Thyroid Gland Lecture (Dr. Lopez) Flashcards
Thyroid Gland
- Produces the Prohormone RETRAIODOTHYRONIN (T4) and Active Hormone TRIIODOTHYRONINE (T3)
- The Thyroid Follicle is the Functional Unit of the Gland
a) Surrounded by a single-layer of Epithelial Cells
b) Follicular Lumen itself is filled with Colloid
c) Size of the Epithelial Cells and Amount of Colloid change with activity
- Also contained C Cells:
a) Parafollicular Cells
b) Secrete CALCITONIN - Receives RICH Blood Supply
Thyroid Hormone are Synthesized by the Follicular Epithelial Cells
- Colloid is composed of Newly Synthesized Thyroid Hormones attached to THYROGLOBULIN
- Epithelium sits on a Basal Lamina (Outermost part of the Follicle)
The Secretory products of the Thyroid Gland are Iodothyronines
- Thyroid Hormones contain LARGE Amount of IODINE
- Synthesis of the Hormones occurs part INTRACELLULARLY and part in the EXTRACELLULAR Compartment
- T4 is the MAJOR Secretory Product (T4: T3 ratio is as HIGH as 20:1)
**T4 is produced very rapidly and there is 10x more T4 than T3 produced!!!!!
Peripheral Conversion of T4 and T3
- PERIPHERAL Conversion occurs through the Action of DEIODINASE
a) 10 to 20% of Circulating T3 comes from Direct Secretion from Thyroid Gland
b) 80 to 90% is produced by PERIPHERAL CONVERSION
- Provides circulating T3 for UPTAKE by other tissues in which T3 Supply is TOO LOW
- There are some Clinical States associated with a Reduction in the Conversion of T4 to T3:
a) Fasting
b) Medical and Surgical Stress
c) Catabolic Diseases
Factors affecting the Conversion of T4 and T3
INCREASE Conversion:
- Obesity
- Cold Exposure
- Hyperthyroid
DECREASE Conversion:
- Pregnancy
- Fasting
- Beta Blockers
- Hepatic and Renal Failure
- Aging
- Hypothyroid
Synthesis of Thyroid Hormones is Complex
1) Synthesis of TG; Extrusion into Collicular Lumen
- Site: ROUGH ER, Golgi Apparatus
2) Na+, I- Cotransport
- Site: BASAL MEMBRANE
- Inhibited by PERCHOLARATE, THIOCYANATE
3) Oxidation of I- —> I2
- Site: APICAL (Luminal) MEMBRANE
- Enzyme: PEROXIDASE
- Inhibitor: PTU
4) Organification of I2 into MIT and DIT
- Site: APICAL MEMBRANE
- Enzyme: PEROXIDASE
- Inhibitor: PTU
5) Coupling Reaction of MIT and DIT into T3 and T4
- Site: APICAL MEMBRANE
- Enzyme: PEROXIDASE
- Inhibitor: PTU
6) Endocytosis of Tg
- Site: APICAL MEMBRANE
7) Hydrolysis of T4 and T3; T4 and T3 Enter Circulation
- Site: LYSOSMES
- Enzyme: PROTEASES
8) Deiodination of residual MIT and DIT recycling of I- and Tyrosine
- Site: INTRACELLULAR
- Enzyme: DEIODINASE
*****When the availability of IODIDE is Restricted, the formation of T3 is favored!!!!
**PTU is an Effective TREATMENT for HYPERTHYROIDISM
****High levels of I- INHIBIT Organification and Synthesis of Thyroid Hormones: WOLFF-CHAIKOFF EFFECT!!!!!!!!!!!!
Levels of Iodine/ Iodide in the Thyroid Gland
- Iodine is STORED and IODINATED as TYORSINES of Thyroglobulin (8,000 Microgram toal, of which 600 microgram is T3 and T4)
- Enough Hormone is stored as IODINATED TG in the Follicular Colloid to last the body for 2 to 3 Months!!!
Activity of Thyroid Gland
- The activity of the Thyroid Gland can be assessed by RADIOACTIVE IODINE Uptake
1) Hyperthyroidism
2) Extreme Stimulation of Thyroid Gland (High Turnover0
- Ex: Graves’ Disease, associated with Thrytoxicosis
3) Normal
- Perchlorate can inhibit
4) Hypothyroidism
Transport of Thyroid Hormones
- Circulate in the Bloodstream either bound to Plasma Proteins (99%) or free (1%)
- There is an Equilibrium between Bound and Free circulating T3 and T4 in the bloodstream
Main Binding Proteins:
1) THYROXINE- BINDING PROTEIN (TBG) (70%)
- Synthesized in the Liver
- Binds 1 molecule of T3 or T4
- Has HIGHER Affinity for T4 than T3
2) TRANSTHYRETIN (TTR) (10 to 15%)
3) ALBUMIN (15 to 20%)
- ***Most circulating Thyroid Hormone is T4!!!
- T4 Half Life: 6 days
- T3 Half Life: 1 day
Changes in the Blood Levels of TGB alter then fraction of Free Thyroid Hormone
1) HEPATIC FAILURE (Decrease Blood Levels of TBG)
- Transient INCREASE in the Level of FREE T3 and T4
- Followed by INHIBITION of Synthesis of T3 and T4 (Negative Feedback)
2) PREGNANCY (Increase TBG Levels)
- INCREASE Bound T3 and T4 = DECREASE Free T3 and T4
- The Transient DECREASE in Free T3 and T4 causes and INCREASE in Synthesis and Secretion of T3 and T4
- INCREASE Total levels of T3 and T4 but levels of Free, Physiologically Active, Thyroid Hormones are normal (Person say to be Clinically EUTHYROID)
Major Controls of the Synthesis and Secretion of Thyroid Hormones via the HPT Axis
1) Role of TSH is t Regulate:
- The Growth of the Thyroid Gland (Trophic Effect)
- The Secretion of Thyroid Hormones
2) TSH is Regulated by:
- Thyrotropin-Releasing Hormone (TRH)
- Free T3
3) TSH Secreiton, in Contrast to the Secretion of GH, occurs at a Steady Rate
Actions of TSH on the Thyroid Gland
- cAMP is the Second Messenger for TSH
- TWH has two Types of actions on the Thyroid Gland:
1) INCREASES the Synthesis and Secretion of Thyroid Hormones
2) TROPHIC Effect on Thyroid Gland
Thyroid Stimulating Immunoglobulins stimulate TSH Receptor without TSH Hormone
- TSH levels are LOWER than NORMAL because the High Circulating Levels of Thyroid Hormones INHIBITS TSH Secretion!!!
Summary of Factors affecting Thyroid Hormone Secretion
STIMULATORY FACTORS:
- TSH
- Thyroid Stimulating Immunoglobulins
- Increased TBG Levels (Ex: Pregnancy)
INHIBITORY FACTORS:
- Iodide Deficiency
- Deiodinase Deficiency
- Excessive Iodide Intake (WOLFF-CHAIKOSS EFFECT)
- Perchlorate, Thiocyanate
- Propylthiouracil (PTU)
- Decreased TBG levels (Ex: Liver Disease)
New Proteins are Synthesized under the Direction of Thyroid Hormones
1) Vast array of New Proteins:
- Na+/ K+ ATPase
- Transport Proteins
- B1-Adrenergic Receptors
- Lysosomal Enzymes
- Proteolytic Proteins
- Structural Proteins
2) In Most Tissues, Synthesis of Na/ K_ ATPase is stimulated by THYROID HORMONES
3) In Cardiac Muscle Cells:
- Myosin
- B1 Adrenergic Receptors
- Ca2+ ATPase
4) In the Liver and Adipose Tissue, Thyroid Hormones include the Synthesis of Key Metabolic Enzymes
Thyroid Hormones has a wide range of Actions in the Human Body
GRWOTH:
- Growth formation
- Bone Maturation
CNS:
- Maturation of CNS
BMR:
- Incr Na+/ K+ ATPase
- Ince O2 Condumption
- Incr Heat Production
- Incr BMR
METABOLISM:
- Incr Glucose Absorption
- Incr Glycogenolysis
- Incr Gluconeogenesis
- Incr Lipolysis
- Incr Protien Synthesis and Degradation (Net Catabolic)
CARDIOVASCULAR:
- Incr Cardiac Output
Thyroid hormones Increase Basal metabolic Rate (BMR)
- The Increased activity of the Na+/ K+ ATPase accounts for MOST of the Increase in the Metabolic Rate
- *** This leads to an INCREASE in O2 Consumption and Heat Production
- The Increase in BMR produced by a single dose of Thyroxine (T4) occurs after Several Hours but is Long Lasting (> 6 hrs)
***HYPERTHYROIDISM leads to a HIGH BMR, while HYPOTHYROIDISM causes a LOW BMR
Thyroid Hormones on Glucose Absorption
- Thyroid Hormones INCREASE Glucose Absorption and potentiates the effects of other Hormones on GLUCONEOGENSIS, LIPOLYSIS, and PROTEOLYSIS
Actions of Thyroid Hormones on Metabolism
1) LIPID METABOLISM:
A) Stimulate FAT Mobilization –> Increased Concentration of FA in Plasma
B) Enhance OXIDATION of FA
C) Plasma Concentration of Cholesterol and Triglycerides are INVERSELY Correlated with Thyroid Hormones
- INCREASED Blood Cholesterol concentration in Hypothyroidism
D) Required for conversion of CAROTENE to VITAMIN A
- Hypothyroid Patients can suffer from Blindness and yellowing of Skin
2) CARBOHYDRATE METABOLSIM
- Increased Gluconeogenesi and Glycogenolysis to generate Free Glucose
- Enhancement of Insulin-Dependent Entry of Glucose into Cells
Cardiovascular Effects of Thyroid Hormones
INDIRECT:
- Incr Heat Production and CO2 in Tissues
- DECR Peripheral Vascular Resistance
- DECR Diastolic Blood Pressure
- Reflex INCR Adrenergic Stimulation
DIRECT:
- INCR Cardiac Muscle
- Myosin Heavy Chain Alpha/ Beta ratio
- Na+/ K+ ATPase
- Sarcoplasma Ca-ATPase
- Beta Adrenergic Signaling
- G Protein Stimulator/ Inhibitor Ratio
- INCR Ventricular Contractility and Function
- DECR Peripheral Vascular Resistance
- *****All of these lead to INCREASED CARDIAC RATE AND OUTPUT!!!!!!!!!
- Increased Blood Volume
Thyroid Hormones stimulates the Synthesis of Cardiac B1 Adrenergic Receptors
- When Thyroid Hormone levels are High, the Myocardium has an Increased number of B1 Receptors and it more Sensitive to Stimulation by SYMPATHETIC Nervous System
Sympathetic: NE = Beta 1
- Positive Effect on HR and Muscle Contraction
Parasympathetic: ACh = M2
- Negative Effect on HR and Muscle Contraction
Additional Effects of Thyroid Hormones
1) GROWTH:
- Thyroid Hormones act SYNERGISTICALLY with GH and SOMATOMEDIN to promote Bone Formation
2) CNS
- Thyroid Hormones are important for CNS Maturation
- Deficiency fo Thyroid Hormones during the PERINATAL period leads to:
A) Abnormal Development of Synapses
B) Decreased Dendritic Branching and Myelination - Neural Changes induced by Thyroid Hormone Deficiency during the Perinatal period are IRREVERSIBLE and lead to CRETINISM unless Replacement Therapy is started soon after birth
Thyroid Pathophysiology
1) METABOLISM: A) Excess: - Heat Intolerance - Weight Loss - INCR BMR
B) Deficiency:
- Cold Intolerance
- Weight Gain
- Decr BMR
2) BONE:
A) Excess:
- Osteoporosis
B) Deficiency:
- Stunted Growth
3) CNS: A) Excess: - Agitation - Anxiety - Difficult Concentrating - Hyperreflexia
B) Deficiency:
- Cretinism (Congenital)
- In Adults: Listlessness, Slowed Movement, Somnolence, Impaired Memory, Decr Mental Capacity
4) SKIN
A) Excess:
- Sweating
B) Deficiency:
- Myxedema
5) CV SYSTEM A) Excess: - Tachycardia - Atrial Fibrillation - Palpitations - High output Heart Failure
B) Deficiceny:
- Bradycardia
- Decr Contractility
- Decr Cardiac Output
- Heart Failure
6) INTESTINE
A) Excess:
- Diarrhea
B) Deficiency:
- Constipation
Causes of Hypotheyroidism
PRIMARY:
- Agenesis
- GLAND DESTRUCTION (Ex: Surgical Removal, Irradiation, Autoimmune Disease, Idiopathic Atrophy)
- ** HASHIMOTO’S THYROIDITS
- Inhibition of Thyroid Hormones Synthesis and Release (Ex: Iodine Deficiency, Inherited Enzyme Defects, Drugs that Interfere with Thyroid Homeostasis)
- Transient (Ex: After surgery or Therapeutic Raidoiodine, Postpartum, Thyroiditis)
SECONDARY:
- Hypothalamic Disease
- Pituitary Disease (Ex: SHEEN’S Syndrome)
- Resistance to Thyroid Hormoens
General Symptoms of Hypothyroidism
- DECR BMR
- DECR Heat production
- Cold Sensitivity
- Weight Gain
- Positive Nitrogen Balance
- Positive Nitrogen Balance
- DECR Cardiac Output
- Hypoventilation
- Lethargy
- Dropping Eyelids
- Myxedema
- Growth Retardation
- Mental Retardait (Perinatal Period)
- Goiter
- Menstrual Dysfunction
Treatment of Hypothyroidism
REPLACEMENT DOSES of T4:
- Because Metabolism of T4 DECREASES and the Plasma Half-Life INCREASES with Age, Higher Doses are required in younger Patients
- In Women beyond, Menopause, Overprescribing T4 can contribute to the development of OSTEOPOROSIS
Hashimoto’s Thyroiditis
- Thyroid Hormone Synthesis is impaired by THYROGLOBULIN or TPO Antibodies, which leads to a DECREASE i T3 and T4 Secretion
- TSH Levels are HIGH!!!
(Have Trophic Effect aka GOITER)
Cretinism
CAUSES:
- Impaired development of Thyroid Gland
- Maternal Intake of Anti-thyroid Medication or Excess Iodine
- Inherent Deficient in the Synthesis of Thyroid Hormones
SYMPTOMS:
- Feeding Problems
- Respiratory Difficulty
- Protruding Tongue
- Curse Facial Features
- Growth Retardation
- Mental Retardation
- Jaundice
- Dry Skin
- Hypotonia
**UNTREATED POSTNATAL HYPOTHYROIDISM results in CRETINISM!!!!!!!!
Hypothyroidism due to Iodine Deficiency
- Leads to tangent DECREASE in the Synthesis of Thyroid hormone
- TSH Levels are Elevated
GOITER:
- If the Gland Maintains normal Blood Levels of Thyroid hormones, patient is EUTHYROID and Asymptomatic
- If Gland cannot maintain Normal Blood Levels of Thyroid Hormones, patient exhibits Hypothyroid
Hyperthyroidism
- Due to the Thyroid Hormone OVERPRODUCTION (Thyrotoxicosis = Hyperthyroidism)
1) PRIMARY HYPERTHYROIDISM:
A) Graves Disease (Most Common cause of Thyrotoxicosis)
**MAJOR CLINICAL SIGNS: Exophthalmos (Abnormal Protrusion of the Eyeball) and Periorbital Edema (Due to Recognition by the Anti-TSH Receptor Antibodies of a Similar EPITOPE within the Orbital Cells)
- *DIAGNOSED BY: Elevated Serum FREE, Total T4 or T3 levels, and Clinical Sings of GOITER and OPHTHALMOPHATY
- *TSH levels are LOW (Due to Negative Feedback by HIGH Levels of Thyroid Hormones)
* *Presence of Circulating TSI (Thyroid- Stimulating Immunoglobulins)
- These help distinguish GRAVES Disease from Adenoma of Pituitary Thyroptrophs (A SECONDARY ENDOCRINE DISEASE)
2) Other Causes:
- TSH Secreting Pituitary Adenoma (SECONDARY HYPERTHYROIDISM)
3) TSH Levels:
- Decrease due to NEGATIVE FEEDBACK of T3 on the Anterior Lobe of the Pituitary Gland
- If defect is in the Anterior Pituitary TSH levels are INCREASED
Circulating levels of TBG can be Indirectly assessed using T3 Resin UPTAKE TEST
- A Resin with Anti T3 Antibodies on it ABSORBS T3
- TBG also binds to T4 and T3
Changes in the Blood Levels o TBG and Free Thyroid Hormones in Clinical Scenarios
1) HYPERTHYROIDISM
- Incr T4
- Incr T3 Resin Uptake
2) HYPOTHYROIDISM
- Decr T4
- Decr T3 Resin Uptake
3) HIGH TBG
- INCR T4
- DECR T3 Resin Uptake
4) LOW TBG
- DECR T4
- INCR T3 Resin Uptake
5) HEPATIC FAILURE
- DECR TBG
- INCR T3 Resin Uptake
6) PREGNANCY
- INCR TBG
- DECR T3 Resin Uptake
In General about Thyroid
- HYPERHTYROIDISM (Too much Thyroid Hormone in the Bloodstream): INCREASES the speed of Bodily Functions and Leads to Weight Loss, Sweating, Rapid Heart Rate, and High Blood Pressure, among other Symptoms
- HYPOTHYROIDISM (Not enough Thyroid Hormone of the Body’s Needs): Without enough Thyroid Hormone, Many of the Body’s Functions SLOW DOWN; People may have symptoms such as fatigue, Weight Gain, and Cold INTOLERANCE
Goiter
- Goiter can develop in response to MULTIPLE Imbalances and Disease within the HPT Axis, Coexisting with Hypothyroidism, Euthyroidism (Normal), and Hyperthyroidism
These Imbalances Include:
1) HYPERTHYROIDISM:
- Excessive Stimulation of the TSH Receptor by an AUTOANTIBODY (Graves Disease)
- Excessive Secretion of TSH from a TSH-Producing TUMOR (Ex Secondary Hyperthyroidism)
- Thyroid Hormone- Producing (TOXIC) Adenoma (NODULAR) or Toxic Multinodular Goiter
2) PRIMARY HYPOTHYROIDISM
- Lack of adequate IODINE in the Diet (Nontoxic Goiter, Edemic Goiter)
- Sporadic Hypothyroidism of unknown Etiology (Nontoxic Goiter)
- Chronic Thyroiditis (Hashimoto Disease; Autoimmune Induced Deficiency in Thyroid Function)
The TSH Test is Used for Diagnosing BOTH Hyperthyroidism and Hypothyroidism
HYPERTHYROIDISM: 1) Gaves Disease A) TSH: Decrease B) T3/T4: Increase C) TSI: POSITIVE D) Radioactive Iodine Uptake Test: INCREASE
2) Thyroiditis (With Hyperthyroidism) A) TSH: Decrease B) T3/T4: Increase C) TSI: Negative D) Radioactive Iodine Uptake Test: DECREASE
3) Thyroid Nodules (Hot, or Toxic) A) TSH: Decrease B) T3/T4: Increase C) TSI: Negative D) Radioactive Iodine Uptake Test: INCREASE or NORMAL
HYPOTHYROIDISM: 1) Hashimoto's Disease (Thyroiditis, EARLY Stage) A) TSH: Increase B) T3/T4: DECREASE or NORMAL C) Antithyroid Antibody: POSITIVE
2) Hashimoto’s Disease (Thyroiditis, LATER Stage)
A) TSH: Increase
B) T3/T4: DECREASE
C) Antithyroid Antibody: POSITIVE
3) Pituitary Abnormality
A) TSH: DECREASE
B) T3/T4: DECREASE
C) Antithyroid Antibody: NEGATIVE
