PHARM 2: Therapeutic Approaches to Thyroid Hormone Disorders Flashcards
What does High T4 and Low TSH indicate?
High T4, Low TSH = problem of the thyroid itself. The pituitary is trying to get the thyroid to decrease production by downregulating TSH but the thyroid is unresponsive
Hormones Secreted by the Thyroid?
Thyroxine(T4)/Triiodothyronine(T3): Normal growth and development + Energy metabolism
Calcitonin: control of plasma calcium
Steps of Synthesis and Secretion of Thyroid Hormone (T3/T4)?
Uptake of plasma iodide by the follicle cells
Oxidation of iodide and iodination of tyrosine residues in the thyroglobulin of the colloid
Secretion of thyroid hormone
Functional unit of thyroid?
Functional unit of thyroid is the follicle
Enzyme responsible for the oxidation of Iodine and Iodination of Tyrosine Residues?
Thyroperoxidase is the enzyme responsible for the oxidation of iodide ions to form iodine molecules (Requires H2O2)
- => Monoiodotyrosine (MIT)
- => Diiodotyrosine (DIT)
Two of these molecules are then coupled –MIT+DIT (T3) or DIT+DIT (T4)
Regulation of Thyroid Function from the Hypothalamus?
____________from the hypothalamus releases _____________ from the anterior pituitary.
- __________can inhibit production of TSH in a negative feedback loop
- ________________ stimulates TSH release while ______________ inhibits TSH release
Thyrotrophin-releasing hormone (TRH) from the hypothalamus releases Thyrotrophin (TSH) from the anterior pituitary.
- T3 & T4 can inhibit production of TSH in a negative feedback loop
- Protirelin stimulates TSH release while Somatostatin inhibits TSH release
Actions of Thyroid Hormones?
Metabolism
- General increase in metabolism of carbohydrates, fats, and proteins
- Modulate actions of other hormones (insulin, glucagon, glucocorticoids, and catecholamines)
- Increase in O2 consumption and heat production
Growth and Development
- Influence growth hormone production and potentiate its effects
- Skeletal development (calcitonin released from thyroid gland)
- Necessary for normal growth and maturation of CNS
Metabolic clearance of T3/T4?
Metabolic clearance of __________________ is 20x higher than ___________- Degraded mainly in_______ by deiodination
- Large pool of _______ in plasma: low turnover rate (6 days)- often given for hormone replacement
- Smaller pool of ______ in plasma: fast turnover rate and found intracellularly
Metabolic clearance of Triiodotyrosine (T3) is 20x higher than Thyroxine (T4)- Degraded mainly in liver by deiodination
- Large pool of T4 in plasma: low turnover rate (6 days)- T4 often given for hormone replacement
- Smaller pool of T3 in plasma: fast turnover rate and found intracellularly
Thyroid Hormone Signalling?
- Both Triiodotyrosine (T3)/Thyroxine (T4) are primarily bound to _____________________ in plasma
- ______ (‘prohormone ’) converted in vivo to ____
- The active form of thyroid hormone _____ binds to a nuclear receptor which then interacts with other promoters to induce or repress gene transcription
- Both Triiodotyrosine (T3)/Thyroxine (T4) are primarily bound to thyroxine-binding globulin (TBG) in plasma
- T4 (‘prohormone ’) converted in vivo to T3
- The active form of thyroid hormone T3 binds to a nuclear receptor which then interacts with other promoters to induce or repress gene transcription
Hyperthyroidism (clinical and biochemical signs)?
- Increased metabolic activity=> Weight loss
- Tremor
- Thyroid enlargement (Goitre)
- Endocrine exophthalmos –bulging of eye anteriorly
- Increased serum T4 + T3
- Decreased serum TSH (primary)
- Thyroid antibodies present (Graves’) => radioactive iodide uptake (RAIU) test increased
Bulging of the eye anteriorly is known as? Associated with what condition?
Endocrine Exophthalmos (Hyperthyroidism)
Most common cause of hyperthyroidism?
Test for this condition?
Graves Disease: immune system disorder caused by the production of antibodies that stimulate the TSH receptor resulting in the overproduction of thyroid hormones
Radioactive iodide uptake (RAIU) test also increased in Graves’ disease
Women with menopausal symptoms should have __________ tests as intolerance, palpitations, and irritability are common symptoms of both menopause and __________.
Women with menopausal symptoms should have thyroid function tests because heat intolerance, palpitations, and irritability are common symptoms of both the menopause and hyperthyroidism.
Primary vs. Secondary Hyperthyroidism TSH/T3/4 Levels?
Primary: LOW TSH / HIGH T3/T4
Secondary: HIGH TSH / HIGH T3/T4
Cause of Secondary Hyperthyroidism?
Treatment?
Pituitary Adenoma => Excess TSH stimulates T3/T4 production in the thyroid gland but fails to suppress TSH release from pituitary=> Elevated TSH, T3 and T4
Treatment: Surgery preferable, if unsuccessful then somatostatin/radiation can be used.
Treatment of Primary Hyperthyroidism?
Radioactive Iodine -Contraindicated in pregnancy.
Thioamides
- Methimazole (MMI): Inhibits thyroperoxidase
- Propylthiouracil(PTU): Centrally inhibits thyroperoxidase, peripherally inhibits deiodinase (preferable in the pregnant hyperthyroid)
β-Adrenergic Blockers (Propranolol):Blocks conversion of T4 to T3 and alleviates symptoms
Iodide (Lugol’s Iodine)
Lithium – those who cannot tolerate iodide
Surgery
Anti-Thyroid Drug preferred in treating hyperthyroidism in pregnancy?
Propylthiouracil(PTU) (Thioamide): Centrally inhibits thyroperoxidase, peripherally inhibits deiodinase
____________________: Blocks conversion of T4 to T3 and alleviates symptoms
β-Adrenergic Blockers (Propranolol): Blocks conversion of T4 to T3 and alleviates symptoms
MOA/Side Effects of Radioactive Iodine? What is it used for?
Used to treat primary hyperthyroidism
- Taken up by the thyroid and incorporated into thyroglobulin (One dose given, Half-life of 8-days –gone by 2 months)
- Emits β-irradiation that exerts cytotoxic action on thyroid follicles
- Hypothyroidism results => requiring life-long replacement therapy with thyroxine
- Contraindicated in pregnancy!!
MOA/Effectiveness of Thioamides (Methimazole (MMI)/Propylthiouracil(PTU))?
- Block synthesis of thyroid hormone by the thyroid gland by: inhibit thyroid peroxidase and Deiodinase (prevents conversion of T4 to T3)
- Don’t interfere with the cause (TSH Receptor antibodies)
- Require at least three weeks (6-8 usually) to lower thyroid hormone levels because they only block synthesis of new T4 and T3; they do not alter the effects of T3 and T4 that are already present in the thyroid and the bloodstream.
Thioamides: Propylthiouracil (PTU) vs. Methimazole(MMI)? IMPORTANT TO KNOW
Methimazole (MMI) advantages
Inhibits thyroperoxidase
10x more potent than PTU
Less toxic to the liver (severe hepatitis can occur with PTU)
Once daily dosing for MMI vs every 6-8h for PTU (both given orally)
Propylthiouracil(PTU) advantages
Inhibits both thyroid hormone production and peripheral conversion of T4 to T3 (Centrally inhibits thyroperoxidase, Peripherally inhibits deiodinase (prevents conversion of T4 to T3))
Less likely to cross the placenta during first trimester of pregnancy
Leading preventable cause of intellectual and developmental disabilities?
Iodine Deficiency
Conseqeunces of Iodine Deficiency?
Iodine deficiency can lead to thyroid enlargement (goitre) or in severe cases to cretinism (growth delays, developmental delays and abnormal features).
Moderate degrees of maternal iodine deficiency in pregnancy can lead to intellectual impairment in the baby.
Growth delays, developmental delays and abnormal features as a result of Severe Iodine Deficiency?
Cretinism
Thyroid enlargement as a result of Iodine deficiency?
Goitre
Conseqeunces of Iodine Excess?
Iodine is converted to iodide (I-) in vivo
Excess iodide temporarily inhibits the release of thyroid hormones => reduces size and vascularity of the gland
________ is converted to ________ (I-) in vivo
Iodine is converted to Iodide (I-) in vivo
Main Use of Potassium Iodide (Lugol’s iodine)?
Preparation for surgery and treatment of the thyroid storm (Excess iodide temporarily inhibits release of thyroid hormones => Reduces size and vascularity of the gland)
Goldilocks effect of Iodine?
Too little iodine causes hypothyroidism while large doses of iodine causes temporary inhibition of thyroxine (T4) production
Turnover of T3/T4 in the plasma?
Large pool of Thyroxine (T4) in plasma low turnover rate (6 days)
Smaller pool of Triiodotyrosine (T3) in plasma: fast turnover rate and found intracellularly
Effect of Protirelin (synthetic tripeptide) on the anterior pituitary?
Stimulates TSH release
___________ stimulates TSH release while __________ inhibits TSH release
Protirelin stimulates TSH release while Somatostatin inhibits TSH release
Role of the hypothalamic-pituitary axis?
The hypothalamic-pituitary axis regulates TSH release. Specifically, neurons in the hypothalamus release TRH, or thyroid-releasing hormone, which stimulates thyrotrophs of the anterior pituitary to secrete TSH. TSH, in turn, stimulates thyroid follicular cells to release thyroid hormones in the form of T3 or T4.
Thyroglobulin (TG) vs. Thyroxine-binding globulin (TBG)
Thyroglobulin (TG) is a protein made by the follicular cells of the thyroid gland. It is used by the thyroid gland to produce T3 and T4
Both Triiodotyrosine (T3)/Thyroxine (T4) are primarily bound to thyroxine-binding globulin (TBG) in plasma
Extreme symptoms of hyperthyroidism resultant from this acute, life-threatening metabolic state?
Thyroid Storm
Cause/Symptoms of Thyroid Storm?
Common after infection but can also be seen after discontinuation of anti-thyroid medication (Treatment for Graves esp.)
Patients can experience elevated body temp (over 40C), tachycardia, arrhythmia, vomiting and death
Thyroid Storm Treatment Strategy? (5)
Rapid and aggressive treatment essential
Therapeutic treatment similar to hyperthyroidism but given more frequently and in higher doses
- Remove excess hormone from the periphery (plasma apheresis)
- Inhibit secretion of new hormone (iodide)
- Inhibit the synthesis of new hormone (PTU)
- Inhibit peripheral conversion of T4 to T3 (Glucocorticoids and PTU)
- Inhibit adrenergic symptoms (Propranolol- Beta Blocker)
Pathology/Treatment of Graves’ Ophthalmopathy?
Insulin-like growth factor (IGF)-1 signaling implicated in pathology
Steroids or immunosuppressive drugs required to treat this condition in some patients
Conditions with Increased Serum TSH?
Secondary Hyperthyroidism (TSH-secreting pituitary adenoma)
Hypothyroidism
Conditions with Decreased Serum TSH?
Primary Hyperthyroidism (Graves Disease most comon)
Which types of hypothyroidism have Goitre, and which do not??
Present early in some hypothyroid cases (Hashimoto’s (Lymphoid infiltrate) & iodine deficiency)
Absent in others (radiation and TSH deficit)
Autoimmune mediated destruction of the thyroid cells?
Hashimoto’s Thyroiditis
Hashimoto’s Thyroiditis vs. Graves Disease
Hashimoto’s Thyroiditis: Antibodies to TSH receptor, iodine transporter, and anti-thyroglobulin produced from B-cells involved in the pathogenesis => Hypothyroidism
Graves Disease: Immune system disorder caused by the production of antibodies that stimulate the TSH receptor resulting in the overproduction of thyroid hormones
Treatment of Hypothyroidism?
L-thyroxine (T4) replacement therapy (levothyroxine):
Preferred therapy as body then converts T4 to T3 as required
Pregnant women require an increase in dose
L-triiodothyronine (T3) replacement therapy (liothyronine):
Faster onset of action but shorter duration of action
Often prescribed after surgery
Iodide
L-thyroxine (T4) replacement therapy drug?
Levothyroxine (Treats Hypothyroidism)
Preferred therapy as body then converts T4 to T3 as required
Pregnant women require an increase in dose
L-triiodothyronine (T3) replacement therapy drug?
Liothyronine (Treats Hypothyroidism)
Faster onset of action but shorter duration of action
Often prescribed after surgery
Causes of Neonatal Hypothyroidism?
Reversible/Irreversible?
Congenital hypothyroidism:inadequate thyroid hormone production in newborn infants. Fetal origin –can resolve if early detection /thyroid hormone therapy
Maternal iodine deficiency (Neurological Cretinism): Impaired cognitive development in fetus. Extreme cases –intellectual disability results (irreversible)
Can thyroid hormone be used to treat obesity?`
There is no consistent evidence that thyroid hormone treatment induces weight loss in euthyroid individuals with obesity.
Strategies for Thyroid Function Testing
Diagnosis of HIGH TSH confirmed with LOW T4?
Primary Hypothyroidism
Diagnosis of LOW TSH confirmed with HIGH T3?
Primary Hyperthyroidism
Diagnosis of HIGH TSH confirmed with HIGH T3?
Secondary Hyperthyroidism
Diagnosis of HIGH TSH confirmed with NORMAL T4?
Subclinical Hypothyroidism
Diagnosis of LOW TSH confirmed with NORMAL T4?
Subclinical Hyperthyroidism
Diagnosis of LOW TSH confirmed with LOW T3?
Secondary Hypothyroidism
Hypothyroidism vs. Hyperthyroidism (Clinical and Biochemical Signs)?
Hypothyroidism:
- Decreased metabolic activity
- Weight gain
- With Goiter (hashimoto’s & iodine deficiency); w/o Goiter (radiation and TSH deficit)
- Decreased serum T4 + T3
- Increased serum TSH (Primary)
- Decreased serum TSH (Secondary
Hyperthyroidism:
- Increased metabolic activity
- Weight loss
- Goiter
- Increased serum T4 + T3
- Decreased serum TSH (Primary)
- Increase Serum TSH (Secondary)
