Parathyroid Hormone, Calcium Regulation

Question 1

Calcium in plasma

Answer 1

• total Ca: 9-10.6 mg/dl
• ionized Ca2+: 4.5-5.2 mg/dl (-50%)= the tightly regulated portion (like PTH)
• total Ca is typically measured
• Acidosis: blocks Ca2+ binding to albumin and increases free ionized Ca
• there is 1 kg Ca in body; 99% in skeleton, 1% in the ECF and muscles, 0.1% resides in the plasma, half of which is ionized
• when albumen is higher than normal, a high total Ca may be a false positive for hypercalcemia as the ionized portion may be perfectly normal. A correction factor is commonly applied to correct for these effects
• also under acidic (acidemia) conditions, albumen in plasma can bind less Ca2+ leading to a true increase in ionized Ca

Question 2

High Calcium

Answer 2

• greater than 12 mg/dl
• fatigue, apathy, anorexia, delirium, coma
• headache, intracranial pressure, muscle weakness
• high Ca2+ increases membrane polarization and reduced neural responses
• bradycardia: short Q-T interval
• polydipsia, polyuria, hypertension, calculi
• Ca2+ can be high in hyperparathyroidism
• an exception is for people with familial hypercalcemic hypocalcuria (FHH) where the Ca2+ is normally high without any symptoms

Question 3

Low Calcium

Answer 3

• less than 7 mg/dl
• learning retardation, apnea (children)
• tetany (spasms, seizures, numbness, muscle cramps)
• low Ca2+ reduced membrane polarization and increases hypersensitivity
• Long QT interval; cardiac output reduced
• Ca/PO4 defiency leads to weak bone development (rickets or osteomalacia)
• can be due to several primary and secondary causes (poor diet, malabsorption in the intestine, during lactation)

Question 4

Calcium Economy

Answer 4

• 3 organ systems: the digestive system (small intestines particularly), where calcium enters the system, the kidneys (renal tubules) and the bone (skeleton)
• over 80% of the ingested daily calcium is excreted into the feces
• the enormous role of the kidneys is in filtering 10X the average daily intake and recapturing all but about 175 mg or so
• the role of bone as a repositiory and buffer of calcium is an active one with a daily turnover under normal conditions of about 280 mg in adults
• if dietary intake of calcium is low the kidneys can compensate by increasing re-absorption of filtered Ca2+. In the long run, however (or when the kidneys aren’t functioning well) the bone reservoir will bear the brunt by increasing bone resorption causing loss of bone mass and density and in more extreme osteoporosis
• normal calcium homeostasis revolve around parathyroid hormone (PTH) and vitamin D, in addition we can list phosphate as well as the binding of PO4 to calcium will reduce the ionized calcium level and tends to buffer the calcium concentration

Question 5

Calcitonin

Answer 5

• produced by the thyroid gland and apparently has a stronger role in early development
• it is a potent inhibitor of bone resorption and salmon derived calcitonin was previously used as a treatment for osteoporosis
• its role in adult bone remodeling and Ca homeostasis remains unclear

Question 6

PTH Parathyroid Hormone

Answer 6

• peptide hormone secreted from parathyroid cells: PTH output high when Ca2+ is low
• target 1: kidney (rapid): increase Ca2+ by increasing re-absorption- distal tubule
• decrease PO4 by reducing re-absorption- proximal tubules
• increase 1,25 (OH)2 D3 (synthesis)
• target 2: bone cells (slow)
• increase osteoclastic resorption via receptors on osteoblasts
• increase Ca2+ and PO4 in ECF and plasma
• increase osteocytic osteolysis (rapid)

Question 7

PTH secretion

Answer 7

• the release of PTH by the chief cells of the parathyroid glands is stimulated by a reduction of Ca2+ in the extra-cellular fluids and plasma
• the calcium sensing receptors is a G protein coupled receptor with a signaling cascade involving intracellular Ca binding/release from the ER that controls the release and synthesis of PTH

Question 8

Familial hypercalcemic hypocalcuria (FHH)

Answer 8

• plasma (Ca2+) is stabilized at a high concentration (11.5 mg/dl) in a rare, curious condition
• urine excretion is low and the individuals are otherwise generally healthy and symptom free
• increased tubular re-absorption of Ca

Question 9

Ca Transport in Kidney

Answer 9

-PTH increases Ca2+ reabsorption by kidney distal tubules into the extracellular fluid and plasma
-60% of daily calcium reabsroption occurs in the proximal tubule (active transport) and 9% in the distal tubule (active transport, controlled by PTH concentration) and the rest is by passive diffusion
-an increase in PTH will recapture more calcium ions to bring up the Ca2+ in the plasma
-if Ca2+ in the plasma becomes too high, then PTH release is reduced below ambient and kidney reabsorption is reduced allowing more Ca to enter the urine
-PO4 reabsorption in the proximal tubule is reduced when plasma PTH is increased.
-The action of PTH on the renal proximal
tubule begins at the basolateral membrane, where the
hormone binds to its receptor. The receptor is coupled,
via a Gs protein, to adenylyl cyclase (Step 1). When
activated, adenylyl cyclase catalyzes the conversion of
ATP to cAMP (Step 2), which activates a series of
protein kinases (Step 3). Activated protein kinases
phosphorylate intracellular proteins (Step 4), leading to
the final physiologic action at the luminal membrane,
inhibition of Na+-phosphate cotransport (Step 5). Inhibition
of Na+-phosphate cotransport results in decreased
phosphate reabsorption and phosphaturia (increased
phosphate excretion)

Question 10

Vitamin D

Answer 10

• second major player in calcium homeostasis. The concentration of the active form of vitamin D is increased when plasma calcium drops. Its production is stimulated by increased plasma PTH releases through several mechanisms
• the two major targets of vitamin D are the small intestine and the skeleton. In the intestine, active vitamin D increases the transport of both Ca2+ and PO4 from the lumen into the plasma
• in bone, vitamin D primarily activates receptors on the osteoblast which in turn cause the cell to produce signaling molecules that promote the maturation and activation of osteoclasts. The stimulated osteoclasts actively resorb bone, liberating Ca2+ and PO4 from the mineral
• also vitamin D assists the transport of Ca2+ during the reabsorption process in the distal convoluted tubules of the kidney
• finally it tends to reduce the production of PTH in the parathyroid gland, acting as a buffer to the effect of low Ca (negative feedback)

Question 11

Vitamin D synthesis

Answer 11

• primary source of vitamin D precursors are cholesterol derivatives generated in the skin and are converted by sunlight to cholicalciferol (D3) which migrates into the bloodstream
• cholicalciferol is converted in the liver to 25-OH-cholicaliferal where it can be stored for a while and released slowly. This precursor is not active in the intestine and bone. It is also the molecule that is typically measured in the plasma to indicate the adequacy of vitamin D level
• finally the active form of vitamin D (1-25 dihydroxy vitamin D3) or calcitriol, is formed in the kidney by the action of the enzyme-1-alpha-hydroxylase on the circulating 25-OH-vitamin D3 and is enhanced by the action of PTH. Thus a low Ca2+ would lead to increased PTH and then to more conversion of vitamin D into its active form
• it is noteworthy that there are extra-renal sources of 1-alpha-hydroxylase that can produce some calcitriol too. Redundancy

Question 12

Calcium- Intestine

Answer 12

-increases active and passive transport of Ca and PO4 into the blood in the small intestine largely by increasing the synthesis of the transporter (calbindin)

Question 13

Rickets

Answer 13

• a chronic deficency of vitamin D and/or the dietary deficency of calcium or phosphorus during early development leads to disturbances in developing bone formation
• these disturbances are a result of poor mineralization due to a lack of sufficient calcium and results in weakened and mechanically distorted (bowed) long bones and is also typified by large and abnormal growth plates (epiphyses) on xray. This is nutritional rickets in children

-in adults, a similar problem with mineralization leads to poor bone formed during remodeling and is called osteomalacia

Question 14

Primary Hyperparathyroidism

Answer 14

• TOO MUCH Ca AND PTH
• a parathyroid gland nodule (adenoma) was out of control, secreting excess PTH, causing kidneys to increase Ca re-absorption, increasing serum Ca, and excrete more PO4
• high PTH also increases bone resoption liberating even more Ca into the ECF and increasing the alkaline phosphatase, a marker for bone turnover
• urinary Ca2+ excretion is high because the chronically high serum Ca will eventually increase Ca excretion despite the PTH effect
• the treatment is surgical removal of the offending nodule, leaving the 3 normal nodules

Question 15

Normal response to a simple hypocalcemic challenge

Answer 15

• increase PTH secretion
• increase bone resorption
• decrease phosphate reabsorption
• increase Ca2+ reabsorption
• increase urinary cAMP
• increase Ca2+ absorption (indirect via 1,25-dihydroxycholecalciferol)
• increase plasma Ca2+ toward normal

Question 16

Humoral Hypercalcemia of Malignancy

Answer 16

• the serum Ca was high due to the release of PTH-related peptide by the lung tumor cells. PTH-rp activates the same receptors as PTH and caused serum Ca2+ to increase from bone resorption and in the kidney and PO4 loss
• the PTH itself was low as it was inhibited by the high serum Ca

Question 17

Secondary hyperparathyroidism

Answer 17

• the parathyroid glands are normal but are stimulated to secrete excessive PTH secondary to hypocalcemia, which can be caused by vitamin D deficiency or chronic renal failure
• circulating PTH is elevated
• blood levels of Ca2+ are low or normal but never higher

Question 18

Hypoparathyroidism

Answer 18

s a relatively
-common, inadvertent consequence of thyroid
surgery (for treatment of thyroid cancer or Graves
disease) or parathyroid surgery (for treatment of
hyperparathyroidism).
- Autoimmune and congenital
hypoparathyroidism are less common. The characteristics of hypoparathyroidism are predictable:
-low circulating levels of PTH, hypocalcemia, and
hyperphosphatemia.
-decreased bone resorption, decreased renal Ca2+
reabsorption, and decreased intestinal Ca2+ absorption.
-Hyperphosphatemia results from increased
phosphate reabsorption.
-This disorder usually is
treated with the combination of an oral Ca2+
supplement and the active form of vitamin D,
1,25-dihydroxycholecalciferol.

Question 19

Pseudohypoparathyroidism

Answer 19

• hypocalcemia,hyperphosphatemia, and a characteristic phenotype consisting of short stature, short neck, obesity, subcutaneous
  calcification, and shortened fourth metatarsals
  and metacarpals.
  -have hypocalcemia and hyperphosphatemia.
  -circulating levels of PTH are increased
  rather than decreased, and administration of exogenous
  PTH produces no phosphaturic response and
  no increase in urinary cAMP.
• inherited autosomal dominant disorder in which the Gs protein for PTH in kidney and bone is defective. -When PTHbinds to its receptor in these tissues, it does not activate adenylyl cyclase or produce its usual physiologic actions. As a result, hypocalcemia and hyperphosphatemia develop.

Question 20

Familial hypocalciuric hypercalcemia

Answer 20

-autosomal dominant disorder is characterized by
decreased urinary Ca2+ excretion and increased
serum Ca2+ concentration.
- It is caused by inactivating
mutations of the Ca2+ sensing receptors in the
parathyroid glands (that regulate PTH secretion) and
parallel Ca2+ receptors in the thick, ascending limb
of the kidney (that mediate Ca2+ reabsorption).
When the renal receptors are defective, a high serum
Ca2+ concentration is incorrectly sensed as “normal”
and Ca2+ reabsorption is increased (leading to
decreased urinary Ca2+ [hypocalciuria] and increased
serum Ca2+ concentration). Because the Ca2+ receptors
in the parathyroid glands are also defective, they
incorrectly sense the increased serum Ca2+ as normal and PTH secretion is not inhibited as it would be in
normal persons.

Question 21

Phosphorus

Answer 21

• plasma (Pi) -2.5-4.5 mg/dl
• this is the inorganic portion (1/3 of total)
• 10-20% of Pi is protein bound
• Pi not very rigidly maintained, + or - 30%/ diurnal variations
• PTH influences reabsorption in proximal tubule

Question 22

Collagen Matrix Synthesis and Mineralization

Answer 22

• pre-collagen triple-helix molecules are synthesized by the osteoblasts, and then polymerized extracellularly forming fibrils and osteoid matrix that eventually mineralizes
• osteoblasts line the bone surfaces and when actively synthesizing become rounder and develop lots of ER
• osteoblasts also do most of the signaling in bone, although the osteocyte also seems to be important in sensing mechanical loading and generating remodeling responses to it
• osteoblasts have receptors for PTH, Vitamin D, estrogen, and many paracrine factors and grwoth factors
• they signal osteoclasts to mature and activate to resorb bone

Question 23

Bone mineralization

Answer 23

• bone mineral is about 65% by weight of bone substance. The rest is collagen (22%), fluid (10%) and 1-2% non collagenous proteins and cells
• microcystalline hydroxylapatite (HA): Ca10(OH)2(PO4)6 with Mg2+, CO3 2- and other trace constituents
• once seeded the crystals begin to coalesce and accumulate within and around the new collagen fibrils until after several weeks the newly formed area because fully mineralized with about 65% by weight of mineral and the structure will be rigid and very strong under compression and tensile loading

Question 24

Bone Remodeling

Answer 24

• despite bones rigid structure and strength, bone is constantly remodeling to one extend or another and has the ability of self repair
• the remodeling rate can accelerate or decline in response to a plasma calcium deficiency (mediated by PTH, and Vitamin D) injury, immobilization and a series of metabolic and hormonal changes and diseases.
• rate varies by location as well as age
• the spinal vertebrae and other trabecular areas of the skeleton can rapidly lose or gain bone whereas the cortex in the tibia in more stable.
• half the entired skeleton is replaced every 10 years
• the ability to dissolve bone in an organized fashion is the responsiblity of the osteoclast, a multi-nucleated large cell derived from the monocytes of the blood or marrow. They secrete acidic molecules to dissolve the mineral, and proteases to digest and phagocytize the collagen matrix
• mature osteoclasts do not divide but must develop from mononuclear precursors- they last a few days as others mature and take their place

Question 25

RANKL

Answer 25

• RANK-L/ORG
• osteoclast maturation and final activation to perform its task of resorbing bone appears to be greatly enhanced by a cytokine from the osteoblast lineage cells called RANK-L which binds to receptors on the osteoclast precursors called RANK
• the osteoblasts release of RANK-L is stimulated endocrine factors and other systemic hormones and growth factors, as well as several paracrine factors
• response to other stimuli, the osteoblastic cells can also produce a soluble substance known as OPG (osteoprotegerin) that specifically binds to the RANK-L sites and competitively inhibits the binding of RANK-L and therefore inhibits the production and activation of osteoblasts. Therefore ORG slows down bone resorption. So the rate of bone resorption in the remodeling sequence appears to be controlled by the ORG/RANK-L ratio. - target for osteoporosis treatment

Question 26

Regulators of Bone Remodeling

Answer 26

• PTH and Vitamin D- increase resorption (via receptors on osteoblastic line)
• Estrogen- reduces resorption (via receptors on osteoblasts), mode of action unclear (modulates IL-1,6?)
• Calcitonin (?)- transient inhibitor of osteoclasts (mainly in childhood)
• Glucocorticoids- primarily inhibits intestinal Ca absorption
• Growth hormones (IGF, TGFbeta)-stimulate formation
• Mechanical loading- locally promotes bone accrual and maintenance

Question 27

Mechanical Loading

Answer 27

• increased loading tends to stimulate bone formation and repair while decreased loading or immobilization tends to favor bone resorption over time
• currently, the osteocyte and its connected canaliculae seem to be the most sensitive elements in the response to mechanical loading and reduce the expression of sclerostin, an inhibitor of bone formation mediator when bone loading is weak

Question 28

Osteoporosis

Answer 28

• loss of bone mass associated with fracture
• trabecular and cortical sites. Can be local, systemic
• related to disease or aging (idiopathic). Women and men
• inappropriate or excessive remodeling (high turnover)
• loss of trabecular sites is most common and tends to occur first (more surface area)
• spicules or walls of trabecular becomes thinner and less numerous or separated and the apparent density is reduced
• in osteoporosis, cortical bone also becomes thinner and sometimes more porous
• the chronic lack of availability of Ca, vitamin D, estrogen or an excess production of PTH can lead to osteoporosis over time, as can immobilization and lack of suitable mechanical loading
• treatment- replacing deficient nutrients, loading exercise, or drugs designed to reduce osteoclastic resorption or stimulate osteoblastic bone formation