Endocrine and Growth: thyroid, PTH, calcitriol

inferior to thyroid cartilage and anterior surface to trachea

• two lobes connected by isthmus (like a shield)
• deep red color (vasculatures, veins and capillaries)
• produces: triiodothyronine (T₃), tetraiodothyronine (T₄)
• calcitonin (CT)

• 1. thyroid follicles
• 2. highly vascularized
• 3. parafollicular cells (Clear Cells; C cells) - larger and clearer
• 

• surrounded by simple cuboidal epithelia, which produces thyroglobulin
• cavity filled with colloid (protein suspended in H₂O)
• -protein: thyroglobulin (in water)
• produce T₃ and T₄ --> goes in bloodstream

• the T₃ and T₄ go into the bloodstream
• when you have vasculatures you have nutrient uptake and waste removal

produce calcitonin

anterior pituitary

• thyrotropin
• tropin - "to turn on"

• GPCR pathway with signaling cascade:
• (1) binds to G protein coupled receptor on follicle cells --> (2) activates G protein --> (3) G protein activates adenylate cyclase (AC) --> (4) ATP turns into cAMP --> (5) cAMP activates kinases --> (6) kinases a) open ion channels and b) activate enzymes that include Na⁺/I^- symporter and transcription/translation (turning on production of) of a) thyroid peroxidase and b) thyroglobulin

• location: follicle cell
• 1. Iodide (I^-) uptake from bloodstream at basal membrane
• 2. Iodide (I^-) diffuses through cells to apical surface
• 3. A) Pendrin transports I^- into follicle cavity
• B) thyroglobulin transported into follicle cavity
• 4. Thyroglobulin (containing T₃ and T₄) endocytosed
• 5. lysosome digests thyroglobulin
• 6. Free T₃ and T₄ diffuse to basal cell surface and diffuse into blood stream
• 7. T₃ and T₄ bound by transport proteins
• 

a way to get negative charge iodide in is via Na⁺/I^- symporter

Na⁺/K⁺ ATPase

• step 3 part a
• Cl^-/anion exchanger that transports I^- into the follicle cavity

• none
• no enzyme present to digest the T₃ and T₄ molecules

• T₃ = 10%
• T₄ = 90% (mostly produced)

• 1. Thyroid-binding globulins (TBGs)
• 2. Thyroid-binding prealbumin (TBPA; transthyretin)
• 3. albumin
• *helps store in the body longer when bound

• bound:
• 7% to thyroid-binding globulins (TBGs)
• 2.97% to thyroid-binding prealbumin (TBPA; transthyretin) and albumin
• unbound: 0.03%

• bound:
• 67.5% of thyroid-binding globulins (TBGs)
• 22.47% of thyroid-binding prealbumin (TBPA; transthyretin) and albumin
• unbound: 0.03%

• location: follicle cavity
• (1) thyroid peroxidase converts I^- to I⁺ --> (2) attaches I⁺ to tyrosines in thyroglobulin --> (3) forms Monoiodotyrosine [MIT] and Diiodotyrosine [DIT] --> (4) covalently bonds DIT/MIT or DIT/DIT --> (5) forms Triiodothyronine [T₃] and Tetraiodothyronine [T₄]/thyroxine
• *MIT/MIT is possible but not often

• T₃: triiodothyronine - thyroid secretion (10%), most in the bloodstream converted from T₄ to T₃ by 5'-deiodinase
• T₄: tetraiodothyronine; thyroxine - thyroid secretion (90%), 4X less active than T₃

enters almost every cell of the body using active and passive transport

• 1. nuclear receptors
• 2. cytoplasmic receptors
• 3. mitochondrial receptors

• TR α1 - widely expressed especially in cardiac and skeletal muscles
• TR β1 - in brain, liver, kidney and use hormone to do glycolysis and glycogenolysis
• TR β2 - in hypothalamus and pituitary and there is feedback regulation of TRH and TSH which stimulates T₃ and T₄ production

• 1. glycolysis
• 2. glycogenolysis
• 3. lipolysis
• 4. accelerated production of Na⁺/K⁺ ATPase to bring back to normal after the products of these three processes hitchhike with Na⁺

storage and released when intracellular levels of thyroid hormones decline

increase rates of mitochondrial ATP production

• 1. general
• 2. fetus/infant/child

• 1. increased metabolic rate
• -increased ATP production
• -increased oxygen consumption
• -increased glucose consumption
• 2. increased heart rate/blood pressure
• 3. increased sensitivity to sympathetic stimulation
• 4. sensitivity of respiratory centers to [O₂/CO₂]
• 5. red blood cell formation
• 6. mineral turnover in bone
• 7. endocrine stimulation

• 1. increased calorgenic effect (increased body heat, increased metabolism to feel warmer)
• 2. skeletal development
• -increase in osteoblast activity (for bone growth)
• 3. muscular development
• 4. nervous system development

• negative feedback: shuts off TRH and TSH when T₃ and T₄ gets high enough
• 

required for the production of T₃ and T₄

• 1. absorbed from digestive tract into blood stream as iodide (I^-) - about 120-150 µg per day (pee out excess with some into bile salt (digestive enzymes) then into feces)
• 2. Taken up by thyroid by the Na⁺/I^- symporter - which is stimulated by TSH - 30X higher concentration of I^- in thyroid than bloodstream

• TRH - levels increase due to low iodine
• TSH - levels increase due to low iodine
• T₄ - low
• T₃ - low

• use ¹³¹I or ¹²⁵I to visualize the size and shape of the thyroid
• shows ability of thyroid to take up iodide, but does not show ability to utilize iodide

• hyperthyroidism - thyroid will take up more
• hypothyroidism - thyroid will take up less

• 1. T₃/T₄ levels
• -problems with pendrin? thyroid peroxidase? thyroglobulin? 5' deiodinase?
• 2. TSH levels
• -problems with pituitary response to TRH or response to T₃/T₄?
• 3. TRH levels
• -problems with hypothalamus production of TRH or response to T₃/T₄?
• 4. Thyroid antibodies
• -autoimmune diseases (those specific to thyroid can occur)

• 1. hyperthyroidism
• 2. hypothyroidism

• high serum T₃/T₄ independent of TSH
• primary: 95% of cases
• -low serum TSH
• secondary: 5% of cases
• -high serum TSH

• high serum T₃/T₄
• low serum TSH - thyroid no responsive to TSH levels

• 1. autoimmune
• ex- Graves' Disease - antibodies to TSH receptors cause receptor activation even without TSH
• 2. cancer
• ex- thyroid tumor (90% adenoma)
• 3. diet
• ex- excess iodine consumption causing increase in T₃/T₄

• high serum T₃/T₄
• high serum TSH

• cancer of upstream:
• hypothalamus - too mush TRH
• pituitary - too much TSH

• 1. increased energy
• 2. increased heat
• 3. increased heart rate and blood pressure
• 4. +/- goiter
• 5. exophthalmos

• 1. restless, excitable, insomnia, emotionally dynamic
• 2. increased appetite, weight loss
• 3. increased energy, but easily fatigued - then quickly lose energy and crash

perspiration, heat intoleration

arrhythmias

• 1. T₃/T₄ production (outpaced) > T₃/T₄ release
• 2. large nodules - more stored

• edema in orbital tissue around eye
• ex - Graves' disease

• 1. perchlorate (ClO₄^-)
• 2. propylthiouracil
• 3. ¹³¹I
• 4. surgical
• 5. Propanolol

competes with I^- for uptake by Na⁺/I^- symporter

inhibits thyroid peroxidase and 5'deiodinase (less active thyroid hormone around)

destroys follicle cells

• when it is compressing the trachea
• last resort because if we lose thyroid gland we will lose the parathyroid gland and both will leave you hypothyroid and hypoparathyroid for life

• β - adrenergic receptor antagonists (β blockers)
• Treat: patients with: tachycardia, arrhythmias, agitation

• low serum T3/T4
• primary: 95% of cases
• -high serum TSH
• secondary: 5% of cases
• -low serum TSH

• low serum T3/T4
• high serum TSH
• -thyroid not responding to TSH
• -impaired T3/T4 synthesis

• 1. autoimmune
• ex- Hashimoto's - antibodies to thyroglobulin/thyroid peroxidase
• 2. iatrogenic
• ex- surgical removal or radiation damage (¹³¹I)
• 3. diet
• ex- inadequate iodine
• 4. drug induced
• ex- Lithium

• low serum T3/T4
• low serum TSH
• -anterior pituitary not producing enough TSH

• cancer of upstream:
• hypothalamus - too little TRH
• pituitary - too little TSH

• 1. fetus/infant onset (1:5000)
• 2. child onset
• 3. adult onset

• 1:5000
• 1. incomplete thyroid development
• 2. Cretinism - 40% decrease in metabolism
• -inadequate skeletal and nervous system development
• -mental retardation

• 1. growth inhibition
• 2. delayed puberty
• 3. mental impairment

• 1. Myxedema (vs. pitting edema)- subcutaneous swelling
• -dry skin, hair loss, low body temperature, muscular weakness, slowed reflexes
• -lethargy, weight gain, cold intolerance, slow heart rate, fatigue
• 2. +/- goiter (maybe)
• -overstimulation of thyroid follicle cells by TSH

• 1. iodine
• 2. synthetic T₄ (levothyroxine sodium)
• 3. synthetic T₃ (liothyronine sodium)

if iodine levels are low give more iodine however may lead to transient hyperthyroidism until it goes to equilibrium

• long long half life - spread out dosing
• converted to T₃ in tissues
• negative feedback on TSH/TRH production to decrease in goiter size

short half life- for emergency use only - fast acting (quick/"now" dosing)

• 1. bone growth/maintanence
• -formation of bone matrix
• 2. blood clotting
• 3. cofactors in enzymatic reactions
• 4. second messengers
• 5. sodium permeability of excitable membranes (muscles, neurons)

• high Ca²⁺: less Na⁺ permeable, less excitable
• -limpness, slow reflexes
• low Ca²⁺: more Na⁺ permeable, more excitable
• -convulsions, spasms

• 1. thyroid
• 2. parathyroid
• 3. kidney

secretes calcitonin in response to Ca²⁺ of the blood

secretes parathyroid hormone (PTH) in response to Ca²⁺ of the blood

secretes calcitriol in response to parathyroid hormone

(1) high blood Ca²⁺ detected directly by Ca²⁺ receptors on C cells (no hypothalamic or pituitary input) --> (2) parafollicular cells (clear cells/C cells) of the thyroid secrete calcitonin

• 1. stimulates Ca²⁺ excretion (pee out) by the kidneys
• 2. cause bone growth/prevents bone loss by inhibiting osteoclasts = dec. Ca²⁺ release from bones to maintain bone mass
• -seen in children, pregnant women, prolonged starvation

embedded in the posterior surface of the thyroid

• two pairs of parathyroid glands (total 4)
• only a portion of one gland is necessary for Ca²⁺ homeostasis

• 1. chief cells
• 2. oxyphil cells

• have Ca²⁺ receptors that sense low blood Ca²⁺ levels (no hypothalamic or pituitary input)
• produces: parathyroid hormone (PTH)

• larger
• less intense staining
• function? unknown but possibly older chief cells due to similar secretion

(1) diet or skin (in response to sunlight) produce vitamin D3 (cholcalciferol) --> (2) vitamin D3 (cholcalciferol) converted to 25-hydroxy-D3 (calcidiol) in the liver --> (3) PTH stimulates kidneys to convert 25-hydroxy-D3 (calcidiol) to 1, 25-dihydroxy-D3 (calcitriol) --> kidneys secrete calcitriol into the bloodstream

• net effect of calcitriol:
• increased absorption of Ca²⁺ and PO₄^3- by the digestive tract

• Start: homeostasis - normal calcium levels
• pathways to disturb homeostasis:
• 1. rising calcium in blood
• 2. falling calcium in blood
• 

(1) homeostasis disturbed --> (2) thyroid gland produces calcitonin --> (3) a) increased excretion of calcium in kidneys b) calcium deposition in bone (inhibition of osteoclasts) --> (4) blood calcium decline --> (5) homeostasis restored

(1) homeostasis disturbed --> (2) parathyroid glands secrete parathyroid hormone [PTH] --> (3) a) release of stored calcium from bone (stimulation of osteoclasts more than osteoblasts) b) enhanced reabsorption of calcium in kidneys c) stimulation of calcitriol production at kidneys; enhanced Ca²⁺, PO₄^3- absorption by digestive tract --> (4) blood calcium increase --> (5) homeostasis restored

• 1. hyperparathyroidism
• 2. hypoparathyroidism

• high serum PTH
• primary: most common
• -high serum Ca²⁺ (hypercalcemia)
• secondary: rare
• -low serum Ca²⁺ (hypocalcemia)

• high serum PTH
• high serum Ca²⁺ (hypercalcemia)
• -chief cells not responding appropriately to Ca²⁺ levels
• *most common cause of hypercalcemia (90%)

• cancer:
• parathyroid adenoma

• high serum PTH
• low serum Ca²⁺ (hypocalcemia)
• -body not responding appropriately to PTH

• secondary (hypocalcemia):
• 1. renal failure
• -insufficient calcitriol production
• 2. hypoalbuminemia
• -transport protein for ions decreased
• 3. hyperphosphatemia
• -inc. phosphate binding to Ca²⁺

• low serum PTH
• primary: 99% cases
• -low serum Ca²⁺
• secondary: 1% cases
• -high serum Ca²⁺

• low serum PTH
• low serum Ca²⁺
• -chief cells not responding appropriately to Ca²⁺ levels

• 1. iatrogenic
• ex- surgical removal of parathyroid or complete thyroidectomy or loss of blood supply
• 2. congenital absence
• 3. autoimmune

• low serum PTH
• high serum Ca²⁺
• -body not utilizing PTH

• 1. cancer
• ex- lung, breast, myeloma
• 2. nutritional
• ex- vitamin D intoxication or hypophosphatemia
• 3. drugs - preventing Ca²⁺ clearance or uptake into bone
• ex- thiazide diauretics (stop Ca²⁺ secretion) or lithium or Al/Mg antacids

• 1º hyperparathyroid/2º hypoparathyroid
• 1. neuromuscular
• 2. GI
• 3. renal
• 4. cardiac

• weaknesses, lethargy, fatigue, slow reflexes, coma, hypotonia
• similar to hypocalcemia: confusion, dementia, memory loss, depression, irritability, anxiety

constipation, nausea, anorexia, ulcers, pancreatitis

polyuria, polydypsia, dehydration, kidney stones, renal failure

ventricular tachycardia, dec. QT interval, hypertension, arrhythmias, calcification

• 1º hypoparathyroid/2º hyperparathyroid
• 1. neuromuscular
• 2. GI
• 3. renal
• 4. cardiac

• tetany (and muscle cramps - tense muscles) numbness/ tingling, spasms, twitching, seizure, wheezing
• similar to hypercalcemia: depression, anxiety, memory loss, confusion, irritability

diarrhea, dysphagia

insufficient calcitriol production

bradycardia, inc. QT interval, hypotension, congestive heart failure, arrhythmias

• 1º hyperparathryoid/2º hypoparathyroid
• decrease Ca²⁺

• 1. IV fluids to counter dehydration
• 2. removal of overactive parathyroid gland(s)
• 3. normalize phosphate levels
• 4. normalize vitamin D levels
• 5. change medications if it is medication induced

• 1º hypoparathyroid/2º hyperparathyroid
• increase Ca²⁺

• 1. oral
• 2. IV for severe cases
• 3. PTH supplementation
• -low supply, expensive
• 4. vitamin D
• -allows increased calcitriol production by causing increased Ca²⁺ absorption in intestines
• 5. normalize phosphate levels
• 6. normalize albumin levels
• 7. change medications if it is medication induced