Concentrations are maintained at very low levels (10,000 fold less than
serum concentration)
Rapidly buffered by cytosolic proteins and transported into organelles
or to the outside of the cell after an increase in intracellular iCa
If levels too high toxicity and eventual cell death
Most intracellular Ca is sequestered in organelles or bound to cellular
membranes or proteins
Most important proteins are calbindin, calmodulin, and troponin C
Calcium regulation requires integrated actions of PTH, vitamin D metabolites, and
calcitonin
o PTH and calcitriol (1,25-dihydroxyvitamin D3) are the main regulators of
calcium homeostasis
PTH is responsible for the minute-to-minute control of serum iCa
concentration
Calcitriol maintains day-to-day control
o Adrenal corticosteroids, estrogens, thyroxine, growth hormone, glucagon, and
prolactin have less influence on calcium homeostasis but may play a role
during growth, lactation, or certain diseases
o Intestine, kidney, and bone are major target organs affected by calcium
regulatory hormones
These interactions allow conservation of calcium in the ECF by renal
tubular reabsorption, increased intestinal transport from the diet, and
internal redistribution of calcium from bone
Intestines and kidneys are the major regulators of calcium balance in
health
Enteric absorption of calcium depends on physiologic status of
the intestines
o Acidity, presence of other dietary components, integrity of
the villi or presence of small intestinal dz, and degree of
enterocyte stimulation by calcitriol
o Most absorption occurs in the duodenum
Non-protein-bound calcium is filtered by the glomerulus and
undergoes extensive renal reabsorption
o Reclaiming >98% of the filtered calcium in health
Skeleton provides a major supply of calcium and phosphorus when
intestinal absorption and renal reabsorption inadequately maintain
normal serum calcium concentrations
Ca and Phos can be mobilized from calcium phosphate in the
bone ECF compartment
o These stores are rapidly depleted
Osteoblast limits the distribution of Ca and Phos b/t bone and ECF
o Exchangeable bone water is separated from ECF water by
the combined membranes of osteoblasts lining bone
surfaces
For greater or prolonged release of calcium from bone,
osteoclastic bone resorption must be activated
Vitamin D
Metabolism
o 25-hydroxyvitamin D produced in the liver is the major circulating form of
vitamin D and serves as a pool for further activation by 1-hydroxylation
Synthesis
o Dogs and cats inefficiently photosynthesize vitamin D in their skin and are
dependent on vitamin D in their diet
o Vitamin D ingested in the diet is absorbed intact from the intestine
o Vitamin D-binding protein transports vit D to the liver
Hydroxylation of vit D occurs in the liver to produce 25-hydroxyvitamin
D (calcidiol)
25-hydroxylase activity is not influenced by calcium or
phosphorus
Calcidiol does not have any known action in normal animals
In vitamin D intoxication, high levels of calcidiol are produced by
the liver and can induce hypercalcemia
Most impt step in bioactivation= 25-hydroxyvitamin D is further
hydroxylated to calcitriol in the proximal tubule of the kidney
This rxn is tightly regulated by ionic and hormonal control
mechanisms that modulate the activity of hydroxylase enzyme
systems
o 25-hydroxyvitamin D-1-hydroxylase system results in
formation of active calcitriol
o 25-hydroxyvitamin D-24R-hydroxylase system is the first
step of catabolism to inactive vitamin D metabolites
o Calcitriol can also be synthesized in activated macrophages and thymic
derived lymphocytes (impt in granulomatous dz and LSA)
o Inactive vitamin D catabolites are excreted through the bile into feces (<4%
is excreted in urine)
PTH
84 amino acid single-chain polypeptide
Synthesis and secretion
o Synthesized, secreted, and degraded by chief cells of the parathyroid glands
o The parathyroids synthesize and secrete PTH at a rate that is inversely
proportional to the concentration of extracellular calcium
o Very little PTH is stored w/in the parathyroid
Synthesis of new specific mRNA and translation to PTH are required to
maintain secretion
o After secretion, T is only about 3-5 minutes in serum
A steady rate of secretion is necessary to maintain serum PTH
concentrations
o Circulating PTH has many forms and not all have bioactivity
Can be confusing in assay interpretation
o Amount of PTH available for secretion is a fxn of the balance of synthesis and
degradation w/in chief cells
Controlled by calcitriol (thru the Vit D receptor) and extracellular iCa
concentration (thru effects on the plasmalemmal calcium receptor)
7
o
In the
o
o
Hypocalcemia
Normal homeostatic response to hypocalcemia
o A marked increase in PTH secretion in response to mild hypocalcemia in
seconds
Secretion of preformed PTH can maintain PTH concentrations for 1-1.5
hrs during hypocalcemia
o Decreased proportion of PTH that is degraded in the parathyroid chief cells
so more is available for secretion in ~40minutes
o Increased PTH leads to renal calcium reabsorption and phosphorus excretion
in minutes
o Increased PTH leads to bone mobilization of calcium and phosphate in 1-2
hrs
o After several hrs, increased PTH secretion stimulates the synthesis and
secretion of calcitriol
o Increased intestinal transport of calcium and phosphorus into blood follow
along w/ internal mobilization from bone
o Increased transcription of the PTH gene and synthesis of PTH mRNA,
enhancing chief cells ability to produce PTH w/in hrs
o Over days or weeks, further increases in PTH secretion are achieved by
hypertrophy and hyperplasia of chief cells in the parathyroid gland
Clinical Signs
o Increased nervous system excitement and tetany
Decrease in extracellular fluid calcium ion concentration results in
progressive nervous system excitement, due to increased neuronal
membrane permeability to sodium ions and increased ease of action
potential initiation
o At plasma calcium ion concentrations ~50% below normal, peripheral nerve
fibers become so excitable that they begin to discharge spontaneously
o Trains of nerve impulses pass to the peripheral skeletal muscles to elicit
titanic muscle contration= tetany (@ 35% below normal)
o The level of calcium ions that determines which features of tetany will be
manifested varies amongst individuals
o Threshold for tetany is lowered in states of hypomagnesemia and alkalosis
and increased in hypokalemia and acidosis
o Hypocalcemia may cause seizures because of its action of increasing
excitability in the brain
Diseases associated with Hypocalcemia
11
o Hypoproteinemia
Decreased albumin can cause low total calcium
most common cause of hypocalcemia but least consequential
usually mild and does not result in clinical signs
o Hypoparathyroidism
May occur spontaneously, but more often occurs following surgical
removal of thyroid and parathyroid tissue
If parathyroid gland suddenly removed, calcium falls from normal to 6-7
mg/dl with 2-3 days, phosphate may double
Insufficient PTH, osteocytic reabsorption of exchangeable calcium
decreases and osteoclasts become almost totally inactive
Tetany may develop
Laryngeal muscles are particularly sensitive and spasm may
cause respiratory obstruction
o Eclampsia
Hypocalcemia caused by a sudden demand (i.e. lactation) and an
inability to respond to this demand
Exacerbated when high calcium diets are fed before breeding or during
gestation
o Malabsorption
Intestinal malabsorption may produce hypocalcemia due to decreased
absorption of calcium and vitamin D (adult rickets)
Deficiency in both vitamin D and calcium can occur with steatorrhea as
vitamin D is fat soluble and calcium forms insoluble soaps with fat and
pass in feces
o Renal failure
2nd most common cause
Acute or chronic renal dz may cause hypocalcemia through several
mechanisms, including decreased formation of 1, 25dihydroxycholecalciferol and soft deposition of calcium salts secondary
to hyperphosphatemia
Increased serum phosphorus can result in decreased calcium due to the
mass law effect
to decrease iCa by 0.1, serum phosphorus must increase by 3.7
o Acute pancreatitis
Suggested mechanisms include sequestration of calcium into
peripancreatic fat (saponification), increased FFAs, increased calcitonin
secondary to glucagonemia, and PTH resistance or deficit from
hypomagnesemia
o Ethylene glycol toxicosis
Hypocalcemia secondary to chelation of calcium by oxalate
o Sepsis/Critical care
Ionized hypocalcemia is common in critically ill people and more
common if septic
Likely occurs in veterinary patients as well
magnitude of hypocalcemia is correlated to severity of illness
12
o
o
Hypercalcemia
Normal homeostatic response to hypercalcemia
o Opposite of what occurs in hypocalcemia
o Decreased PTH secretion, increased intracellular degradation of PTH in chief
cells, and decreased PTH synthesis
o Increased calcitonin secretion is stimulated in an attempt to minimize the
magnitude of hypercalcemia
o Hyperplasia of C cells in the thyroid gland results if the hypercalcemic
stimulus is sustained
This is an ineffective mechanism due to transitory effects of calcitonin
on osteoclastic bone resorption
o Calcitriol synthesis is decreased through direct inhibition by iCa and as a
result of decreased stimulation b/c of decreased PTH concentration
Clinical Signs
o Nervous system depression, decreased reflex activities, weakness,
coma/seizures
o Decreased QT interval, bradycardia, poor contractility
o Anorexia, nausea, vomiting, constipation, likely 2ndary to depressed GI
motility
o Renal effects
Decreased renal blood flow and decreased GFR due to the
vasoconstrictive properties of calcium
Decreased sensitivity of distal convoluted tubules and collecting ducts
to pH
13
o
o
o
o Non-pathologic
Lab error
Lipemia
Dehydration secondary to hemoconcentration
Increased serum protein due to increased binding of calcium to albumin
Young, growing animals
17
1 HyperPTH
Nutritional 2ndary
HyperPTH
Renal 2ndary
HyperPTH
HHM
Hypervitaminosis
D
Addisons
Idiopathic
Raisin/grape
toxicity
1 HypoPTH
Ethylene glycol
toxicity
Phosphate enema
Eclampsia
Hypoalbuminemia
tCa
or N
iCa
or N
Phos
or N
or N
PTH
or N
PTHrP
N
N
Vit D
N or
N or
, or N
or N
or N
N or
or N
or N
or N
or N
N
or N
or N
or N
or N
or N
unknown
N
N
unknown
unknow
n
, or N
N or ( w/
calcipotriene)
N or
, or N
Unknown
or N
or N
N or
N
N
N or
N or
N
N
, or N
or N
or N
Mild or
N
or N
or N
18