Endocrine and Growth: thyroid, PTH, calcitriol

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Endocrine and Growth: thyroid, PTH, calcitriol
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2010-12-03 21:56:05
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Endocrine: Thyroid and Parathyroid. IBHS 525 final. Munson.
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  1. Location of the thyroid
    inferior to thyroid cartilage and anterior surface to trachea
  2. Characteristics of thyroid
    • two lobes connected by isthmus (like a shield)
    • deep red color (vasculatures, veins and capillaries)
    • produces: triiodothyronine (T3), tetraiodothyronine (T4)
    • calcitonin (CT)
  3. 3 parts in the histology of the thyroid gland
    • 1. thyroid follicles
    • 2. highly vascularized
    • 3. parafollicular cells (Clear Cells; C cells) - larger and clearer
  4. context: histology of thyroid gland- 3 parts of thyroid gland
    thyroid follicles
    • 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
  5. context: histology of thyroid gland- 3 parts of thyroid gland
    highly vascularized
    • the T3 and T4 go into the bloodstream
    • when you have vasculatures you have nutrient uptake and waste removal
  6. context: histology of thyroid gland- 3 parts of thyroid gland
    parafollicular cells (Clear Cells; C cells)
    produce calcitonin
  7. What produces Thyroid-stimulating hormone (TSH)?
    anterior pituitary
  8. What is another name for thyroid-stimulating hormone (TSH)?
    • thyrotropin
    • tropin - "to turn on"
  9. context: Thyroid-stimulating hormone (TSH)
    process of 6 steps after TSH is released
    • 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
  10. Name the 7 steps for T3 and T4 production
    • 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
  11. context: 7 steps for T3 and T4 production
    step 1
    How is iodide taken up from bloodstream to basal membrane?
    a way to get negative charge iodide in is via Na+/I- symporter
  12. context: 7 steps for T3 and T4 production
    step 1
    How do you bring the imbalance of Na+ back to equilibrium after taking in iodide?
    Na+/K+ ATPase
  13. context: 7 steps for T3 and T4 production
    what is Pendrin?
    • step 3 part a
    • Cl-/anion exchanger that transports I- into the follicle cavity
  14. context: 7 steps for T3 and T4 production
    step 5
    What are the enzymes that degrade T3 and T4?
    • none
    • no enzyme present to digest the T3 and T4 molecules
  15. context: 7 steps for T3 and T4 production
    step 6
    What is the percentages of T3 and T4 produced?
    • T3 = 10%
    • T4 = 90% (mostly produced)
  16. context: 7 steps for T3 and T4 production
    step 7
    T3 and T4 can be bound to what proteins?
    • 1. Thyroid-binding globulins (TBGs)
    • 2. Thyroid-binding prealbumin (TBPA; transthyretin)
    • 3. albumin
    • *helps store in the body longer when bound
  17. context: 7 steps for T3 and T4 production
    step 7
    percentage breakdown of form of T3
    • bound:
    • 7% to thyroid-binding globulins (TBGs)
    • 2.97% to thyroid-binding prealbumin (TBPA; transthyretin) and albumin
    • unbound: 0.03%
  18. context: 7 steps for T3 and T4 production
    step 7
    percentage breakdown of form of T4
    • bound:
    • 67.5% of thyroid-binding globulins (TBGs)
    • 22.47% of thyroid-binding prealbumin (TBPA; transthyretin) and albumin
    • unbound: 0.03%
  19. context: T3 and T4 production
    the actual formation of T3 and T4
    • 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
  20. T3 vs T4
    • 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
  21. Since bound T3 and T4 stay longer in bloodstream, what do unbound T3 and T4 do?
    enters almost every cell of the body using active and passive transport
  22. Name 3 receptors unbound T3 and T4 bind to
    • 1. nuclear receptors
    • 2. cytoplasmic receptors
    • 3. mitochondrial receptors
  23. context: unbound T3 and T4 - 3 receptors
    List 3 nuclear receptors and function
    • 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
  24. context: unbound T3 and T4 - 3 receptors
    result of binding to nuclear receptors
    • 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+
  25. context: unbound T3 and T4 - 3 receptors
    result of binding to cytoplasmic receptors
    storage and released when intracellular levels of thyroid hormones decline
  26. context: unbound T3 and T4 - 3 receptors
    result of binding to mitochrondrial receptors
    increase rates of mitochondrial ATP production
  27. the net effects of T3 and T4 target 2 areas
    • 1. general
    • 2. fetus/infant/child
  28. context: net effects of T3 and T4
    7 general effects of thyroid hormones on peripheral tissues
    • 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
  29. context: net effects of T3 and T4
    4 fetus/infant/child effects
    • 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
  30. Type of regulation of T3 and T4 secretion
    • negative feedback: shuts off TRH and TSH when T3 and T4 gets high enough
  31. importance of iodine
    required for the production of T3 and T4
  32. context: importance of iodine
    steps to get iodine into thyroid
    • 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
  33. context: importance of iodine
    what would you expect if the diet was iodine deficient?
    • TRH - levels increase due to low iodine
    • TSH - levels increase due to low iodine
    • T4 - low
    • T3 - low
  34. what can we do with iodine?
    • 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
  35. context: use of 131I or 125I
    how does it show ability of thyroid to take up iodide?
    • hyperthyroidism - thyroid will take up more
    • hypothyroidism - thyroid will take up less
  36. context: use of 131I or 125I
    4 areas of blood work to determine problem since the iodine used does not show ability to utilize iodide
    • 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)
  37. Name 2 thyroid disorders
    • 1. hyperthyroidism
    • 2. hypothyroidism
  38. context: 2 thyroid disorders
    2 types of hyperthyroidism
    • high serum T3/T4 independent of TSH
    • primary: 95% of cases
    • -low serum TSH
    • secondary: 5% of cases
    • -high serum TSH
  39. context: 2 thyroid disorders
    primary hyperthyroidism
    • high serum T3/T4
    • low serum TSH - thyroid no responsive to TSH levels
  40. context: 2 thyroid disorders
    3 causes of primary hyperthyroidism
    • 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
  41. context: 2 thyroid disorders
    secondary hyperthyroidism
    • high serum T3/T4
    • high serum TSH
  42. context: 2 thyroid disorders
    1 cause of secondary hyperthyroidism
    • cancer of upstream:
    • hypothalamus - too mush TRH
    • pituitary - too much TSH
  43. context: 2 thyroid disorders
    5 symptoms of hyperthyroidism
    • 1. increased energy
    • 2. increased heat
    • 3. increased heart rate and blood pressure
    • 4. +/- goiter
    • 5. exophthalmos
  44. context: 2 thyroid disorders - 5 symptoms of hyperthyroidism
    increased energy
    • 1. restless, excitable, insomnia, emotionally dynamic
    • 2. increased appetite, weight loss
    • 3. increased energy, but easily fatigued - then quickly lose energy and crash
  45. context: 2 thyroid disorders - 5 symptoms of hyperthyroidism
    increased heat
    perspiration, heat intoleration
  46. context: 2 thyroid disorders - 5 symptoms of hyperthyroidism
    increased heart rate and blood pressure
    arrhythmias
  47. context: 2 thyroid disorders - 5 symptoms of hyperthyroidism
    +/- goiter
    • 1. T3/T4 production (outpaced) > T3/T4 release
    • 2. large nodules - more stored
  48. context: 2 thyroid disorders - 5 symptoms of hyperthyroidism
    exophthalmos
    • edema in orbital tissue around eye
    • ex - Graves' disease
  49. context: 2 thyroid disorders
    Name 5 treatments of hyperthyroidism
    • 1. perchlorate (ClO4-)
    • 2. propylthiouracil
    • 3. 131I
    • 4. surgical
    • 5. Propanolol
  50. context: 2 thyroid disorders - 5 treatments of hyperthyroidism
    perchlorate (ClO4-)
    competes with I- for uptake by Na+/I- symporter
  51. context: 2 thyroid disorders - 5 treatments of hyperthyroidism
    propylthiouracil
    inhibits thyroid peroxidase and 5'deiodinase (less active thyroid hormone around)
  52. context: 2 thyroid disorders - 5 treatments of hyperthyroidism
    131I
    destroys follicle cells
  53. context: 2 thyroid disorders - 5 treatments of hyperthyroidism
    surgical
    • 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
  54. context: 2 thyroid disorders - 5 treatments of hyperthyroidism
    Propanolol
    • β - adrenergic receptor antagonists (β blockers)
    • Treat: patients with: tachycardia, arrhythmias, agitation
  55. context: 2 thyroid disorders
    2 types of hypothyroidism
    • low serum T3/T4
    • primary: 95% of cases
    • -high serum TSH
    • secondary: 5% of cases
    • -low serum TSH
  56. context: 2 thyroid disorders
    primary hypothyroidism
    • low serum T3/T4
    • high serum TSH
    • -thyroid not responding to TSH
    • -impaired T3/T4 synthesis
  57. context: 2 thyroid disorders
    4 causes of primary hypothyroidism
    • 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
  58. context: 2 thyroid disorders
    secondary hypothyroidism
    • low serum T3/T4
    • low serum TSH
    • -anterior pituitary not producing enough TSH
  59. context: 2 thyroid disorders
    1 cause of secondary hypothyroidism
    • cancer of upstream:
    • hypothalamus - too little TRH
    • pituitary - too little TSH
  60. context: 2 thyroid disorders
    3 stages of onset of symptoms of hypothyroidism
    • 1. fetus/infant onset (1:5000)
    • 2. child onset
    • 3. adult onset
  61. context: 2 thyroid disorders - 3 stages of onset of symptoms of hypothyroidism
    2 symptom of fetus/infant onset
    • 1:5000
    • 1. incomplete thyroid development
    • 2. Cretinism - 40% decrease in metabolism
    • -inadequate skeletal and nervous system development
    • -mental retardation
  62. context: 2 thyroid disorders - 3 stages of onset of symptoms of hypothyroidism
    3 symptoms of child onset
    • 1. growth inhibition
    • 2. delayed puberty
    • 3. mental impairment
  63. context: 2 thyroid disorders - 3 stages of onset of symptoms of hypothyroidism
    2 symptoms of adult onset
    • 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
  64. context: 2 thyroid disorders
    Name 3 treatments of hypothyroidism
    • 1. iodine
    • 2. synthetic T4 (levothyroxine sodium)
    • 3. synthetic T3 (liothyronine sodium)
  65. context: 2 thyroid disorders - 3 treatments of hypothyroidism
    iodine
    if iodine levels are low give more iodine however may lead to transient hyperthyroidism until it goes to equilibrium
  66. context: 2 thyroid disorders - 3 treatments of hypothyroidism
    synthetic T4 (levothyroxine sodium)
    • long long half life - spread out dosing
    • converted to T3 in tissues
    • negative feedback on TSH/TRH production to decrease in goiter size
  67. context: 2 thyroid disorders - 3 treatments of hypothyroidism
    synthetic T3 (liothyronine sodium)
    short half life- for emergency use only - fast acting (quick/"now" dosing)
  68. 5 importance of calcium homeostasis
    • 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)
  69. context: calcium homeostasis - 5 importance
    high calcium vs low calcium affecting 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
  70. context: calcium homeostasis
    3 hormonal players
    • 1. thyroid
    • 2. parathyroid
    • 3. kidney
  71. context: calcium homeostasis - 3 hormonal players
    thyroid
    secretes calcitonin in response to Ca2+ of the blood
  72. context: calcium homeostasis - 3 hormonal players
    parathyroid
    secretes parathyroid hormone (PTH) in response to Ca2+ of the blood
  73. context: calcium homeostasis - 3 hormonal players
    kidney
    secretes calcitriol in response to parathyroid hormone
  74. process of releasing calcitonin
    (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
  75. 2 functions of 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
  76. Location of the parathyroid gland
    embedded in the posterior surface of the thyroid
  77. Characteristics of parathyroid gland
    • two pairs of parathyroid glands (total 4)
    • only a portion of one gland is necessary for Ca2+ homeostasis
  78. 2 parts in the histology of the parathyroid gland
    • 1. chief cells
    • 2. oxyphil cells
  79. context: histology of parathyroid gland- 2 parts of parathyroid gland
    chief cells
    • have Ca2+ receptors that sense low blood Ca2+ levels (no hypothalamic or pituitary input)
    • produces: parathyroid hormone (PTH)
  80. context: histology of parathyroid gland- 2 parts of parathyroid gland
    oxyphil cells
    • larger
    • less intense staining
    • function? unknown but possibly older chief cells due to similar secretion
  81. process of releasing calcitriol
    (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
  82. 1 function of calcitriol
    • net effect of calcitriol:
    • increased absorption of Ca2+ and PO43- by the digestive tract
  83. calcium homeostasis
    • Start: homeostasis - normal calcium levels
    • pathways to disturb homeostasis:
    • 1. rising calcium in blood
    • 2. falling calcium in blood
  84. context: calcium homeostasis - 2 pathways
    pathway of rising 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
  85. context: calcium homeostasis - 2 pathways
    pathway of falling calcium in blood
    (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+, PO43- absorption by digestive tract --> (4) blood calcium increase --> (5) homeostasis restored
  86. Name 2 parathyroid disorders
    • 1. hyperparathyroidism
    • 2. hypoparathyroidism
  87. context: 2 parathyroid disorders
    2 types of hyperparathyroidism
    • high serum PTH
    • primary: most common
    • -high serum Ca2+ (hypercalcemia)
    • secondary: rare
    • -low serum Ca2+ (hypocalcemia)
  88. context: 2 parathyroid disorders
    primary hyperparathyroidism
    • high serum PTH
    • high serum Ca2+ (hypercalcemia)
    • -chief cells not responding appropriately to Ca2+ levels
    • *most common cause of hypercalcemia (90%)
  89. context: 2 parathyroid disorders
    1 cause of primary hyperparathyroidism
    • cancer:
    • parathyroid adenoma
  90. context: 2 parathyroid disorders
    secondary hyperparathyroidism
    • high serum PTH
    • low serum Ca2+ (hypocalcemia)
    • -body not responding appropriately to PTH
  91. context: 2 parathyroid disorders
    3 causes of secondary hyperparathyroidism
    • secondary (hypocalcemia):
    • 1. renal failure
    • -insufficient calcitriol production
    • 2. hypoalbuminemia
    • -transport protein for ions decreased
    • 3. hyperphosphatemia
    • -inc. phosphate binding to Ca2+
  92. context: 2 parathyroid disorders
    2 types of hypoparathyroidism
    • low serum PTH
    • primary: 99% cases
    • -low serum Ca2+
    • secondary: 1% cases
    • -high serum Ca2+
  93. context: 2 parathyroid disorders
    primary hypoparathyroidism
    • low serum PTH
    • low serum Ca2+
    • -chief cells not responding appropriately to Ca2+ levels
  94. context: 2 parathyroid disorders
    3 causes of primary hypoparathyroidism
    • 1. iatrogenic
    • ex- surgical removal of parathyroid or complete thyroidectomy or loss of blood supply
    • 2. congenital absence
    • 3. autoimmune
  95. context: 2 parathyroid disorders
    secondary hypoparathyroidism
    • low serum PTH
    • high serum Ca2+
    • -body not utilizing PTH
  96. context: 2 parathyroid disorders
    3 causes of secondary hypoparathyroidism
    • 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
  97. context: 2 parathyroid disorders
    4 areas of symptoms of hypercalcemia
    • hyperparathyroid/2º hypoparathyroid
    • 1. neuromuscular
    • 2. GI
    • 3. renal
    • 4. cardiac
  98. context: 2 parathyroid disorders - 4 areas of symptoms of hypercalcemia
    neuromuscular
    • weaknesses, lethargy, fatigue, slow reflexes, coma, hypotonia
    • similar to hypocalcemia: confusion, dementia, memory loss, depression, irritability, anxiety
  99. context: 2 parathyroid disorders - 4 areas of symptoms of hypercalcemia
    GI
    constipation, nausea, anorexia, ulcers, pancreatitis
  100. context: 2 parathyroid disorders - 4 areas of symptoms of hypercalcemia
    renal
    polyuria, polydypsia, dehydration, kidney stones, renal failure
  101. context: 2 parathyroid disorders - 4 areas of symptoms of hypercalcemia
    cardiac
    ventricular tachycardia, dec. QT interval, hypertension, arrhythmias, calcification
  102. context: 2 parathyroid disorders
    4 areas of symptoms of hypocalcemia
    • hypoparathyroid/2º hyperparathyroid
    • 1. neuromuscular
    • 2. GI
    • 3. renal
    • 4. cardiac
  103. context: 2 parathyroid disorders - 4 areas of symptoms of hypocalcemia
    neuromuscular
    • tetany (and muscle cramps - tense muscles) numbness/ tingling, spasms, twitching, seizure, wheezing
    • similar to hypercalcemia: depression, anxiety, memory loss, confusion, irritability
  104. context: 2 parathyroid disorders - 4 areas of symptoms of hypocalcemia
    GI
    diarrhea, dysphagia
  105. context: 2 parathyroid disorders - 4 areas of symptoms of hypocalcemia
    renal
    insufficient calcitriol production
  106. context: 2 parathyroid disorders - 4 areas of symptoms of hypocalcemia
    cardiac
    bradycardia, inc. QT interval, hypotension, congestive heart failure, arrhythmias
  107. context: 2 parathyroid disorders
    way of treatment of hypercalcemia
    • hyperparathryoid/2º hypoparathyroid
    • decrease Ca2+
  108. context: 2 parathyroid disorders - treatment of hypercalcemia
    5 ways to 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
  109. context: 2 parathyroid disorders
    way of treatment of hypocalcemia
    • hypoparathyroid/2º hyperparathyroid
    • increase Ca2+
  110. context: 2 parathyroid disorders - treatment of hypocalcemia
    7 ways to 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

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