toxic Nodular Goitre (I 131).
Preoperatively – render pts. euthyroid.
Along with I 131 ( to prevent initial hyperthyroidism following I
131due to release of stored T4).
45. Advantages
No surgical risk, scar or injury.
Reversible hypothyroidism
Used in children / young adults.
Disadvantages
Long Rx / Relapse rate high.
Uncooperative / Unintelligent pt.
Drug toxicity
46. B. Inhibit Iodide Trapping ( Ionic Inhibitors)
Thiocynates, Perchlorates & Nitrates.
Block N+/ I+ symporter (NIS).
Perchlorates 10 more times potent than thiocynates in blocking
NIS.
These drugs not used due to toxicity.
47. C. Inhibit Hormone Release ( Iodine & Iodides)
Commonly used preps. are Lugol’s Iodine (collosal iodine 0.16 % or
aqueous KI solution).
Oldest remedy for thyroid disorder.
Excess iodide if introduced, shows Wolff Chaikoff effect resulting in
decreased T3, T4.
Inhibit hormone release ( Thyroid constipation), less vascular.
Effect fades after few days, gland escapes and hormone synthesis
resumes.
48. Uses
Preoperatively – surgery preparation in Grave’s disease. Lugol’s
Iodine given 10 days before surgery. Carbimazole added before
starting iodide to render euthyroid.
Thyroid storm – L.I. solution (6 – 10 drops) orally lowers hormone
release & conversion.
Prophylaxis of Goitre – as iodized salt
As antiseptic – tincture iodine, povidone iodine.
Adverse events
Acute reaction – iodine sensitive pts.
49. Chronic overdose (Iodism) – Inflammation of mucous membrane,
salivation, lacrimation, rhinorrhoea, burning sensation in mouth.
Iodide cause acne flare up.
D. Destroy Thyroid Tissue
Radioactive Iodine I 131, t ½ - 8 days.
I 131 emit X rays & Beta particles (destructive effect).
Large dose – concentrate colloid – destroy cells from inside.
Pyknosis, necrosis & fibrosis takes place.
Taken as sodium salt of I 131 in water orally.
52. E. Iodinated Contrast Media
Oral Ipodate, Ipanoic acid, Diatrizoate IV.
Richly iodinated compounds inhibit DID – 1 & 2. Also peripheral
conversion inhibited.
Used as adjunctive therapy with Thioamides.
Can develop resistance. Used for short term treatment of severe
hyperthyroidism (control T3).