Professional Documents
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Dr. M. Alzaharna (2014)
Thyroid Hormones
• The thyroid hormones are α-amino
acid derivatives of tyrosine
• Thyroxine & Triiodothyronine are
exceptionally rich in iodine, which
comprises more than half of their
molecular weight
• Thyroxine contains four atoms of
iodine and is abbreviated as T4
• Triiodothyronine, which has three
atoms of iodine, is abbreviated as
T3
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Dr. M. Alzaharna (2014)
Thyroid Hormone Biosynthesis & Secretion
• Iodide (I-) is transported into the
thyroid follicular cell by the
sodium/iodide symporter (NIS)
• Thyroglobulin (TG) is synthesized
by microsomes on the rough
endoplasmic reticulum (ER)
• Iodide reacts with tyrosine
residues in TG in the follicular
lumen to produce
monoiodotyrosyl (MIT) and
diiodotyrosyl (DIT) within the
peptide chain
• The TPO reaction also catalyzes
the coupling of iodotyrosines to
form thyroxine (T4) and some
• Iodide channel called pendrin (P)
triiodothyronine • Thyroid oxidase ( TO)
• Thyroid peroxidase ( TPO)
• Iodotyrosine deiodinase ( ITDI) 8
Dr. M. Alzaharna (2014)
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Dr. M. Alzaharna (2014)
Control of Thyroid Function
• The principal regulator of thyroid function is the
thyroid-stimulating hormone (TSH), which is
secreted by thyrotropes in the pituitary gland
• Binding of TSH to the G-protein coupled receptor
results in its activation and production of c-AMP
• Each step of hormone biosynthesis, storage, and
secretion appears to be directly stimulated by a c-
AMP-dependent process
• This lead finally to phosphorylation of proteins
including transcription factors and protein
production
• TSH also increases blood flow to the thyroid
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Dr. M. Alzaharna (2014)
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Dr. M. Alzaharna (2014)
Physiological Effects of Thyroid Hormones
• Growth and maturation
– Skeletal system
– C.N.S. DEVELOPMENT & FUNTION
• Metabolism
– Oxidative metabolism and thermogenesis
– Carbohydrate metabolism
• increases glucose absorption from the digestive tract,
glycogenolysis and gluconeogenesis
• and glucose oxidation in liver, fat, and muscle cells 14
Dr. M. Alzaharna (2014)
– CHO METABOLISM
• Increases:
– Glucose absorption of the GI tract
– Glucose consumption by peripheral tissues
– Glucose uptake by the cells
– Glycolysis
– Gluconeogenesis
– Insulin secretion
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Dr. M. Alzaharna (2014)
Physiological Effects of Thyroid Hormones
– Lipid metabolism
• The primary determinant of lipogenesis is not T3
– Nitrogen metabolism
• Cardiovascular system
– Cardiac output is increased in hyperthyroidism
and decreased in thyroid deficiency
• Autonomic nervous system
– Thyroid hormones increase the abundance of
receptors for epinephrine and norepinephrine in
the myocardium and some other tissues
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Dr. M. Alzaharna (2014)
• Brain----growth & development of nervous system
– VITAMIN METABOLISM
– HEMATOPOIETIC SYSTEM
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Dr. M. Alzaharna (2014)
Regulation of Thyroid Hormone
Secretion
• Secretion of thyroid hormones depends on stimulation of
thyroid follicular cells by TSH
– TSH absence: quiescent and atrophy of thyroid cells
– administration of TSH increases both synthesis and
secretion of T4 and T3
• TSH bears primary responsibility for integrating thyroid
function with bodily needs
• Secretion of TSH by the pituitary gland is governed by:
– positive input from the hypothalamus by way of
thyrotropin releasing hormone (TRH)
– and negative input from the thyroid gland by way of T3
and T4
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Dr. M. Alzaharna (2014)
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Dr. M. Alzaharna (2014)
Primary hypothyroidism
– Iodine deficiency- most common cause worldwide
– Congenital
– Autoimmune mediated
• Hashimoto’s thyroiditis- B lymphocytes invade thyroid
– Iatrogenic- post-thyroidectomy or radio-iodine
treatment
– Drug-induced – Anti-thyroid, lithium, amiodarone
– Severe infection
– Trauma to thyroid/pituitary/hypothalamus
– Absent or ectopic thyroid gland
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Dr. M. Alzaharna (2014)
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Dr. M. Alzaharna (2014)
• CONGENITAL HYPOTHYROIDISM
Treatment:
Supplemental Tx. With Levothyroxine
is “essential” for a normal C.N.S.
Development and prevention of
mental retardation
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Dr. M. Alzaharna (2014)
Hypothyroidism Symptoms
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Hypothyroidism Signs
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Dr. M. Alzaharna (2014)
• underproduction of thyroid hormones
slows metabolism, leading to fluid
retention and swollen tissues that can
exert pressure on peripheral nerves
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Dr. M. Alzaharna (2014)
Chronic Autoimmune Thyroiditis
(Hashimoto Thyroiditis)
• Occurs when there is a severe defect in thyroid hormone
synthesis
– Is a chronic inflammatory autoimmune disease characterized by
destruction of the thyroid gland by autoantibodies against
thyroglobulin, thyroperoxidase, and other thyroid tissue
components
– Patients present with hypothyroidism, painless goiter, and other
overt signs
• Persons with autoimmune thyroid disease may have other
concomitant autoimmune disorders
– Most commonly associated with type 1 diabetes mellitus
• Will often have significantly elevated anti-TPO ab
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Dr. M. Alzaharna (2014)
Endemic goiter
(occurs in the
deficit of iodine in
water, soil and air)
Connective tissue is
enlarged in gland and
it is increased in size
markedly
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Dr. M. Alzaharna (2014)
Hypothyroidism Treatment Goal
Euthyroidism
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Dr. M. Alzaharna (2014)
Therapy Initiation and Titration
• Therapy with levothyroxine sodium products requires
individualized patient dosing
– Careful titration: use a formulation with consistent doses
– Clinical evaluation: symptoms resolve more slowly than TSH
response
– Laboratory monitoring: need consistent, sensitive TSH
measurements
• Individualized patient dosing is influenced by
– Age and weight
– Cardiovascular health
– Severity and duration of hypothyroidism
– Concomitant disease states and treatment
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Dr. M. Alzaharna (2014)
• Levothyroxine sodium is the treatment of choice for the
routine management of hypothyroidism
– Adults: about 1.7 g/kg of body weight/d
– Children up to 4.0 g/kg of body weight/d
– Elderly <1.0 g/kg of body weight/d
• Clinical and biochemical evaluations at 6- to 8-week
intervals until the serum TSH concentration is normalized
• Given the narrow and precise treatment range for
levothyroxine therapy, it is preferable to maintain the
patient on the same brand throughout treatment
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Dr. M. Alzaharna (2014)
Primary Hypothyroidism Treatment
Algorithm
Initial Levothyroxine Dose
6-8 Weeks
Repeat TSH Test
TSH >3.0 IU/mL TSH <0.5 IU/mL
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Dr. M. Alzaharna (2014)
Hypothyroidism - Management
• Conservative
– Lifestyle - smoking cessation, weight loss
• Medical
– Levothyroxine (T4)
• Repeat TSH in 6/52
• Adjust dose according to clinical response and
normalisation of TSH
• Caution in patients with IHD- risk of exacerbation of MI
• Clinical improvement may not begin for 2/52
• Symptom resolution 6/12 if not consider +T3
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Dr. M. Alzaharna (2014)
Hyperthyroidism Causes
Hyperthyroidism (thyrotoxicosis) is excess thyroid hormone
– Autoimmune
• Graves Disease (76%)
– F>M, age 20-40
– IgG auto antibodies bind TSH receptors T3 & T4
– Leads to gland hyper function
– Toxic adenoma and toxic multinodular goitre
– Viral Thyroiditis (de Quervain’s)
• Fever and ESR- self limiting
– Exogenous Iodine
– Neonatal thyrotoxicosis
– Drugs- Amiodarone
– TSH secreting pituitary adenoma (rare)
– HCG producing tumour
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Hyperthyroid Symptoms
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Hyperthyroid Signs
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accumulation of hyaloronic acid in
dermis- manifestation of graves
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Dr. M. Alzaharna (2014)
Hyperthyroidism – Eye Disease
• Associated with Graves’ disease
– Inflammation of retro-orbital tissues
– Optic nerve compression atrophy
• Symptoms
– Eye discomfort, grittiness
– Excess tear production
– Photophobia
– Diplopia
– Decreased acuity
• Signs
– Exopthalmos- Graves
– Proptosis
– Opthalmoplegia
– Oedema
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Dr. M. Alzaharna (2014)
• Symptoms: • Signs:
– Hyperactivity – Tachycardia
– Irritability – Atrial fibrillation
– Dysphoria – Tremor
– Heat intolerance & – Goiter
sweating – Warm, moist skin
– Palpitations – Muscle weakness,
– Fatigue & weakness myopathy
– Weight loss with – Lid retraction or lag
increased appetite – Gynecomastia
– Diarrhea – * Exophtalmus
– Polyuria – * Pretibial
– Sexual dysfunction myxedema
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Dr. M. Alzaharna (2014)
• Investigating Thyroid Disease
• TSH- first thing you assess
– Normal range 0.5-5 U/ml
– Supressed= Hyperthyroid
– Elevated= Hypothyroid
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Dr. M. Alzaharna (2014)
TSH
TSH
TSH TSH
T3, T4 T3, T4
T3, T4 T3, T4
• Medical
– Symptomatic – β-blockers
– Carbimazole, propylthiouracil (50% relapse)
• Risk of agranulocytosis
– Radio-iodine treatment –avoid contact with
pregnant women and small children
• Long term likely to become hypothyroid
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Dr. M. Alzaharna (2014)
• Anti-thyroid drugs:
• Inhibit the iodination of tyrosyl residues in
thyroglobulin. They inhibit TPO catalysed
oxidation reaction.
• Propylthiouracil reduce the de-iodination of
T4 into T3 in peripheral tissues.
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Dr. M. Alzaharna (2014)
• Surgical
– Subtotal/total thyroidectomy
– Orbital decompression if thyroid eye disease causing
compression of optic nerve
• Beta blockers
• Corticosteroid therapy
• Bile acid sequestrants
• Iodide
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Dr. M. Alzaharna (2014)
• Treatment:
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Dr. M. Alzaharna (2014)
Which Treatment to choose?
Depends on:
• Patient preference
• Severity of hyperthyroidism
• Evidence of complications of
hyperthyroidism
• Pregnancy
• The cause of hyperthyroidism
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Dr. M. Alzaharna (2014)
Complications of Thyroid Disease
• Myxoedema
• Severe hypothyroidism (TSH T4 )
– Accumulation of mucopolysaccaride in subcutaneous
tissues
– Presents with
• Hyponatraemia
• Hypoglycaemia
• Hypotension
• Hypothermia
• Coma
• Confusion
• HF
• Anaemia
HIGH MORTALITY
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Dr. M. Alzaharna (2014)
Thyroid Storm
• Life threatening emergency (rare) – 30% mortality even with early
recognition and management
• Signs
– Fever
– Agitation and confusion
– Tachycardia +/- AF
• Management
• IV fluids
• Broad spectrum antibiotics
• Propanolol, digoxin
• Antithyroid drugs – sodium ipodate, Lugol’s solution, carbimazole
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Dr. M. Alzaharna (2014)
Thyroid Cancers
Type of tumour Frequency (%) Age at 20 year survival
presentation (%)
(years)
Papillary 70 20-40 95
Follicular 20 40-60 60
Medullary 5 >40 50
Lymphoma 2 >60 10
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Dr. M. Alzaharna (2014)
Investigating Thyroid cancers
• Serum calcitonin & CEA in Medullary cancer
• Radioactive iodine scan
• Ultrasound
• FNA
• CT scan- detects metastases
• MRI and PET scans- distant metastases
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Dr. M. Alzaharna (2014)
Definition of Subclinical
Hypothyroidism
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Dr. M. Alzaharna (2014)
Thyroid function tests
Estimation of thyroid Estimates of free
hormones hormone
• Total T4 concentration
• Total T3 • FT4E (T4 X %FT4)
Estimation of free • FT3E (T3 X % FT3)
hormone fraction • FT4I (T4 X THBR)
• Free T4 fraction %FT4 • FT3I (T3 X THBR)
• Free T3 fraction %FT3 • T4: TBG ratio
• THBR
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Dr. M. Alzaharna (2014)
Serum binding proteins • Anti TPO antibodies
• Thyroxine binding • TSH receptor anti
globulin bodies
• Thyroxine binding Other hormones &
prealbumin thyroid related
Tests for autoimmune proteins
thyroid disease
• TRH
• Anti thyroglobulin
Abs • Thyroglobulin
• Anti microsomal Abs • calcitonin
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Dr. M. Alzaharna (2014)
Measurement of T4,T3 &rT3
• METHOD
• Immunoassay
• Chemiluminiscence
• The major clinical role for T3 measurements are
in the diagnosis & monitoring of hyperthyroid pts
with suppressed TSH & normal FT4
• r T3 test is not always elevated with illness. It is
seldom used in pts with euthyroid sick syndrome
• Specifially, renal failure is associated with low r T3
conc.
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Dr. M. Alzaharna (2014)
FT4 index
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Dr. M. Alzaharna (2014)
TSH stimulation test
Measurement of serum T4 after TSH injection
• No response - primary
• Increase of T4- secondary
• Useful for distinguishing primary from
secondary hypothyroidism
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Dr. M. Alzaharna (2014)
TRH response test
• TRH administration will stimulate the production of TSH
• Useful for differentiating hypothalamic from a pituitary
hypotyroidism
• There is increase of TSH after TRH in hypothalamic disorder
If the hypothalamo pituitary axis is normal .the T3 and T4
secretions will be increased
An abnormal response is seen in
Hyperthyroidism – T4 elevated
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Dr. M. Alzaharna (2014)
Determination of thyroid binding
globulin
• TBG is the thyroid binding globulin with the
greatest affinity for T4
• TBG is very important for regulating the conc.
And availability of the FT4 hormone.
• Method - immunoassay
- commercial kit methods available
- chemiluminiscence
• Estrogen induced TBG excess and congenital
TBG deficiency are important abnormalities
that affect the test results
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• Thyroglobulin is used primarily as tumor marker in pts
carrying a diagnosis of differentiated thyroid carcinoma
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Dr. M. Alzaharna (2014)