Download 2. Thyroid gland

Thyroid gland
By
Dr.Mohamed Abd AlMoneim Attia
Thyroid hormone synthesis
• Uptake of iodide by thyroid gland
• Oxidation of iodide to produce molecular iodine
• Organification
– Iodination of tyrosine residues on thyroglobulin
– Monoiodotyrosine (MIT) and diiodotyrosine (DIT).
• Coupling – formation of T4 and T3
• Proteolysis of thyroglubulin and secretion of thyroid
hormones
• Conversion of T4 to T3 in peripheral tissues
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Thyroid hormone synthesis
T
4
TBP T3
& Free T4 &
T3
(Iodide Organification)
4. Coupling
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Metabolism of thyroid hormones
Outer ring
Inner ring
(T4)
5’-deiodinase
(4X potent than T4)
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General principles
• T4 secretion is stimulated by thyroid-stimulating
hormone (TSH). In turn, TSH secretion is
inhibited by T4, forming a negative feedback
loop.
• The gland synthesizes T4 > T3 (20:1) but T3 is
4-times more potent than T4
• Most of the circulating T3 is derived from
peripheral deiodination of T4.
• B-blockers and corticosteroids inhibit
peripheral conversion of T4 into T3.
Thyroid hormones
• Mechanism of action
• T4 and T3 must dissociate
from
thyroxine
binding
globulin (TBG) in plasma
before entering into the cells.
• In the cells, T4 is deiodinated
to T3 that enters nucleus and
attaches to specific receptors
which promotes mRNA and
protein synthesis.
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Preparations of thyroid hormones
• L-thyroxine: a synthetic sodium salt of T4 (t ½ is 7
days).
• Liothyronine: a synthetic sodium salt of T3 (t ½ is
1 day).
Hypothyroidism (myxodema)
• Hypothyroidism in infants leads to cretinism .
• It is treated by replacement with L-thyroxin (T4).
• Children require more T4 than adults due to rapid
growth.
• During pregnancy, hypothyroid woman require
higher doses
• T3 has a shorter t ½ than T4 and is therefore used for
emergency treatment of myxoedema coma.
Management of myxedema coma
Management:
• Hospitalization in intensive care unit (ICU).
• All medications must be given intravenously .
• Intravenous fluids should be given with caution (can
aggravate hyponatremia commonly associated with
hypothyroidism and avoid excessive water intake.
• L-thyroxine (T4): 400 μg IV initially, followed by 50 μg
daily I͘ ntravenous .T3 can be used.
• Hydrocortisone: 200 mg I.V. because the patient
usually has associated adrenal insufficiency.
• Treatment of associated diseases e.g. infection or heart
failure.
Hyperthyroidism (thyrotoxicosis)
• It is a clinical syndrome results from high
levels of thyroid hormones.
• Clinical picture:.It resemble sympathetic
over-activity because thyroxin increases
sensitivity of B-receptors to circulating
catecholamines.
• There are tachycardia, arrhythmia, sweating,
exophthalmos, etc.
Investigations:
• Measuring serum T3, T4, and TSH: T4 is ↑ and TSH is
decreased
• Assay for positive thyroid antibodies: 90% +ve in
Grave's disease.
• Thyroid scan for tumors.
Management:
• Medical treatment: mainly for Grave’s disease
• Surgical thyroidectomy: mainly for multiple nodular
goiter
Antithyroid Drugs
1. Thiouracil drugs (thioamides):
• (Carbimazole - Methimazole - Propylthiouracil)
Pharmacokinetics:
• Methimazole is the active metabolite of Carbimazole.
• The t1/2 of propylthiouracil is 1.5 hr while the t1/2 of
methimazole is 6 hrs.
• The short t½ of these drugs has little effect on their
effect because they are selectively accumulated in
the thyroid.
• Propylthiouracil is preferable during pregnancy
because it does not cross placental barrier
(because it is strongly bound to plasma protein).
Mechanism of action:
• They inhibit oxidation of iodides by
inhibiting peroxidase enzyme.
• Propylthiouracil also inhibits the peripheral
conversion of T4 into T3.
• They have slow onset of action (3-4 weeks) but
propylthiouracil has faster effect (so it is used
in thyrotoxic crisis).
Doses and duration:
• Carbimazole (Neomercazole): start with 30
mg/d till reach euthyroid state (after 4-8
weeks) then maintain on 15 mg /d for 1-2
years (until the gland undergo spontaneous
remission).
• Propylthiouracil: start with 300 mg/d for 4-8
weeks then 150 mg/d for 1-2 years.
Adverse effects:
• Agranulocytosis & bone marrow depression.
• Hypothyroidism with
increased
size
and
vascularity of the gland due to ↑ TSH ͘
• Hypothyroidism of the infant (fetal goiter) if
given during pregnancy.
• Cholestatic jaundice.
• Hypersensitivity reactions: may require stopping of
the drugs.
• There is 50-68% incidence of relapse.
Precautions during thiouracil (thioamides)treatment:
• Therapy with thiouracil drugs should
continue for 1-2 years and should be
stopped gradually (to prevent relapse).
• Follow up with WBC count.
• If used during pregnancy, propylthiouracil is
the drug of choice.
2. β-blockers
• Propranolol
• It controls sympathetic over activity e.g. tachycardia
and arrhythmia.
• It ↓ insomnia, and tremors
• It inhibits peripheral conversion of T4 to T3.
• If propranolol is contraindicated give diltiazem
(calcium channel blocker).
3. Radioactive iodine
• It is an effective oral treatment for
thyrotoxicosis caused by Graves’ disease or by
toxic nodular goiter.
• Delayed hypothyroidism is the main adverse
effect so; replacement therapy with T4 is
required after functional ablation.
Contraindication:
• Pregnancy and lactation: I131 crosses placental
barrier and excreted in milk.
• Age < 16 years for fear of delayed malignant
changes.
4. Iodides
• Potassium iodides or Lugol’s iodine: (10% KI + 5%
iodine) is given 1-2 weeks before surgery in order to:
• Inhibit synthesis and release of T4 & T3.
• Inhibit release of TSH leading to ↓↓ size and
vascularity of the gland.
• Improvement in thyrotoxic symptoms occurs within
2-7 days, but if therapy with iodides is continued
(>2-4 weeks), the beneficial effects disappear and
manifestations of hyperthyroidism reappear (iodine
escape).
Therapeutic uses:
• Preparation of the patient before operation to
decrease size and vascularity of the gland.
• Treatment of thyroid storm .
Adverse effects:
• Metallic taste.
• Swollen salivary glands, mucous membrane ulceration
and gastric irritation.
• Increased lacrimal and nasal secretions (rhinorrhea).
• Allergic reactions: skin rash, drug fever, etc.
• Iodine escape if used > 2-4 weeks.
Preparation of patient before operation:
• Carbimazole: 10 mg t.d.s. 7-10 weeks before
operation to reach euthyroid state.
• Potassium iodide: 1-2 weeks before operation
to ↓ size and vascularity of the gland (see
below).
• Propranolol: to control HR and cardiac arrhythmia.
• Sedatives (phenobarbitone or diazepam): to ↓
anxiety ͘
Thyrotoxic crisis
(thyroid storm)
• It is a sudden severe exacerbation of the manifestations
of thyrotoxicosis due to sudden release of T3&T4
(medical emergency).
• It is a common postoperative complication if the patient
was not well-prepared.
Manifestations:
• High fever with vomiting and sweating
• Tachycardia and arrhythmia, occasionally heart failure
and shock.
• Convulsions, coma, and even death from heart failure.
Management:
• Intravenous fluids and antipyretics to control
dehydration and fever. Aspirin must be avoided because
it displaces thyroid hormones binding from thyroid
binding globulin (TBG)
• Propranolol: 1-2 mg slowly I.V. or 40 mg oral /6 hrs. It
controls excessive adrenergic response (tachycardia,
arrhythmia, tremors, etc.).
• Esmolol is short-acting β-blocker can be also given.
• If β-blockers are contraindicated give diltiazem orally or
by I.V. infusion.
• Potassium iodides: 10 drops orally/day to block
hormone release and peripheral conversion of T4 to
T3.
• Propylthiouracil: 250 mg/6 hrs orally to block
hormone synthesis. It acts more rapidly than
other thiouracil drugs.
• Hydrocortisone: 50 mg I.V./6h to elevates BP and
reduces toxemia. It also blocks peripheral
conversion of T4 to T3.
GOOD LUCK