Lecture 13: Regulation of Calcium and Phosphate Metabolism

Question 1

Where is calcium stored?

Answer 1

Bones and Teeth

Question 2

What is the biologically active form of calcium?

Answer 2

Free, ionized Ca²⁺

About 50% of calcium in body

Question 3

What are symptoms of hypocalcemia

Answer 3

• Hyperreflexia
• Spontaneous twitching
• Muscle cramps
• Numbness and tingling
• Tetany

Question 4

What is Chvostek sign?

Answer 4

Twitching of the facial muscles elicited by tapping on facial nerve

Question 5

What are two indicators of hypocalcemia?

Answer 5

Carpopedal spasm upon inflation of blood pressure cuff

Question 6

What are symptoms of hypercalcemia?

Answer 6

• Decreased QT interval
• Constipation
• Lack of appetite
• Polyuria
• Polydipsia
• Muscle weakness
• Hyporeflexia
• Lethargy
• Coma

Question 7

How does hypocalcemia affect membrane excitability?

Low extracellular calcium

Answer 7

• Reduces activation threshold for Na⁺ channels
  
  • Easier to evoke action potentials
• Increased membrane excitability
  
  • Spontaneous action potentials
  • Hypocalcemic tetany (spontaneous muscle contractions)

Question 8

How does hypercalcemia affect membrane excitability?

High extracellular calcium

Answer 8

• Increases activation threshold for Na⁺ channels
  
  • Harder to evoke action potentials
• Decreased membrane excitability
  
  • Less action potentials
  • Nervous system depressed and reflex responses are slowed

Question 9

How can calcium concentration be altered?

Answer 9

• Changes in plasma protein concentration
  
  • Increase in plasma protein means increase in total Ca²⁺ concentration and vice versa
  • No change in Ca²⁺ ionized (protein changes are usually more chronic issues)
• Changing anion concentration
  
  • Increase in P_i concentration will decrease Ca²⁺ ionized concentration
• Acid-Base Abnormalities
  
  • Alters ionized concentration by changing the fraction of Ca²⁺ bound to albumin

Question 10

What happens to calcium levels in acidemia?

Answer 10

• Increase in free ionized Ca²⁺ since less calcium is bound to albumin
• Instead, H⁺ is taking up Ca²⁺ binding spots

Question 11

What happens to calcium levels in alkalemia?

Answer 11

• Decrease in free ionized Ca²⁺ because more is bound to albumin
• Less H⁺ bound to albumin

Question 12

What three organs are important in maintaining Ca2+ homeostasis?

Answer 12

• Bone
• Kidney
• Intestine

Question 13

What three hormones are important in maintainin Ca2+ homeostasis?

Answer 13

• PTH
• Vitamin D
• Calcitonin

Question 14

What is the role of the kidneys to maintain calcium homeostasis?

Answer 14

Kidneys must excrete same amount of calcium absorbed by GI tract?

Question 15

What is the relationship between calcium and phosphate concentration in the ECF?

Answer 15

• Inversely proportional to one another
  
  • High Ca²⁺ means low P_i
• Both are regulated by the same hormones

Question 16

What is the normal range for phoshate?

How is phoshpate distributed?

Answer 16

• 2.5-4.5 mg/dL
• Distribution of phosphate:
  
  • 84% ionized
  • 15% ICF
  • 1% plasma
    
    • mostly ionized
    • some protein bound

Question 17

What secretes PTH?

What stimulates the secretion of PTH?

Answer 17

Chiefe cells of parathyroid gland

Low calcium levels

Question 18

How is PTH regulated?

Answer 18

• CaSR sense increasing calcium plasma levels
  
  • Gq and Gi send inhibitory signals to PTH gene
• 1,25 Vitamin D also inhibits PTH gene

Question 19

How does chronic hypercalcemia affect the regulation of PTH gene expression and secretion?

Answer 19

• Decrease synthesis and storage of PTH
• Breakdown of stored PTH
• Inactive PTH is released

Question 20

How does chronic hypocalcemia affect the regulation of PTH gene expression and secretion?

Answer 20

• Increased synthesis and storage of PTH
• Hyperplasia of parathyroid glands

Question 21

How does magnesium affect the regulation of PTH gene expression and secretion?

Answer 21

Severe hypomangesium can inhibit PTH synthesis, storage, and secretion

Maybe from alcoholism

Question 22

PTH acts on the bone and kidney tubule via which type of receptor?

Answer 22

• GPCR (Gs)
• Increased cAMP
  
  • Pathological increases in activity of PTH will show concomitant increase in urinary cAMP

Question 23

How does PTH act on the bone, kidney, and intestine?

Answer 23

• Bone: Increased bone resorption
• Kidney:
  
  • Increased reabsorption of Ca²⁺
  • Increased excretion cAMP and P_i in the urine
• Intestine: Indirectly increases absorption of Ca²⁺ via Vitamin D

Question 24

What is the function of Vitamin D?

Answer 24

• Increases both Ca²⁺ and Pi plasma concentrations
• Promotes mineralization of new bone

Question 25

What enzyme converts 25-OH-cholecalciferol to its active form of 1,25 dihydroxycholecalciferol? Where is this enzyme located? What stimulates this enzyme?

Answer 25

* **Enzyme:** 1 α-hydroxylase * **Location:** Proximal tubule of the kidney * **Stimulus:** Low calcium and phosphate levels & high PTH

Question 26

How is 1 α-hydoxylase regulated?

Answer 26

* Inhibits: * Calcium * 1,25 dihydroxycholecalciferol * Promotes: * PTH

Question 27

Where are PTH receptors located in bones? What are its actions?

Answer 27

* PTH receptors are located on _osteoblasts_ * Short term: PTH promotes bone formation * Long term: Increase bone resorption (indirectly through the release of cytokines from osteoblasts acting on osteoclasts)

Question 28

What are the steps of the bone resorption?

Answer 28

1. PTH stimulates osteoblasts 2. Osteoblasts release M-CSF 3. Stem cells form into osteoclast precursors 4. Osteoblasts release Vit D 5. Mononuclear osteoclasts form 6. IL-6 and RANK ligand help form multinucleated osteoclasts

Question 29

What is the function of M-CSF?

Answer 29

Induces stem cells to differentiate into osteoclast precursors, mononuclear osteoclasts, and mature multinucleated osteoclasts

Question 30

What is the function of RANKL?

Answer 30

* Receptor for NF-kB ligand * Cell surface protein produced by osteoblasts, bone lining cells, and apoptotic osteocytes * **Primary mediator of osteoclast formation**

Question 31

What is the function of RANK?

Answer 31

* Cell surface protein receptor on osteoclasts and osteoclast precursors

Question 32

What is the function of OPG?

Answer 32

* Produced by osteoblasts * Decoy receptor for RANKL * Inhibits RANKL/RANK interaction

Question 33

How does PTH work on the agents in bone formation/reabsorption?

Answer 33

* Increase RANKL * Decrease OPG

Question 34

How does vitamin D work on the agents in bone formation/reabsorption?

Answer 34

* Increase RANKL

Question 35

How does PTH work on the kidney?

Answer 35

* PTH binds GPCR on basolateral surface of cell in proximal tubule of kidney * Activates Gs and cAMP/PKA * PKA phosphorylates Na⁺/P_i cotransporter on apical surface, preventing P_i reabsorption * cAMP is excreted w/ Pi

Question 36

How does Vitamin D promote Ca²⁺ absorption in the intestine?

Answer 36

* Increases transcription of : * Ca²⁺ transporter (TRPV6) on apical membrane * Ca²⁺/3 Na⁺ exchanger on basolateral membrane * Calbindin

Question 37

What are the actions of calcitonin?

Answer 37

* Responds to increase in blood Ca²⁺ * Decreases blood Ca²⁺ and P_i by inhibiting bone resorption * Calcitonin receptors on osteoclasts * Decrease activity and number of osteoclasts * No role in chronic regulation of plasma Ca²⁺

Question 38

How do thyroidectomies and thyroid tumors affect regulation of calcitonin?

Answer 38

* Affect calcitonin levels but have no effect on Ca²⁺ metabolism * Thyroidectomy: reduce calcitonin * Thyroid tumors: increase calcitonin

Question 39

What is the function of estradiol-17B?

Answer 39

* Stimulates intestinal Ca²⁺ absorption and renal tubular Ca²⁺ absorption * Promotes survival of osteoblasts and apoptosis of osteoclasts * Favors bone formation over resorption

Question 40

How do adrenal glucocorticoids (e.g. cortisol) affect bones?

Answer 40

* Promotes _bone resorption_ * Promotes renal Ca²⁺ wasting * Inhbits Ca²⁺ absorption in the SI *Chronic use of glucorticoids can lead to osteoporosis*

Question 41

What is seen in patients with primary hyperparathyroidism?

Answer 41

Blood levels: * PTH levels increase * Ca²⁺ levels increase * P_i levels decrease * Vitamin D levels increase Symptoms: Stones, Bones, and Groans * Hypercalciuria (stones) * Increased bone resorption (bones) * Constipation (groans) Treatment: Parathyroidectomy

Question 42

What is seen in patients with secondary hyperparathyroidism?

Answer 42

* Increase in PTH levels secondary to low blood Ca²⁺ * Low blood Ca²⁺ causes: * Renal failure * Vitamin D deficiency * Blood Levels: * PTH increased * Low Ca²⁺ * Low Vitamin D

Question 43

How does renal failure differ from Vitamin D deficieny?

Answer 43

* Renal failure: P_i increases * Vitamin D: P_i decreases

Question 44

What causes hypoparathyroidism? What is a treatment?

Answer 44

Causes * Thyroid/parathyroid surgery * Autoimmune or congenital disorder Treatment * Oral Ca²⁺ supplement and active form of Vitamin D

Question 45

What do you see with patients that have hypoparathyroidism?

Answer 45

Symptoms * Muscle spasm or cramping * Numbness/tingling or burning around mouth and fingers * Seizures * Kids: poor teeth development and mental deficiences Blood Levels: * Decreased PTH * Decreased Ca²⁺ * Increased P_i * Decreased Vitamin D

Question 46

What is Albright hereditary osteodystrophy (Pseudohypoparathyroidism type 1a)? What symptoms do you see?

Answer 46

* Autosomal dominant disorder * Gs for PTH in bone and kidney is defective * Hypocalcemia and hyperphosphatemia develop * Increase in PTH levels * Symptoms * Short stature and short neck * Obesity * Subcutaneous calcification * Shortened metatarsals and metacarpals * Levels: * ​PTH increased * Ca₂₊ decreased * P_i increased * Vitamin D decreased

Question 47

What is humoral hypercalcemia of malignancy?

Answer 47

1. PTHrP produced by tumor cells 2. Binds and activates the same receptor as PTH 3. Decreased PTH levels 4. Decreased Vitamin D 5. Increased urinary Ca²⁺ 6. Increased urinary P_i and cAMP 7. Increased blood Ca²⁺ 8. Decreased blood P_i

Question 48

What is familial hypocalciuric hypecalcemia (FHH)?

Answer 48

* Autosomal dominant disorder * Mutations that inactivate CaSR in parathyroid glands and parallel Ca²⁺ receptors in ascending limb of the kidney * PTH levels are normal or increased * Serum Ca²⁺ elevated * Urine Ca²⁺ low * P_i normal * Vitamin D normal

Question 49

What is the physiology behind rickets and osteomalacia?

Answer 49

* Impaired Vitamin D metabolism * GI disorders * Chronic renal failure * P_i depletion

Question 50

What is seen with patients who have rickets?

Answer 50

* Insufficient amount of calcium and phosphate to mineralize growing bone * Characterized by growth failure and skeletal deformities * Blood Levels * Increased PTH * Normal or decreased Ca²⁺ * Decreased P_i * Increased phosphate and cAMP in urine * Decreased Vitamind D

Question 51

What is osteomalacia?

Answer 51

* New bones fail to mineralize * Bending and softening of weight bearing bones

Question 52

What is the treatment for osteoporosis?

Answer 52

* Anabolic Therapy * PTH * Antiresorptive therapy * Bisphosphates * Estrogen * Selective estrogen receptor modulators (SERMS: Raloxifene, Tamoxifen) * Calcitonin * RANKL inhibitors (Denosumab)