Transcript Methods - Shantou University

Thyroid
 Anatomic
prominence; one of first endocrine
glands to be correlated with clinical condition
caused by malfunction
 Releases two types of hormones:
I. T3: triiodothyronine (59% iodine)
T4: thyroxine (65% iodine)
Important in growth and development; regulate
energy metabolism; maintain body temperature
II. Calcitonin: important in regulating calcium
metabolism
Thyroid
Thyroid gland unique- stores large
amounts T3 and T4
T3 and T4 synthesized and stored as
amino acid residues in thyroglobulinprotein, constitutes vast majority thyroid
follicular colloid
Thyroid Hormones (T3 and T4)
 Active
form: L–isomers
 Iodine essential part of both hormones
T3 59% iodine
T4 65% iodine
 T3
more potent than T4
 Bind to specific cell surface receptors on
sensitive targets; leads to increased uptake of
glucose and amino acids
 T3 also binds to cytoplasmic binding protein
leads to increased protein synthesis
 Starvation: decreasesT3 and T4 receptors
Thyroid Gland
Thyroid consists of follicles (vesicles) made up of
thyroid follicular cells; thyroglobulin
associated with inner surface of follicle
thyroglobulin
thyroid
follicular cell
(glycoprotein)
colloid
Thyroid follicle
(cuboid
epithelial cells)
Thyroid Gland
Thyroglobulin (TG)- synthesized at
colloid/cell interface
T3 and T4 synthesized and stored as
amino acid residues in TG
Thyroid Hormone Synthesis
1. Uptake of Iodide (iodide trapping)
2. Iodide organification
(oxidation and iodination)
3. Coupling of MIT and DIT
4. Secretion of thyroid hormones
5. Conversion of T4 to T3
1. Uptake of Iodide
 Iodide
trapping; iodide concentration in blood
normally very low; thyroid concentrates and
stores iodide
 Uptake involves transport of iodide from blood
into thyroid follicular cell
 Autoregulatory control:
decreased iodide storage  increased uptake
 Uptake stimulated by TSH from anterior
pituitary
 Inhibited by monovalent anions:
perchlorate, thiocyanate, pertechnetate
2. Iodide Organification
Oxidation and iodination of iodide
 Occurs
in thyroid follicular cell
 Thyroid peroxidase: oxidizes iodide to iodine
Heme containing enzyme; utilizes hydrogen
peroxide derived from oxidation of NADPH
as an oxidant; inhibited by: thionamides
 Iodine rapidly iodinates tyrosine residues in
thyroglobulin forming MIT (mono-iodotyrosine)
and DIT (di-iodotyrosine)
3. Coupling of MIT and DIT
Coupling reaction involves oxidation by
thyroid peroxidase
MIT + DIT  T3
DIT + DIT  T4
 Stored in thyroglobulin in colloid matrix


Synthesis: T4/T3 = 5:1; mostly T4 released

Inhibited by thionamides
4. Secretion of T4 and T3
 Proteolysis
releases T4 and T3 stored within
thyroglobulin (TG)
 Endocytosis of TG/colloid from follicular lumen
 Fusion with lysosomal granules containing
proteolytic enzymes
 Breakdown of TG and release of T4 and T3
 MIT and DIT deiodinated; iodine reutilized
 T4 and T3 reversibly bind to specific serum
proteins thyroxine binding globulin and
transthyretin; protect against metabolism
5. Conversion of T4 to T3
 80%
T4 converted to T3
 De-iodination of T4 (thyroxine) to active T3
(triiodothyronine) and to reverse T3 (inactive)
 Very low levels free T4 and T3 in blood
(0.04% T4, 0.4 % T3)
 T4
and T3 mostly bind to thyroxine binding
globulin (TBG): acidic glycoprotein, higher
affinity for T4 than T3
 Other T4 and T3 binding proteins (transthyretin):
decreased affinity
Regulation of Thyroid
Hormone Synthesis
Pituitary-Hypothalamus
Autoregulation
Abnormal stimulators
Pituitary-Hypothalamus
(-)
Hypothalamus
TRH
(-)
Anterior Pituitary
TSH
Thyroid
adenyl cyclase
T4 and T3
Thyroid Regulation
Autoregulation
Increased iodine
decreased iodide uptake
and organification (conversion to iodine)
Abnormal stimulators
Graves disease: production of thyroid stimulating
immunolglobulin (antibody) by lymphocytes;
mimics action of TSH; longer duration action;
autoimmune disease
Tumors: thyrotoxicosis- excessive hormone
production
Effects of Thyroid Hormones




Growth and Development
Calorigenic Effects
Cardiovascular Effects
Metabolic Effects
Growth and Development
Thyroid hormone (TH) regulates optimal growth
and development of all body tissue; stimulates
protein synthesis presumably by increasing
DNA transcription; TH critical for nervous,
skeletal and reproductive tissues
Cretinism: deficiency in iodine; failure of thyroid
to develop; dwarfism, mental retardation, pale
skin, slow heart rate, low body temperature
normal development-requires early diagnosis
and treatment
Calorigenic Effect
Thyroid hormones increase resting or basal
metabolic rate of whole organism
Most sensitive tissues: heart, skeletal muscle,
liver, kidneys
Thyroid hormones increase body temperature
Alterations in body temperature regulate TH
production
Cold
Increased T3 and T4 production
Cardiovascular Effects
Thyroid hormones:
increase heart rate
increase force of contraction
increased cardiac output
Mechanism:
Direct effect: binding to thyroid hormone
receptors in heart; not just response to
increased in basal metabolism
Indirect effect: Increased number of beta
receptors in heart
Metabolic Effects




Stimulate metabolism of
cholesterol to bile acids
Increase binding of LDL by liver
Increase carbohydrate
metabolism
Increase glucose uptake
Thyroid Hyperfunction
Signs and Symptoms










Increased body temperature
Increased motor activity
Increased sympathetic nervous
system activity
Skin- flushed, warm
Weak muscles; fatigue
Increased heart rate; arrhythmias; CHF
Increased appetite
Nervousness; jittery
Increased basal metabolic rate; decreased
cholesterol and triglycerides
Menstrual irregularities; decreased fertility
Thyroid Hyperfunction
Excessive secretion thyroid hormones
Difuse Toxic Goiter (Graves Disease)
-Characterized by thyrotoxicosis and opthalmopathy
-Most common in young, middle age females
-Autoimmune disease
-IgG antibodies to TSH receptors- activate receptors
 increased T3 and T4 release
-Genetic defect in TSH: increase TH  increase Ts-Ig
Toxic Nodular Goiter (Plummer’s Disease)
-Occurs in older patients
-Arises from long-standing nontoxic goiter
Treatment of Hyperthyroidism
 Agents
that interfere with production
of T3 and T4
 Agents that modify tissue responses
to T3 and T4
 Destruction of thyroid gland:
surgery; radiation
Thyroid Hyperfunction Treatment
 Antithyroid
drug therapy
 Thyroidectomy
 131Iodine
Thyroid Storm (thyrotoxic crisis)
life threatening; need immediate
treatment: propanolol
Anti-thyroid Hormone Drugs
Goitrogens: agents that decrease
production of TH
Thionamides
-methimazole (10x more potent)
-propylthiouracil
-carbimazole (UK)
Accumulate in thyroid
Thionamides
Mechanism of Action
 Inhibit
thyroid peroxidase catalyzed
reactions:
– Block iodine organification
– Coupling of MIT and DIT
 Inhibit
peripheral de-iodination of
T3 and T4
 Block
synthesis T3 and T4 not release,
therefore slow onset of action
Thionamides
Therapeutic Use
– Hyperthyroidism
Untoward Effects
– Relatively low incidence (3 – 12%)
– Most occur early
– Agranulocytosis (<1%)
Anti-thyroid Hormone Drugs
Anion Inhibitors
Monovalent anions:
resemble Iodide; competitve inhibitors
inhibit transport of iodide into thyroid
overcome by increased Iodide
– Perchlorate (ClO4-)
– Pertechnetate (TcO4-)
– Thiocyanate (SCN-)
Therapeutic use: Diagnostic
Anti-thyroid Hormone Drugs
Iodides
- Oldest remedy
- Paradoxical action
- Observe effects within 24 hours
- Maximum effects: 10 –15 days
- Effects temporarily
- Inhibit TH release*, inhibit organification of
iodide
- Decreased size and vascularity of
hyperplastic gland
- No longer used alone (thionamides)
Radioactive Iodine (131I)
- Rapidly absorbed (orally)
- Concentrated in thyroid
- Emits b radiation  destruction of thyroid
gland (painless)
- Short half life (8 d)
- Widely used to treat hyperthyroidism
- Disadvantage: delayed hypothyroidism
-Alternative: 123I; emits x-rays;
used for thyroid scans; half life = 13 hr
Iodinated Contrast Media
Ipodate and Iopanoic Acid
-Inhibit conversion T4 3 T in liver,
kidney, pituitary and brain
-Used in adjunct therapy
Adrenoceptor Blocking Agents
Many symptoms of thyrotoxicosis mimic
sympathetic stimulation
Need to use agents that rapidly deplete
catacholamines or b-blockers
Block physiologically effects of sympathetic
nervous system stimulation
Guanethidine
Propanolol
Thyroid Hypofunction
Thyroid hormone deficiency
(Gull’s Disease)
Hypothyroidism: mild
Myxedema: more severe symptoms
Degeneration or atrophy thyroid gland may be
associated with goiter
Hashimoto’s Thyroiditis: autoimmune
destruction of thyroid gland; most common
in US
Thyroid Hypofunction:
Signs and Symptoms
Pale puffy skin
Droopy eyelids
Decreased peripheral vascular resistance
Decreased heart rate and cardiac output
bradycardia
Decreased appetite
Lethargy, slowing of mental processes
Decreased kidney and reproductive function
(infertility)
Decreased basal metabolism
Children: mental retardation, dwarfism
Diagnosis and Treatment of
Hypothyroidism
Diagnosis: decreased T4 production;
presence of anti-thyroid antibody (autoimmune)
Treatment:
Replacement therapy with levothyroxine (T4);
Stable, long half-life (7 d), converted to T3; used
to treat hypothyroidism, myedemia, coma,
cretinism, simple goiter, nodular goiter