lecture 7/8: regulation of calcium and phosphate balance

hydroxyapatite; contains calcium and phosphorus

what is the main crystalline salt of bone?

-form a crystal precipitate!

-we don't want that, so there are mechanisms of exchange

in a physiologic fluid, calcium and phosphtae

increases the number of sodium fast channels, hence easier depolarization

how does low calcium increase excitability of cells?

8.5-10.5

normal calcium range:

intestinal calcium absorption is less than calcium excretion, and the deficit comes from the maternal bones

how is there a negative calcium balance in pregnant women?

intestinal calcium absorption exceeds urinary excretion, and the excess is deposited in the growing bones

explain the positive calcium balance in growing children:

1,25-dihydroxycholecalcirerol

active form of vitamin D

ionized

-rest is bound to albumin (40%) or complexed with anions (10%)

the most abundant form of calcium:

-only calcium bound to albumin cannot be filtered

-only ionized calcium is biologically active

is calcium filtered? is calcium active?

-pH

-albumin: increased H+ binds to albumin, raising amount of ionized calcium

factors modifying ionized calcium

-decreases protein bound calcium

-no change in free ionized calcium

-decreased total calcium

how does hypoalbuminemia (cirrhosis, critical illness) impact calcium levels

-increased protein bound calcium, no change in free ionized

-increased total calcium

how does hyperalbuminemia (hypovolemia, high protein intake) impact calcium levels?

-increased pprotein bound, decreased free, normal total

how does alkalosis alter plasma calcium levels?

-increased protein bound calcium, normal free ionized calcium, increased total calcium

how does pregnancy alter plasma calcium levels?

phosphate

-major intracellular acid-base buffer

-uptake from gut is linear with diet levels

-regulation via urinary excretion

leads to increased binding of free calcium, therefore there is decreased free calcium

how does hyperphosphatemia affect calcium?

Insulin; contributes to refeeding syndrome

____ promotes phosphorus uptake into peripheral cells

FGF23

peptide produced by osteocytes

-negative regulator or serum phosphate via ability to inhibit Pi reabsorption in the kidney

2.5-4.5

normal serum phosphate level

-Ricketts, osteomalacia

hypophosphatemic disorders associated with excess production of FGF23

-AD: mutation in FG23

-X linked: excess FGF23 secondary to PHEX mutation

inheritance types of hypophosphatemic rickets

FGF23

_______ sometimes ectopically produced by slow-growing occult mesenchymal tumors, causing a hypophosphatemic paraneoplastic syndrome.

hyperphosphatemia and 1,25 dihydroxyvitamin Dd

production of FGF23 is increased by

FGF23

-inhibits 1,25-dihydroxyvitamin D, resulting in decreased phosphate absorption intestinally and renally

there is a calcium sensing receptor on the plasma membrane of chief cells

how do chief cells monitor calcium levels?

decreases transcription of prepro PTH as well as post translational processing

how does chronic hypercalcemia impact PTH production?

C terminal fragment

PTH derived fragment that is most represented in serum, has a longer half life

within seconds!

how fast does PTH respond to calcium levels?

magnesium

_______ has parallel, but less important effects on PTH secretion compared to calcium

DIRECTLY on bone and kidney

INDIRECTLY on intestine

what does PTH work on?

-increase 1-OHase, making more active vitamin D

-increase calcium reabsorption in the distal tubule

-decrease PO4 reabsorption in the proximal tubule

effects of PTH on the kidney

-indirectly: the increased vitamin D from the kidneys increase calcium and phosphate uptake

effects of PTH on the intestines

-increase reabsorption of mineralized bone, with increases serum calcium

-Phosphate will increase initially

effects of PTH on the bone

Bind to osteoblasts, which respond by activating osteoclasts to resorb bone-

how does PTH increase bone resorptionn?

hydroxyproline (collagen fragments) excretion

increased bone resorption is reflected by what excretion?

effects in the kidney!

what effect of PTH happens the quickest?

increased urinary cAMP, low phosphate

PTHs effect on the proximal tubule results in what finding?

NO!

-PTH increases intestinal Calcium absorption indirectly by stimulating 1,25 dihyddroxycholecalciferol in the kidney

are there PTH receptors in the intestine?

-PTH and vitamin D bind osteoblasts

-osteoblasts release M-CSF and RANK-L promoting osteoclastogenesis and osteoclast activity

-mineralization occurs over weeks once calcium becomes available from the exposed bone

how does PTH increase bone resorption?

androgens, estrogens

-thyroid hormone, GH, IGF, calcitonin, vitamin D

hormones promoting bone formation

PTH, cortisol, HIGH thyroid hormone, inflammatory cytokines

hormones favoring bone resorption

androgens, estrogens, calcitonin

hormones inhibiting bone resorption

increases calcium release

bone resorption's effect on calcium levels

NERF proteins

-urinary cAMP indicates PTH action

cAMP activation on _____ proteins in the proximal tubule results in decreased reabsorption of phosphate in response to PTH

PTH action

urinary cAMP indiicates

1 alpha hydroxylase

enzyme that converts 25, Vitamin D to its active form

-upregulated by PKA in the distal tubule in response to PTH, increasing calcium reabsorption

short term: increases bone resorption

long term: enhances mineralization

long term and short term effects of vitamin D on bone

-nucleus of osteoblasts (binding activates osteoclasts)

-GI tract

where are vitamin D receptors located

increase plasma calcium and PO4- so it can be used to promote bone mineralizaiton

what is the goal of Vit D?

vitamin D

a group of related secosteroids either derived from the diet or from metabolism of cholesterol

Ergocalciferol (Vitamin D2)

precursor of vitamin photochemically synthesized in plants

Cholecalciferol (Vitamin D3)

-form of vitamin D synthesized in skin in ressponse to sunlight

25-OH vitamin D made in the liver by 25-hydroxylase

when we measure vitamin D levels, this is what we measure

1,25-(OH)2 D synthesized by 1-alpha hydroxylase in the kidney

the active form of vitamin D

7-dehydrocholesterol; converted to D3 by UV light

precursor to Vitamain D3 (cholecalciferol)

conversion of calcidiol to calcitriol in the kidney by 1-alpha hydroxylase

primary regulatory step of vitamin D formation

-25-hydroxycholecalciferol on the liver

-1,25 hydroxycholcalciferol

negative feedback of vitamin D produciton

25-hydroxycholecalciferol stays relatively constant, regardless of D3 intake; represents negative feedback

why do we measure 25, Vit D to assess vitamin D status?

-decreased calcium

-increased PTH

-decreased phosphate

1 alpha hydroxylase activity is increased by

-increased 1,25 Vit D activates 24-OHase, which converts vit D to an inactive form

negative feedback regulator of 1,25 Vit D

FGF-23

_____________ represses 1a-hydroxylase activity to reduce phosphate absorption

-freely enters cells and binds to DNA receptor

signaling of Vit D

-stimulate calcium and phosphate absorption through intestinal brush border

-increases sodium-phosphate transporters in enterocytes

-increases epithelial calcium transporters

-increases calbindins

effect of vitamin D on the intestiinie

calbindins

Protein that transports Ca across osteoblasts to mineralizing (osteoid) side.

slightly increases reabsorption of calcium and phosphate

affect of Vit D on kidney

-interacts with osteoblast Vit. D receptors, causing increase in RANKL and M-CSF and hence resorption in the short-term. BUT, increases availability of both Ca++ and Phosphate, so lots of substrate for mineralization during bone formation

affect of Vit D on Bone

calcitonin

-works to lower plasma calcium, beginning only at calcium levels of 9.5 or higher

osteoclast

-bind up osteoclasts to decrease bone resorption to decrease serum calcium

what is the target cells of calcitonin

vitamin D

increases serum calcium and phosphate

-cause loss of calcium at the kidney

-reduces calcium absorption in the intestine

affect of cortisol on calcium:

decrease bone formation during remodeling-

-leads to OSTEOPOROSIS

long term effects of cortisol on bone

increased bone turnover

increased alkaline phosphatase is a sign of

yes! due to the increased filtered load of calcium

does PTH increase calcium excretion?

-decreased production of 1,25-dihyddroxycholecalciferol decreases calcium gut absorption

-kidney failure decreases calcium reabsorption

-causes increased PTH---> bone loss (osteomalacia)

-increased serum phosphate complexes free calcium, decreasing calcium

affect of chronic renal failure on calcium and bones

Secondary hyperparathyroidism

high PTHH, low calcium, high phosphate, VERY low vitamin D

tertiary hyperparathyroidism due to sustained secondary hyperparathyroidism

ESRD may also be called

primary hypoparathyroidism

-low PTH, low calcium and tetany , high serum phosphate, low urinary phosphate

Pseudohypoparathyroidism

Defective Gs protein in kidney and bone, which causes end-organ resistance to PTH.

Heterozygous inactivating mutation in the GNAS1 gene that codes for α-subunit of the stimulatory G protein

Pseudohypoparathyroidism type 1A (Albright hereditary osteodystrophy)

•Hypocalcemia and hyperphosphatemia occur (as in hypoparathyroidism), which are not correctable by the administration of exogenous PTH

-Circulating PTH levels are elevated

•Round face, short stature with a stocky habitus, brachydactyly, subcutaneous ossification, and dental anomalies, Developmental delay, obesity (early-onset), and relative macrocephaly

presentation of pts with pseudohypoparathyroidism

PTH-related peptide (PTHrP)

some malignant tumors secrete _________ resulting in hypercalcemia, hypophosphatemia, increased urinary pohsphate, decreased serum PTH

familial hypocalciuria hypercalcemia

AD mutation in calcium sensing receptor or downstream regulators

-increase the parathyroids setpoinnt for calcium, making parathyroids less sensitive to calcium

-decreased ionized calcium and increased PTH; secondary hyperparathyroidism

result of rickets and osteomalacia

calcipenic rickets

-vit D deficiency due to decreased 25-OH causing rickets

phosphotenic rickets

phoshapte transport defects, excessive FGF23 causing rickets

Secondary hypoparathyroidism

rare but seen in sarcoidosis