(5) GI & Endo: Thyroid etc (3.1-3.4) Flashcards
What cell type is responsible for iodine uptake and thyroid hormone production?
What cell type is responsible for iodine uptake and thyroid hormone production?
How is iodide transported into the thyroid follicular cell?
Na+/I- symporter
Where is thyroglobulin found?
Thyroid follicu-LAIR lumen
Name 3 functions of thyroid peroxidase
(1) Oxidation of I- → I2
(2) Organification of thyroglobulin
(3) Coupling of iodinated tyrosine residues
In what compartment is thyroid hormone cleaved off of thyroglobulin?
Follicular cell’s cytoplasm
Is T3 or T4 more potent?
T3
What enzyme converts T4 to T3 in the peripheral tissues?
5’ deiodinase
Broadly, what can we attribute the symptoms of hyperthyroidism to?
↑ β-adrenergic receptors
(⇒ Hypermetabolic and hyperadrenergic state)
Which thyroid disorder causes exophthalmos?
Graves disease
Adverse Effects (3) : I131 ablation therapy
(1) Hypothyroidism
(2) Exacerbation of hyperthyroidism
(3) Exacerbation of Graves ophthalmopathy
* (Exacerbation of ophthalmopathy MOA: Rapid reduction in thyroid hormone ⇒ ↑ TSH ⇒ Binds pre-adipocytic fibroblasts ⇒ ↑ Glycosaminoglycan and adipose deposition)*
MOA: Propylthiouracil
(1) Inhibits TPO
(2) Inhibits 5’ deiodinase
MOA: Methimazole
Inhibits TPO
(TPO: thyroid peroxidase enzyme; involved in iodide oxidation & organification)
(Methimazole is 10x more potent than Propylthiouracil and is usually the DOC. The exception is in FIRST trimester of pregnancy)
MOA: β-blockers (in treating hyperthyroidism)
(1) β-blocker
(2) Inhibit 5’ deiodinase
MOA: Glucocorticoids (in treating hyperthyroidism)
Inhibits 5’ deiodinase
Which pharmacologic treatment of hyperthyroidism is particularly effective against Graves’s ophthalmopathy?
Glucocorticoids
(Glucocorticoids induce lymphocyte apoptosis and ∵ ↓ production of autoantibodies ⇒ ↓ Fibroblast proliferation ⇒ ↓ Ophthalmopathy)
Treatment: Thyroid storm
(1) β-blockers
(2) Methimazole
(3) Glucocorticoids
* (Methimazole preferred over PTU∵ of increased efficacy)*
Adverse Effects (3) : Propylthiouracil (unique from methimazole)
(1) Hepatotoxicity
(2) Maculopapular rash
(3) ANCA-associated vasculitis
Name 3 adverse effect that Propylthiouracil and Methimazole share
(1) Agranulocytosis
(2) Aplastic anemia
(3) Drug-induced lupus
Treatment: Hypothyroidism (in a first-trimester pregnant woman)
Propylthiouracil
(Methimazole is contraindicated in the first trimester due to teratogenicity, whereas PTU is contraindicated in second and third trimester due to risk of hepatotoxicity)
Name a T4 analog
Levothyroxine
Treatment: Radioactive iodine exposure
Anions
(Such as perchlorate, pertechnetate, and thiocyanate which inhibit the Na+/I- symporter)
Suffix: Biphosphonates
“-dronate”
Biphosphonates have a chemical structure similiar to what molecule?
Pyrophosphate
Name 3 ways biphosphonates affect osteoclasts
(1) Inhibit bone adherence
(2) Inhibit recruitment/development
(3) Induce apoptosis
Other than osteoporosis, what can biphosphonates be used to treat?
(1) Hypercalcemia
(2) Paget’s Disease
* (Note: Calcitonin has similar indications, but is the second line)*
Adverse Effects (3) : Biphosphonates
(1) Corrosive esophagitis
(2) Osteonecrosis of jaw
(3) Hypocalcemia
What is the mechanism of estrogen therapy in the treatment of osteoporosis?
Inhibit osteoclast precursor development
What drug is an estrogen agonist in bone but antagonist in the breast and uterus?
Raloxifene
How does parathyroid hormone stimulate osteoclasts?
↑ RANKL on Osteoblasts
(⇒ Osteoclast activation)
MOA: Denosumab
anti-RANKL antibody
Does calcitonin bind receptors on osteoclasts or osteoblasts?
Osteoclasts
How does Calcitonin reduce serum calcium?
(1) Inhibits osteoclasts
(2) ↓ Renal Ca2+ reabsorption
Name two hormones which upregulate RANKL
(1) PTH
(2) Calcitriol
Name two mechanisms of negative feedback on PTH
(1) ↑ Ca2+
(2) ↑ Calcitriol
* (A rare instance where ↑ intracellular Ca2+ inhibits exocytosis)*
What effect does the RANK-RANKL interaction have on osteoclasts?
(1) Differentiation
(2) Activation
* (RANKL is upregulated by PTH, whereas osteoprotegrin is upregulated by Calcitriol)*
What effect does PTH have on osteoblasts?
Maturation of pre-OB → OB
(The net effect of PTH is bone resorption. Vit. D also stimulates OB maturation)
What effect does PTH have on renal electrolyte handling?
(1) ↑ Ca2+ reabsorption
(2) ↑ PO42- excretion
Name 3 ways PTH elevates serum [Ca2+]
(1) Activates osteoclasts
(2) ↑ Renal Ca2+ reabsorption
(3) Activates Vitamin D
MOA: Teriparatide
PTH analog
Identify an important physiologic distinction between Teriparatide and endogenous PTH
(1) Teriparatide: Net bone formation
(2) Parathormone: Net bone resorption
* (Pulsatile Teriparatide ⇒ bone formation. Constant dosing would likely instead lead to bone resorption)*
Indication: Teriparatide
Osteoporosis
What are the source(s) of Vitamin D3?
(1) Dairy products
(2) UVB radiation
* (Vit. D3 = Cholecalciferol. The 3 of Vit. D3 to remember Cholecalciferol starts with the third letter of alphabet)*
What are the source(s) of Vitamin D2?
Plants
Describe how dietary Vitamin D is converted into the active form
(1) 25-hydroxylated in the liver
(2) 1-hydroxylated in the kidney
* (∴ Calcitriol would be indicated over Vit. D2/D3 in the setting of renal/liver disease)*
What effect does Calcitriol have on renal electrolyte handling?
(1) ↑ Ca2+ reabsorption
(2) ↑ PO42- reabsorption
What effect does Calcitriol have on GI electrolyte handling?
(1) ↑ Ca2+ reabsorption
(2) ↑ PO42- reabsorption
Indication: Topical Vit. D
Psoriasis
(Vit. D plays an important role in T-cell homing to skin ∴ topical Vit. D exerts immunomodulatory effects)
Name 2 endocrine etiologies of hypocalcemia treated with Calcitriol
(1) Hypothyroidism
(2) Hypoparathyroidism
MOA: Cinacalcet
Activates CaSR in parathyroid gland
- (CaSR = calcium-sensing receptor)*
- (⇒ reduced secretion of PTH and ∴ is helpful against renal osteodystrophy secondary to CKD)*
Indication: Cinacalcet
Hyperparathyroidism
MOA: Sevelamer
Reduces absorption of PO42- in GI tract
(It is a non-absorbable oral formulation)
Indication: Sevelamer
Hyperphosphatemia
(Secondary to chronic kidney disease)
Suffix: Glucocorticoids
“-sone”
Where is the glucocorticoid receptor found?
Cytoplasm
What inflammatory enzyme do glucocorticoids inhibit?
Phospholipase A2
(By upregulating Lipocortin = Annexin)
What transcription factor do glucocorticoids inhibit?
NF-κB
(∴ Inhibiting production of inflammatory cytokines and activation of B and T cells)
How do glucocorticoids prevent leukocyte migration?
Inhibit adhesion molecules
(∴ Also increase WBC count ∵ fewer WBCs are attached to endothelium and more are freely floating in blood)
What cell type are glucocorticoids most effective at inducing apoptosis in?
TH
(Induce apoptosis of B-cells, T-cells, and eosinophils)
Name 5 metabolic effects of glucocorticoids
(1) Insulin resistance
(2) ↑ Gluconeogenesis
(3) ↑ Glycogenesis
(4) ↑ Proteolysis
(5) ↑ Lipolysis
Name 4 physical symptoms of Cushing’s syndrome
(1) Moon facies
(2) Central adipose tissue
(3) Muscle wasting
(4) Skin thinning
What CNS effects can glucocorticoids cause?
Psychosis
What electrolyte abnormality can glucocorticoids cause?
Hypokalemia
(Due to mineralocorticoid effects)
