Mineral

Front 1

Name five common disorders of bone and mineral metabolism.

Back 1

Osteoporosis, primary hyperparathyroidism, Vitamin D deficiency, Rickets and osteomalacia, Hypercalcemia of malignancy, Bone disease of kidney failure, Hypomagnesemia.

Front 2

Name five physiologic functions of calcium.

Back 2

*Maintain skeletal integrity
*Excitation-contraction coupling
*Coagulation
*Membrane stability & permeability
*Cell secretion of hormones
*Transmembrane signaling (cAMP, PI, calmodulin)
*Skeletal mineralization

Front 3

Where is calcium found in the body and at what proportions?

Back 3

Skeleton: 99%
Extraskeletal: 1% (of that, 70% soft tissues, 30% blood)

Front 4

Give a breakdown of calcium in blood – how it might be found and in what proportions? Which is physiologically active?

Back 4

Protein-bound – 40% (mainly albumin)
Ultrafilterable: Complexed to anions (phosphate and sulfate) – 10%
Ultrafilterable: Ionized Ca2+ -- 50%

Only free, ionized Ca2+ is physiologically active.

Front 5

What are clinical symptoms and signs of hypocalcemia?

Back 5

Irritability/Hyperactivity of the CNS: Irritability & anxiety, Paresthesia (tingling), Seizures, Laryngospasm, Bronchospasm

Also: Heart failure and muscle cramping.

Front 6

What are the clinical symptoms and signs of hypercalcemia?

Back 6

CNS: Decreased ability to concentrate; Increased sleep requirement; Depression; Confusion and Coma; Death

Also: Arrhythmias, Bradycardia, Muscle weakness

Front 7

What is measured in a lab calcium concentration test? What could influence the results of this test?

Back 7

Serum Calcium is measured (so protein-bound, complexed, and ionized)

This may be influenced by:
1.) Albumin levels (ex: liver disease = decreased albumin = decreased total Ca2+; or dehydration = increased albumin = increased total Ca2+)
2.) Anion concentration (ex: high phosphates and sulfate)
3.) Acid-base status

Front 8

What is “corrected calcium” in a lab measurement and why is this necessary?

Back 8

Serum calcium is measured in a lab value and that includes bound calcium. Fluctuations in albumin can change the result, but the free, ionized Ca2+ (remember, that’s what’s physiologically active) does not change.

So in order to measure free Ca2+, an adjustment is needed: For every gram the serum albumin is below 4.0, add 0.8 mg to the total serum calcium.

corrected Ca2+ = total Ca2+ + {(4.0 – measured serum albumin) x 0.8}

Front 9

What is the effect of an increase in anion concentration on serum calcium measurement? When might this occur?

Back 9

Proportion of free, ionized Ca2+ goes down (more is being complexed). Total serum calcium does not change, though. Increase in anion concentration could occur in kidney failure, for example.

Front 10

One patient exhibits symptoms of hypocalcemia with “normal” serum calcium lab values, while another exhibits no symptoms with “abnormal (low)” serum calcium lab values. How might this be explained?

Back 10

Person with symptoms of hypocalcemia probably has an increase in anion concentration. This alters free calcium levels but not total serum calcium.

Person with low values but no symptoms probably has lower albumin levels. This lowers serum calcium levels but does not affect free calcium.

Front 11

How does acid-base status affect serum calcium measures? What is the effect on total vs. free calcium levels?

Back 11

Changes in acid-base status change the ionized calcium levels by changing the fraction of Ca2+ that is bound to albumin. For example, if acidity goes up, albumin will bind more H+ ions in an attempt to buffer the excess acid. This kicks off Ca2+ from its place on albumin and results in an increase in free, ionized Ca2+.

Total serum calcium measurements do not change.

Front 12

At what three sites in the body is calcium regulated (mainly)?

Back 12

Bone, gut, kidney.

Front 13

True or false, diet is the only source for calcium?

Back 13

True (well, there’s also bone, but you don’t want that as your source)

Front 14

Where is calcium absorbed in the gut and how is it done? What other substance is necessary for absorption?

Back 14

Absorbed in the duodenum and upper jejunum.

1.) Active transport
2.) Concentration-dependent paracellular transport (when really high levels)

Vitamin D [1,25(OH)2 D] is critical to Ca2+ absorption

Front 15

What proportion of consumed Ca2+ will be absorbed in the gut in the presence of and in absence of Vitamin D?

Back 15

1/3 of consumed Ca2+ will be absorbed in the presence of Vitamin D. Only 5% will be absorbed in its absence.

Front 16

Ca2+ absorption decreases with intestinal diseases (like celiac disease), aging, and ________ deficiency in women.

Back 16

Estrogen

Front 17

The kidney filters 10,000 mg of Ca2+ daily. Of that, ___% is reabsorbed in the proximal tubule. The remaining __% is either actively reabsorbed or excreted by the distal tubule, under regulation by __________.

Back 17

98
2
Parathyroid hormone

Front 18

How much calcium is normally consumed, absorbed, and excreted in a day?

Back 18

1000 mg consumed
200 mg net absorption
200 mg net excretion

Front 19

What is idiopathic hypercalciuria?

Back 19

For unknown reasons, patients excrete too much calcium in their urine. This leads to osteoporosis as Ca2+ is lost from bones.

Front 20

What are some key functions of phosphorus?

Back 20

Maintain skeletal integrity
Intracellular: energy transfer, cell membrane stability, protein phosphorylation
Extracelular: Acid-base buffer, bone mineralization

Front 21

What is normal serum phosphate range? What is normal serum calcium range?

Back 21

Phosphate: 2.5-4.5 mg/dl
Calcium: 8.5-10.4 mg/dl

Front 22

True or false: phosphate levels are tightly regulated in the body?

Back 22

False. In contrast to calcium, there are wide excursions in phosphate levels. This is influenced by age, sex, diet, pH, hormones.

Front 23

What is “acid soluble phosphate”? What proportions of phosphate are ionized, complexed, and protein-bound in the body?

Back 23

Acid soluble phosphate is what the lab measures – it is what remains after acid-precipitation of phosphoproteins.

Ratios: 45% ionized, 40% complexed, 15% protein-bound

Front 24

Compare phosphate to calcium in terms of 1.) what the body’s source is 2.) where it is absorbed in the gut 3.) how it is absorbed 4.) role of vitamin D

Back 24

1.) Same as Ca2+: Diet is the only source for PO43– (mostly meat and dairy)
2.) Ca2+ absorbed in the duodenum and upper jejunum; PO43– in the jejunum.
3.) Same as Ca2+: PO43– has a both passive transport and vitamin D-dependent active transport mechanisms.
4.) UNLIKE Ca2+: Significant absorption of PO43– CAN occur in the absence of 1,20(OH)2D.

** PO43– is more directly linked to intake than Ca2+ → if you eat it, you will absorb it.

Front 25

What are the implications of the fact that PO43– does not require Vitamin D for absorption?

Back 25

This is part of the basis of the bone disease associated with kidney failure. You can’t get rid of the phosphate because of kidney failure, and you aren’t making any more 1,25(OH)2D -- yet more phosphate keeps coming in with the diet. This sets off some sort of cascade that she didn’t describe that somehow leads to bone disease.

Front 26

The kidney filters about 700 g of phosphorus/day, of which _____% is reabsorbed. PO43– reabsorption in the kidney is controlled by _____ , _______, and the newly-discovered _______. Phosphate metabolism is under the control of the kidney, and in order to maintain PO43– levels, urinary excretion must match ___________.

Back 26

85-90
1,25D
PTH
Phosphatonins
Intestinal absorption

Front 27

What are the three major functions of bone cells?

Back 27

1.) Modeling → dictate development of the structure
2.) Remodeling → control bone turnover (combined break down and formation)
3.) PO43– and Ca2+ balance

Front 28

What are the 3 types of bone cells and what are they for (in one word)?

Back 28

1.) Osteoclasts – Resorption (break down)
2.) Osteoblasts – Formation
3.) Osteocytes – end-stage osteoblasts (mechanotransducers)

Front 29

What is the source of osteoclasts? What is their function? What receptors do they have?

Back 29

Source: Hemopoietic stem cells that fuse into huge, multinucleated cells.

Function: 1.) dissolve the calcified bone matrix (hydroxyapatite) and in doing so … 2.) release PO43– and Ca2+ into the ECF.

Receptors: They have receptors for 1.) cytokines, which signal for the resorption to occur. Also 2.) calcitonin, which reduces osteoclast activity (lowers blood Ca2+ levels).

Front 30

What is the source of osteoblasts? What is their function? What receptors do they have?

Back 30

Source: mesenchymal stem cells that form clusters of mononuclear, cuboidal cells.

Function: 1.) synthesize bone collagen matrix and then 2.) mineralize it.

Receptors: They have receptors for 1.) PTH, which actually enhances osteoClast activity and increases blood Ca2+ levels. 2.) Vitamin D. 3.) Estrogen. 4.) Cytokines.

Front 31

Osteocytes are end-stage ______ that get incorporated into the matrix that they form. They are bathed in _____ and communicate with each other via _______.

Back 31

Osteoblasts
ECF
Canaliculi

Front 32

How do PO43– and Ca2+ flow in between bone?

Back 32

Through the canaliculi (long slender processes that link osteocytes).

Front 33

What does it mean that osteocytes are “mechanotransducers”?

Back 33

They are what transmit the message to osteoblasts that bone remodeling is needed (ex: during exercise or increased weight bearing). Note: astronauts lose bone density b/c no weight bearing.

Front 34

Describe the process of bone remodeling

Back 34

Starts with quiescence. Then the osteoblast attracts osteoclast to cell surface. Osteoclasts resorb bone to form Howship’s Lacunae (aka “resorption pit”). Osteoclasts disappear. Osteoblasts show up again and fill the pit, then fill it with osteoid and mineralize it from the inside out (or “bottom up”).

Front 35

Bone formation and resorption should be in balance. During what phases in life are they out of balance? During what phase will you have the most bone?

Back 35

Growing: more bone is formed than resorbed.

A couple years after puberty: you have the most bone you’ll ever have.

Resorption exceeds formation starting around age 40. Women have a very rapid drop-off of bone mass during menopause, and then it becomes a more gradual decline again. Men just go steadily downhill.

Front 36

Where is PTH stored? Where is it cleaved? Which is the active form (cleaved or uncleaved)?

Back 36

PTH is stored in secretory granlules in cells in the parathyroid gland. After secretion, the 84 amino acid polypeptide is cleaved at amino acid 34. This cleavage takes place in the kidney and liver. Only the intact 84 peptide is active (even though “activity” of the hormone resides in the first 34 amino acids). So the kidney and liver inactivate PTH.

Front 37

What are the functions of PTH?

Back 37

1.) Regulate serum PO43– and Ca2+ concentrations
2.) Bone remodeling
3.) Synthesis of 1,25(OH)2D

The overarching goal of all of this is to keep plasma calcium levels normal. (Remember: PTH acts on bone (directly), kidney (directly) and gut (indirectly) → increases bone resorption, prevents renal excretion, boosts intestinal absorption.)

Front 38

When plasma calcium ____(rises or falls)_____, parathyroid secretes PTH. (And visa versa.)

Back 38

Falls

Front 39

What is the primary regulator of PTH synthesis/secretion?

Back 39

Serum ionized Ca2+ levels.

Front 40

The mechanism of PTH secretion is by a _______ receptor on the plasma membrane of parathyroid cells. This receptor is linked by a G protein ____(what type)_____ to the effector protein _________. Activation leads to an increased in intracellular concentrations of _____ and _____, which ____(inhibits or stimulates)_____ PTH secretion.

Back 40

Calcium-sensing
Gq
Phospholipase C
IP3
Ca2+
Inhibits

Front 41

What are calcium emetics (sp?)?

Back 41

Molecules that bind to the calcium-sensing receptor on parathyroid cells. They are used for patients with renal-bone disease who produce too much PTH in order to fool parathyroid gland into thinking the calcium levels are higher than they really are → so they don’t get the adverse effects of too much PTH acting on bone.

Front 42

In the kidney, PTH binds to the ________ receptor, which activates a G protein _____(which one)____ that is coupled to effector protein _______. This effector protein catalyzes the conversion of ATP to ______, which activates protein kinases. Protein kinases phosphorylate intracellular proteins leading to inhibition of _____________. The net effect is ____(increased or decreased)_____ renal phosphate reabsorption and ____(increased or decreased)_____ renal phosphate losses.

Back 42

PTH/PTHrP
Gs
Adenylate cyclase
cAMP
Na+-PO43- cotransport at the luminal membrane
Decreased
Increased

Front 43

A high PTH ___(raises or lowers)____ calcium plasma levels and ___(raises or lowers)_____ phosphate plasma levels.

Back 43

Raises
Both! – raises it via bone and gut and lowers it via kidney. So net balance of 0.

Front 44

In a nutshell: what is the effect of PTH on the kidney?

Back 44

Proximal tubule:
*Inhibits Na+-PO43- cotransport – so increases PO43- excretion (phosphaturia), decreases plasma PO43-
*Increases 1,25D synthesis – so increases Ca2+ and PO43- reabsorption and plasma levels.

Distal tubule:
*Increases Ca2+ reabsorption – so increases plasma Ca2+

Note: Kidney effectively “uncouples” the release of PO43- with Ca2+. When bone is resorbed during a calcium shortage, phosphate comes along for the ride. Your body doesn’t need that, so it’s up to the kidney to eliminate it.

Front 45

In a nutshell: what is the effect of PTH on the bone?

Back 45

On osteoblasts: short-term effect → increases release of both Ca2+ and PO43- from bone.

On osteoclasts: long-term effect → increases plasma Ca2+ and PO43-.

Front 46

In a nutshell: what is the effect of PTH on the gut?

Back 46

INDIRECT!

In the upper jejunum – via 1,25 D (PTH doesn’t act on gut directly) → increases both Ca2+ and PO43- reabsorption and hence plasma levels.

Front 47

What is primary hyperparathyroidism and what is the main cause?

Back 47

Increased PTH even when serum Ca2+ is elevated. Also results in decreased PO43- levels. The most common cause is a benign tumor of the parathyroid gland. Tumor needs to be removed because too much PTH can harm bones. Also, hypercalcemia can cause all kinds of crazy badness.

Front 48

What type of hormone is Vitamin D (peptide, amine, steroid)? How is it activated?

Back 48

Steroid hormone. Biologically inert prohormone undergoes 2 hydroxylations to become biologically active → first in liver, second in kidney.

Front 49

What are the general actions of Vitamin D (list 4)?

Back 49

*Promotes mineralization of newly deposited bone.
*Actions increase both serum Ca2+ and PO43- by increasing 1.) absorption in the gut and 2.) reabsorption in the kidney.
*Increases 1.) osteoclastic bone resorption (at high levels) and 2.) osteoblastic bone formation.
*Regulates PTH secretion.

Front 50

What are sources of Vitamin D? What forms are more potent?

Back 50

(D3) Formed by action of UV light on 7-dehydrocholesterol in skin; also, fatty fish and cod liver oil.

(D2) formed by irradiation of ergosterol in plants and yeast (this is the supplement form).

Vitamin D3 is more potent and better than D2.

Front 51

What is used to measure body stores of vitamin D?

Back 51

Serum 25-(OH)D → (this is Vitamin D that has undergone the first round of hydroxylation in the liver)

Front 52

What is the biological “switch” in Vitamin D? What is the main site of regulation and what are the main regulators?

Back 52

In the kidney, 25(OH)D can be hydroxylated at two different spots:

C1 yields the biologically active 1,25(OH)2D
C24 yields the biologically inert 24,25(OH)2D

The hydroxylation occurs at different spots depending on the body’s need. The main site of regulation is via the 1α-hydroxylase in the kidney. The main regulators are plasma ionized Ca2+ and PO43- concentrations and by PTH.

Front 53

What are the target organs of Vitamin D? What are its receptors?

Back 53

Organs: Intestine, Bone, Kidney, Parathyroids (all direct)

Binds to NUCLEAR receptors for vitamin D → VDR

Front 54

Low serum PO43- _____(stimulates or inhibits)_____ 1α-hydroxylase action (and visa versa). PTH directly _____(stimulates or inhibits)____ 1,25(OH)2D production. 1,25(OH)2D ______(stimulates or inhibits)_____ PTH secretion.

Back 54

Stimulates
Stimulates
Inhibits

Front 55

What are the clinical consequences of Vitamin D deficiency?

Back 55

Vitamin D deficiency causes inadequate mineralization in bone. leads to painful, soft, tender bones that don’t hold their shape and fracture easily. (Rickets in children, osteomalacia in adults.)

Front 56

Where is calcitonin synthesized? What is the major stimulus for its secretion?

Back 56

Synthesized by parafollicular C cells of the thyroid.

Major stimulus – rise in plasma Ca2+

Front 57

What are the actions of calcitonin? What two conditions can it be used to treat?

Back 57

Inhibits osteoclastic bone resorption and increases urinary calcium excretion.

(Note: only seems to work this way as a drug agent → to treat osteoporosis or hypercalcemia. Absence of endogenous calcitonin (via thyroidectomy, etc) does NOT affect bone resorption nor calcium metabolism.)

Front 58

True or false, calcitonin plays a crucial role in calcium metabolism?

Back 58

False

Front 59

What are the clinical hallmarks for Primary Hyperparathyroidism vs. Humoral Hypercalcemia of Malignancy vs. Secondary Hyperparathyroidism?

Back 59

Primary Hyperparathyroidism : Both serum calcium AND the serum PTH are high.

Humoral Hypercalcemia of Malignancy : Serum calcium is high BUT the serum PTH is low.

Secondary Hyperparathyroidism : Serum calcium is low → which results in high PTH.

Front 60

What can cause secondary hyperparathyroidism?

Back 60

Not a disorder of parathyroid glands. Usually accompanies any clinical disorder that causes LOW SERUM Ca2+ → ex: dietary deficiency (or malabsorption disorders) of calcium or vitamin D, kidney failure.

Front 61

What causes humoral hypercalcemia of malignancy?

Back 61

Malignant tumors (ex: ovarian, lung, etc) can secrete a peptide very similar to PTH that acts on the same receptor. This leads to high serum calcium levels, but assays that measure PTH show low levels.