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Endocrine Physiology > CH5 Parathyroid Gland & Ca++ & PO4- Regulation > Flashcards

CH5 Parathyroid Gland & Ca++ & PO4- Regulation Flashcards

1
Q

What is the broad effect of Parathyroid Hormone PTH?

A

increase serum concentration of Ca++

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2
Q

What thyroid hormone counteracts parathyroid hormone?

A

calcitonin

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3
Q

Where does calcitonin come from? How does it effect blood Calcium level? What is its mechanism?

A

produced by Parafollicular “C” Cells of the Thyroid; decrease serum concentration of Ca++ & PO4– by inhibiting Osteoclasts in bone & stimulating renal excretion of Ca++

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4
Q

How does Parathyroid Hormone effect bone? [general]

A

stimulates bone resorption (release of Ca++) (indirectly through stimulation of osteoblast activity) – releases Ca++ & PO4–

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5
Q

How does Parathyroid Hormone effect the kidney? [general]

A

promotes Ca++ resorption and EXCRETION of inorganic phosphate in urine

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6
Q

What is the active form of vitamin D? How is it formed?

A

calcitriol; PTH stimulates the hydroxylation of 25-hydroxyvitamin D via 1-alpha Hydroxylase in the Kidney

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7
Q

How does Vitamin D effect the Kidney?

A

Vitamin D enhances calcium reabsorption by stimulating the synthesis of Vitamin D dependent Calbindin to form Calbindin-D for the diffusion of Ca++ from apical (influx) to basolateral membrane (efflux); also stimulates activity of Ca++-ATPase

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8
Q

How does Vitamin D effect the gut?

A

increases intestinal absorption of dietary Ca++

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9
Q

How does Vitamin D effect bone?

A

increases bone resorption (release Ca++)

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10
Q

How does Calcitonin effect bone?

A

inhibits bone resorption by osteoclasts

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11
Q

How does Calcitonin effect the Kidney?

A

increases renal Ca++ EXCRETION

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12
Q

What stimulates PTH release?

A

decrease in concentration of Ca++ OR increase in concentration of Pi; catecholamines, PTH

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13
Q

What inhibits PTH release?

A

high concentration of Ca++ & Vitamin D (negative feedback inhibition); severe hypomagnesemia

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14
Q

What cells secrete PTH?

A

Chief Cells of the Parathyroid Gland

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15
Q

How is Parathyroid Hormone Synthesized & Released & Degraded?

A

synthesized as a pre-pro-hormone –> pro-PTH –> mature PTH. Synthesis and release is continuous. PTH is degraded by the kidney and liver.

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16
Q

What occurs during hypocalcemia?

A

1) preformed PTH is released, 2) reduction in intracellular degradation of PTH, 3) increase in PTH release

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17
Q

What does active Vitamin D do at the molecular level?

A

decrease PTH gene transcription

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18
Q

What is the broad effect of increased Phosphate concentration in serum?

A

stimulate PTH release

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19
Q

What is the effect of slightly decreased & severely decreased Magnesium?

A

slight decrease stimulatse PTH release (increase Ca++ serum conc) if magnesium is slightly low, it’ll let calcium go up; severe decrease inhibits PTH release (severe hypomagnesemia is linked to hypocalcemia) – if magnesium is super low, it won’t let calcium go up without it.

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20
Q

What ion is Magnesium closely linked to?

A

Ca++ (magnesium depletion or deficiency is frequently associated with hypocalcemia)

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21
Q

How do Catecholamines affect PTH concentration in serum?

A

stimulate PTH release

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22
Q

What type of receptor is the Ca++ sensor? Where is it found?

A

Gq (when Ca++ bound) & Gi (when unbound); parathyroid chief cells, thyroid parafollicular C cells, kidney tubule cells

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23
Q

When Ca++ is bound to Ca++ sensor, what happens?

A

Ca++ release activates phospholipase C, D, & A2. Phospholipase A2 activates arachidonic acid cascade, which increases leukotriene synthesis. Leukotriene inhibits PTH secretion. (degrades pre-formed PTH, so if released, it will be in inactive form).

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24
Q

How does Ca++ sensor react during hypocalcemia?

A

Ca++ sensor is unbound, relaxed, & does not activate (no PTH degredation)

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25
Q

What is the broad effect of decreased Phosphate concentration in serum?

A

decrease PTH release

26
Q

How does Phosphate increase or decrease PTH release at the molecular level?

A

Phosphate, at high conc., decreases Phospholipase A2 activity (degradation pathway) - to stimulate PTH release; also decrease plasma Ca++ & vitamin D activation

27
Q

How does severe hypomagnesemia effect bone?

A

prevents responsiveness of bone to PTH-mediated bone resorption (cannot take Ca++ from bone to increase serum Ca++ conc.)

28
Q

Where does PTH exert its effects? What receptor do these cells display? What kind of receptor is it? What does it bind?

A

mainly kidney & bone osteoblasts (indirectly intestinal absorption through Vitamin D); Parathryroid Receptor 1 PTHR1; G-protein coupled (Gs & Gq); Binds PTH & PTHrP

29
Q

What is PTHrP? What is it clinically responsible for? What does it bind to? Where is it expressed?

A

Parathyroid Hormone-related Protein. Clinically responsible for hypercalcemia of malignancy. Binds to PTHR1. Expressed in multiple tissues, therefore it acts locally (paracrine, autocrine)

30
Q

What kind of receptor is PTHR1? What does it do?

A

Gprotein-coupled (Gs & Gq). PKA results in induction of gene transcription; IP3 results in increase in cytosolic Ca++ (RECALL: this is occurring in bone and kidney)

31
Q

Track how PTH increases Ca++ reabsorption in the Kidney starting with binding of PTH to PTHR1.

A

PTH enters kidney and binds to PTHR1 of the DISTAL TUBULES, stimulating insertion and opening of apical Ca++ channels. Ca++ enters cell. Ca++ binds to Calbindin-D and diffuses to basolateral membrane. Here, Ca++ is exported in one of two ways: Na+/Ca++ exchanger (3:1) OR Ca++-ATPase

32
Q

What is transcellular vs paracellular routes for Ca++ reabsorption? Which is important to PTH and why?

A

transcellular is active, paracellular is passive; PTH regulates the active, transcellular component (esp. in distal tubules); passive paracellular Ca++ absorption is dependent on sodium absorption.

33
Q

What is Calbindin? What does it do?

A

calbindin is a Vitamin-D dependent Ca++-binding protein. It facilitates the cytosolic diffusion of Ca++ from apical (influx) to basolateral (efflux) as Calbindin-D

34
Q

How do thiazide diuretics influence Ca++ concentration?

A

Thiazide Diuretics are calcium-sparing drugs. Act like PTH and increase Ca++ reabsorption

35
Q

How does PTH suppress PO4– reabsorption in the Kidney and Intestine?

A

decreases expression of Type II Na+/PO4– Cotransporter by stimulating irreversible internalization (degraded) within the kidney (type IIa) & intestine (type IIb)

36
Q

Track how PTH increases Ca++ release in bone starting with PTH binding to PTHR1.

A

PTH binds to PTHR1 on OsteoBLASTS. This causes synthesis and activation of Osteoclast-Differentiating Factor ODF (also known as receptor activator of nuclear factor-kB ligand RANKL) (also known as Osteoprotegerin Ligand). Result is activation of osteoblasts and recruitment of osteoclasts, which release Ca++ from bone matrix.

37
Q

Why is PTH used to stimulate bone formation when it causes bone resorption?

A

Chronic elevations of PTH result in bone resorption. Intermittent administration of PTH stimulates bone formation over bone resorption.

38
Q

What are the other names for Osteoclast-Differentiating Factor ODF?

A

Receptor activator of nuclear factor-kb ligand (RANKL) & Osteoprotegerin Ligand

39
Q

What is Osteoprotegerin? How does it work? What stimulates/inhibits it?

A

antagonist protein secreted by osteoblasts that binds to RANKL to inhibit RANKL-RANK mediated differentiation of osteoclasts; stimulated by estrogens, inhibited by PTH and glucocorticoids

40
Q

How do Osteoclasts work?

A

Osteoclast differentiation is stimulated by RANKL-RANK interaction. To dissolve bone, osteoclasts attach to bone surface via beta-integrins (microenvironment), generate H+ ions via Carbonic Anhydrase II, & release H+ ions via H+-ATPases (pH~4). This dissolves HYDROXYAPATITE. Osteoclast then releases lysosomal proteases (collagenase, cathepsins). Products are endocytosed and released via transcytosis (Ca++, PO4–, & alkaline phosphatases).

41
Q

What molecule in bone serves as a reservoir for Ca++? What other ion is sequestered there?

A

hydroxyapatite; phosphate is also released when degraded

42
Q

How does pH effect free blood calcium levels?

A

Majority of protein-bound calcium is bound to albumin, which is sensitive to pH changes. Acidosis decreases binding (increase free Ca++); Alkalosis increases binding (decreases free Ca++)

43
Q

What are the sources for Vitamin D precursors? How is Vitamin D synthesized?

A

2 sources (cholecalciferol D3 & ergocalciferol D2) are bound to Vitamin D-Binding Protein in circulation and go to Liver. In liver, they are hydroxylated at C-25 –> 25(OH)D (25-hydroxyvitamin D). Travels to kidney bound to Vitamin D-Binding Protein. In Kidney PROXIMAL tubules, 1-alpha-Hydroxylase works at C1 –> 1,25(OH)2D (calcitriol/active Vitamin D). Calcitriol is released and functions as an endocrine hormone.

44
Q

What is the Vitamin D reserve in the body?

A

25-hydroxyvitamin D bound to Vitamin D-binding Protein; this is the principle storage form of Vitamin D & the major circulating form of Vitamin D. half life of 15 days

45
Q

How is Vitamin D concentration regulated?

A

PTH stimulates 1-alpha-hydroxylase; high Ca++ levels and Vitamin D (negative feedback) suppress 1-alpha-hydroxylase (forms inactive 24,25(OH)2D instead)

46
Q

What type of hormone is Vitamin D?

A

steroid (derived from cholesterol, lipid-soluble)

47
Q

What are problems caused by Vitamin D excess?

A

Calcinosis (calcification of soft tissues), deposition of Ca++ & PO4 in kidney, & increased Ca++ levels (can lead to cardiac arrhythmia)

48
Q

How do patients with Vitamin D deficiency present? What are possible causes?

A

bone deformities (rickets in children), decreased bone mass (osteomalacia in adults), weakness, bowing of weight bearing msucles, dental defects, hypocalcemia; possible causes are mutation in 1-alpha-hydroxylase or resistance to vitamin D via Vitamin D Receptor mutation

49
Q

What is Paget Disease?

A

abnormal bone remodeling with increased bone resorption accompanied by hypercalcemia

50
Q

What factors regulate Ca++ & bone metabolism? How?

A

Sex Steroids (increase 1-alpha-hydroxylase activity, increase osteoprotegerin synthesis, net decrease of bone loss “get Ca++ from anywhere but bone”), Growth Hormone/IGF-1 (stimulate bone synthesis and growth), Glucocorticoids (increase bone resorption, decrease bone synthesis), Inflammatory Cytokines [Tumor Necrosis Factor, Interleukin 1, Interleukin 6] (increase bone resorption via osteoclast proliferation and differentiation)

51
Q

In a state of hypocalcemia (simple calcium deficiency), what occurs?

A

[ex. of secondary hyperparathyroidism] stimulation of PTH release –> increase bone resorption, increase of Vitamin D, excretion of PO4–, Ca++ isn’t resorbed because it’s deficient –> excretion of PO4– (hypophosphatemia) prevents mineralization of new bone, Vitamin D stimulates also increases bone resorption –> overall loss of bone mass

52
Q

How does Vitamin D deficiency differ from simple calcium deficiency (hypocalcemia)?

A

Vitamin D Deficiency reduces the mineral content of the bony tissue itself and leads to abnormal bone composition, but begins with calcium malabsorption (simple calcium deficiency) – Recall: Vitamin D stimulates bone resorption, but more importantly, Calbindin is Vitamin D dependent.

53
Q

What does bone density determine? How is it measured?

A

bone density determines degree of osteoporosis (bone loss) and fracture risk; measured using Dual-Energy X-Ray Absorptiometry (DEXA) scan. Two scores given: T score (comparison to avg. peak bone density) & Z score (comparison to avg. bone density of similar stats)

54
Q

What hormones & abnormalities are often seen with elevated ionized calcium levels in serum?

A

elevated PTH, elevated Vitamin D, elevated bone resorption

55
Q

What hormones and abnormalities are often seen with elevated plasma phosphate?

A

renal failure (can’t filter it out), hypoparathyroidism (no PTH to degrade phosphate resorption channels), vitamin D intoxication (increases bone resorption which causes increases in Ca++, PO4–, & alkaline phosphatase)

56
Q

What hormones and abnormalities are often seen with decreased levels of plasma phosphate?

A

hyperparathyroidism (lots of PTH to degrade phosphate resorption channels), vitamin D deficiency (lack of bone resorptino, so no release of Ca++, PO4–, or alkaline phosphatase)

57
Q

What hormones and abnormalities are often seen with elevated levels of plasma alkaline phosphatase?

A

increased osteoblastic activity

58
Q

In a patient with Primary Hyperparathyroidism, what clinical manifestations are seen?

A

elevated intact PTH levels, hypercalcemia, hypercalciuria (increased urinary calcium excretion) - which may lead to urolithiasis (kidney stones); decreased plasma phosphate levels

59
Q

What is the principle example of Secondary Hyperparathyroidism? What symptoms are seen?

A

Chronic Renal Failure. First, a decrease in plasma Vitamin D and free Ca++ is seen –> results in increased PTH release. As chronic renal failure progresses, Parathyroid decreases expression of Vitamin D & Ca++ receptors (becomes very resistant to negative feedback), so regardless of Vitamin D/Ca++ levels, PTH is continuously released. Will also notice hyperphosphatemia (elevated plasma phosphate) due to inability to filter & bone resorption.

60
Q

What is the Chvostek Sign?

A

Nerve Hyperexcitability (tetany): (seen in hypoparathyroidism/hypocalcemia) twitching or contraction of facial muscles in response to tapping a facial nerve.

61
Q

What is Pseudohypoparathyroidism? How does it present?

A

defect with PTHR1. 2 types: Ia (resistance to hormones, short stature, skeletal anomalies) & Ib (renal resistance to PTH, normal appearance). Patients present with low plasma Ca++, high phosphate levels, elevated PTH

Endocrine Physiology (15 decks)

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