SM_198a: Calcium and Phosphate Regulation

Question 1

Describe normal Ca²⁺ homeostasis

Answer 1

Normal Ca²⁺​ homeostasis

• Some reabsorbed from GI tract
• Mainly stored in bone
• Excreted by kidney

Question 2

Describe the distribution of calcium in the blood

Answer 2

Distribution of calcium in the blood

• Ionized Ca²⁺ (biologically active): 50%
• Protein-bound non-diffusible Ca: 40%
• Ca²⁺ complexed w/ citrate, phosphate, and bicarbonate: 10%

Question 3

______ Ca²⁺ is biologically active

Answer 3

Ionized Ca²⁺ is biologically active

Question 4

Alkalemia will ______ protein binding of Ca²⁺, ______ the ionized Ca²⁺ fraction, but total serum calcium may stay the same

Answer 4

Alkalemia will increase protein binding of Ca²⁺, decreasing the ionized Ca²⁺ fraction, but total serum calcium may stay the same

Question 5

Change in [albumin] changes the _____ and the _____ Ca²⁺, but not the _____ Ca²⁺

Answer 5

Change in [albumin] changes the bound fraction and the total serum Ca²⁺, but not the ionized Ca²⁺

Question 6

Describe mechanism of Ca²⁺ absorption in the intestine

Answer 6

Ca²⁺ absorption in the intestine

• Ca²⁺ enters cell through TRPV6
• Ca²⁺ exits cell into serum through Na⁺/C²⁺ exchanger and Ca²⁺ ATPase
• CaSR prevents too much Ca²⁺ from being in the body - decreases reabsorption of Ca²⁺ in the intestine

Question 7

Describe Ca²⁺ reabsorption in the intestine

Answer 7

Ca²⁺​ reabsorption in the intestine

• Absorbed mainly in duodenum and jejunum
• Gastric acid enhances Ca²⁺ absorption: take supplements with food; antacids, PPI, and H₂ blockers decrease absorption
• Biliary and pancreatic insufficiency: Ca²⁺​ remains bound to unabsorbed fat

Question 8

Describe bone formation and bone resorption

Answer 8

Bone formation and bone resorption

• Bone formation (movement of Ca²⁺ into bone): upregulated by intermitant PTH and androgens, downregulated by immobilization
• Bone resorption (movement of Ca²⁺ out of bone): upregulated by low Ca²⁺ (PTH) and downregulated by calcitonin and vitamin D

Question 9

Most Ca²⁺ is reabsorbed in the ______

Answer 9

Most Ca²⁺​ is reabsorbed in the PCT

(also the TAL and DCT)

Question 10

Describe how Ca²⁺ is reabsorbed in the thick ascending loop

Answer 10

Ca²⁺ reabsorption in the thick ascending loop

1. Na⁺/K⁺/2Cl^- channel takes these ions into cell
2. Cl^- leaves to interstitium via Cl^- transporters and Na⁺ leaves via Na⁺/K⁺ ATPase
3. K⁺ returns to lumen through ROMK
4. Excess + charge in lumen
5. Ca²⁺ and Mg²⁺ travel paracellularly into interstitium via Claudin 16

(CaSR decreases production of Claudin 16 and ROMK as negative feedback)

Question 11

Describe Ca²⁺ reabsorption in the DCT

Answer 11

Ca²⁺ reabsorption in the DCT

• Ca²⁺ enters cell via TRPV5 and leaves to interstitium via Na⁺/Ca²⁺ exchanger and Ca²⁺ ATPase

Question 12

In the DCT, PTH leads to _____ of _____ and _____

Answer 12

In the DCT, PTH leads to upregulation of TRPV5 (Ca²⁺ transporter in apical membrane) and Ca²⁺ ATPase in basolateral membrane

Question 13

In the DCT, CaSR _____, so that _____

Answer 13

In the DCT, CaSR upregulates phosphate transport through Np2a so that Ca²⁺ is alone and does not form stones

Question 14

Describe normal phosphorus homeostasis

Answer 14

Normal phosphorus homeostasis

• Less than 1% in blood (this is biologically active)
• Excreted mostly by kidney but also GI tract

Question 15

Describe intestinal absorption of phosphorus

Answer 15

Intestinal absorption of phosphorus

• NAPI absorbs phosphorus in conjunction w/ Na⁺
• Phosphorus cross basolateral membrane into interstitium with the help of a particular Na⁺ channel
• Vitamin D helps reabsorption of Ca²⁺ and phosphorus

Question 16

Most phosphorus is reabsorbed in the _____

Answer 16

Most phosphorus is reabsorbed in the PCT

Question 17

Describe renal tubular handling of phosphorus

Answer 17

Renal tubular handling of phosphorus

• NAPI reabsorbs phosphorus in kidneys and intestines
• Kidneys have FGF23 which stimulates excretion of phosphorus
• PTH promotes excretion of phosphorus

Question 18

Describe the production of Vitamin D

Answer 18

Production of Vitamin D

1. 7-dehydrocholesterol via UV light to
2. Cholecalciferol and dietary sources via 25 alpha hydroxylase to
3. 25-OH Vitamin D₃ via megalin mediated endocytosis involving glomerulus and D-binding protein to
4. 25-OH Vitamin D₃ via 1 alpha hydroxylase to
5. 1,25-OH₂ VItamin D₃

Question 19

____ increases production of 1,25-OH₂ Vitamin D₃

Answer 19

PTH increases production of 1,25-OH₂ Vitamin D₃​

Question 20

____ decreases production of 1,25-OH₂ Vitamin D₃

Answer 20

FGF23 decreases production of 1,25-OH₂ Vitamin D₃

Question 21

Describe regulation of PTH

Answer 21

Regulation of PTH

1. CaSR senses too much Ca²⁺ in serum
2. Downregulates production of PTH
3. Reduces PTH activity and subsequently Ca²⁺ levels

Question 22

____ is the single most important factor regulating PTH

Answer 22

Ca²⁺ is the single most important factor regulating PTH

Question 23

FGF23-Klotho system is _____

Answer 23

FGF23-Klotho system is principal phosphate-regulating endocrine axes

(FGF23 is secreted from bone)

Question 24

FGF23 is secreted from _____

Answer 24

FGF23 is secreted from bone

Question 25

Describe the effects of FGF23 and PTH on Vitamin D

Answer 25

Effects of FGF23 and PTH on Vitamin D

• FGF23 acts on kidney to decrease Vitamin D synthesis
• Vitamin D increases FGF23 expression in bone
• FGF23 acts on parathyroid to decrease PTH
• PTH increases FGF23

Question 26

Describe the FGF23-phosphate axis

Answer 26

FGF23-phosphate axis

1. FGF23
2. Decreased NAPI-2a and NAPI 2c / decreased 1 alpha hydroxylase and calcitriol
3. Increased phosphate excretion and decreased phosphate absorption
4. Decreased serum phosphate level

Question 27

Describe causes of hypercalcemia

Answer 27

Hypercalcemia causes

• Production or intake: increased GI absorption
• Utilization or excretion: increased bone resorption, decreased bone mineralization, increased renal excretion
• Cellular shift
• Pseudo-states: acidosis (decreased total Ca²⁺ but normal ionized Ca²⁺)

Question 28

Describe diagnostic approach to hypercalcemia

Answer 28

Diagnostic approach to hypercalcemia

• PTH related peptide (PTHrP) means malignancy is likely
• Tumor reduces active Vitamin D levels so high Ca²⁺ levels

Question 29

Describe the clinical presentation of hypercalcemia

Answer 29

Clinical presentation of hypercalcemia

• Renal: polyuria, nephrolithiasis, AKI
• Cardiac: bradycardia, short QT
• Neuro: confusion, fatigue
• MSK: weakness, bone pain, osteopenia
• GI: nausea, vomiting, constipation, pancreatitis

(painful bones, renal stones, abdominal groans, and psychic moans)

Question 30

Describe management of hypercalcemia

Answer 30

Management of hypercalcemia

• Improve excretion: sodium containing IV fluids, loop diuretics, dialysis
• Decreased production: calcitonin (increase renal excretion and decrease bone resorption), bisphosphonates (inhibit osteoclast-mediated bone resorption)
• Treat underlying cause

Question 31

Describe causes of hypocalcemia

Answer 31

Hypocalcemia

• Low PTH in post-surgical
• High PTH when Vitamin D deficiency or loss of Ca²⁺ from circulation
• Drugs
• Disorders of Mg²⁺ metabolism

(if give Vitamin D -> PTH normalizes -> Ca²⁺ normalizes, Mg²⁺ comes before Ca²⁺ so need to fix Mg²⁺ level and then Ca²⁺ will normalize)

Question 32

Describe clinical manifestations of hypocalcemia

Answer 32

Clinical manifestations of hypocalcemia

• Neuro: anxiety, irritability, tetany, twitching, carpopedal spasm, and seizures
• Bone: fractures
• GI: cramps
• Cardiac: prolonged QT, dysrhythmia
• Blood: hypocoagulable state

Question 33

Describe management of hypocalcemia

Answer 33

Management of hypocalcemia

• Ca²⁺ supplementation: oral vs IV
• Thiazide diuretics (hypocalciuric)
• Treat underlying cause: replete Mg²⁺ or Vitamin D, withdraw offending drugs

Question 34

Look at level of phosphorus in the _____

Answer 34

Look at level of phosphorus in the blood

Question 35

Describe causes of hyperphosphatemia

Answer 35

Causes of hyperphosphatemia

• Too much protein -> protein fraction increases -> serum phosphate fraction decreases -> phosphate more concentrated
• Decreased kidney function decreases phosphate excretion
• Rhabdomyolysis increases production and decreases phosphate excretion

Question 36

Describe the connection between chronic kidney disease and secondary hyperparathyroidism

Answer 36

Question 37

Describe clinical manifestations of hyperphosphatemia

Answer 37

Clinical manifestations of hyperphosphatemia

• Symptoms of hypocalcemia
• Itching
• Metastatic calcifications

Question 38

Describe management of hyperphosphatemia

Answer 38

Management of hyperphosphatemia

• Low phosphorus diet
• Phosphorus binders to bind dietary phosphorus
• Hemodialysis
• Treat underlying cause

Question 39

Describe the approach to hypophosphatemia

Answer 39

Approach to hypophosphatemia

• Serum P low but total P may not be low
• If hyperparathyroidism, defect in PTH: when treat PTH, Ca²⁺ goes up so P decreases

Question 40

Describe clinical manifestations of hypophosphatemia

Answer 40

Clinical manifestations of hypophosphatemia

• Neuro: lethargy, parasthesias, seizures
• Cardiac: arrhythmia, hypotension
• Hematologic: hemolysis
• Skeletal: bone demineralization

Question 41

Describe management of hypophosphatemia

Answer 41

Management of hypophosphatemia

• Replete: IV vs oral
• Treat underlying cause
• Dietary phosphorus (beware of refeeding syndrome if person was in starvation conditions)