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Pathophysiology Rounds 6/24/2010

Calcium Regulation: PTH, Vit D, Calcitonin, PTHrp


Calcium
Functions of Calcium
o Many intracellular and extracellular fxns and skeletal support
o Coagulationnecessary for activation of factors IX, X, prothrombin
o Muscle contractionbinds to troponin C which changes its shape and pulls
tropomyosin out of the way so that the myosin head and actin can
interdigitate
o Cardiac muscle contraction
o Stabilizes Na+ channels on axons of nerves and prevents tetany
o Bone formation and resorption
o Control of hepatic glycogen metabolism
o Cellular growth and division
o Essential for release of Ach vesicles at nerve terminals
o Involved in many enzymatic reactions
o Intracellular calcium is one of the primary regulators of the cellular response
to agonists and is an important second messenger in the response to
biochemical signals
Calcium distribution w/in the body
o ~98% of body calcium is in the skeleton stored as hydroxyapatite
Most skeletal calcium is poorly exchangeable and <1% is readily
available
The small amt of rapidly exchangeable bone calcium arises from the
ECF in bone that is present between osteoblasts and osteocytes and
the bone matrix
o Almost all non-skeletal calcium resides in the extracellular space
Small and biologically impt quantities are found intracellularly though
o Extracellular Calcium (plasma/serum tCa)
Exists in 3 fractions
Ionized (iCa)
o ~55%
o The most impt biologically active fraction
Complexed
o Bound to phosphate, bicarbonate, sulfate, citrate, and
lactate
o ~10%
o May have an active biologic role
Protein bound (mostly albumin)
o ~35%
o No biologic role other than as a storage pool or buffering
system for iCa
o Intracellular Calcium
Important secondary messenger in response to biochemical signals (i.e.
hormones) transduced through the cell membrane
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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

o Osteoclasts secrete acid and proteases that result in


dissolution of the mineralized matrix of bone and mobilize
calcium and phosphorus
o Extracellular iCa is the actively regulated fraction of total Ca
When decreased PTH secretion is stimulated
PTH directly affects bone and kidney and indirectly effects the
intestine through calcitriol
Increases synthesis of calcitriol by activating renal mitochondrial
1-hydroxylation of 25-hydroxycholecalciferol
Calcitriol increases calcium absorption from the intestine and acts
with PTH to stimulate osteoclastic bone resorption
Calcitriol is necessary for differentiation of osteoclasts from
precursor mononuclear cells
PTH increases osteoclast number and stimulates osteoclast
function to increase bone resorption and the release of calcium
from bone to blood
Calcitriol induces renal transport mechanisms activated by PTH that increase
tubular reabsorption of calcium from the glomerular filtrate, preventing calcium loss
in urine

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)

Stimulation of calcitriol synthesis


o Serum PTH, calcitriol, phosphorus, and calcium concentrations are the
principal regulators for renal calcitriol synthesis
o Chronic changes in serum calcium regulate the synthesis of calcitriol
These calcium changes can override signals from serum phosphorus
and PTH
o Deficiencies of phosphorus, calcium, and calcitriol lead to increased calcitriol
formation
PTH and hypophosphatemia enhance the activity of 1-hydroxylase
o Low calcium or calcitriol concentrations lead to increased PTH concentrations
In the kidney, PTH mediates dephosphorylation of renal ferredoxin
(renoredoxin) and results in increased synthesis of calcitriol
Renredoxin is the regulatory constituent of the 1-hydroxylase enzyme
system and is inhibited by phosphorylation in the presence of high
concentrations of phosphorus or calcium in the renal tubule
PTH not only activates the renal 1-hydroxylase system but also
induces synthesis of the enzyme from the renal gene encoding it
Reduced dietary calcium intake can lead to stimulation of renal 1hydroxylase in the absence of detectable hypocalcemia
o Conversion of 25-hydroxycholecalciferol to 1,25-di-hydroxycholecalciferol
requires PTH
Inhibition
o Synthesis is inhibited by calcitriol, hypercalcemia, and phosphate loading
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o Calcium directly and indirectly inhibits calcitriol synthesis


Indirectly by inhibition of PTH synthesis and secretion
Inhibitory effects of chronic hypercalcemia can override the stimulatory
effects of increased PTH concentration in calcitriol production (as in
primary hyperparathyroidism)
Inhibitory effects of high concentrations of phosphorus on calcitriol
synthesis are impt and affect the activity of existing enzyme molecules
The Calcitriol Receptor (VDR)
o Present in many tissues in addition to bone, kidney, intestine, and
parathyroids
o Importance of calcitriol in a tissue is proportional to the abundance of the
VDR in the cells
Actions of calcitriol
o Overall effects of active Vitamin D
(1) Increase calcium absorption from the intestinal tract
(2) Enhance bone release of calcium and phosphorus
(3) Enhance renal absorption of calcium and phosphorus
(4) Suppress PTH production
o 1000x as effective as parent vitamin D and 500x as effective as its precursor
calcidiol in binding to the natural calcitriol receptor (VDR) in target cells
o Increases serum calcium and phosphorus concentrations, and its major
target organ for these effects is the intestine
There is also an impt contribution from bone
o Stimulates the kidney to reabsorb both calcium and phosphorus from the
glomerular filtrate
o Indirect effects on calcium balance
Up-regulation of calcitriol receptors in patients w/ uremia
Regulation of PTH synthesis and secretion by the parathyroids
Prevention or reversal of parathyroid hyperplasia in the uremic patient
Effects of calcitriol on intestine
o Enhances the transport of calcium and phosphate from the intestinal lumen
to plasma across the enterocyte
o ATP is required to transport calcium from the enterocytes into the blood and
to absorb phosphate from the intestinal lumen
Calcitriol induces synthesis of the plasma membrane calcium pump
(ATPase) that removes calcium from the enterocytes and the Na+phosphate co-transport protein that transports phosphorus into the
enterocyte
o It also increases the brush border permeability to calcium and induces the
synthesis of calbindin-D 9k
Calbindins serve as buffers to protect enterocytes from toxic
concentrations of calcium ion while ferrying calcium across the cell
o Directly stimulates rapid calcium transport across the enterocyte
o Normal dogs have a progressive decrease in the number of calcitriol
receptors and calbindin concentrations that regulate the efficiency of
calcium absorption in enterocytes from the duodenum to the ileum
Effects of calcitriol on bone
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o Necessary for bone formation and mineralization because it ensures an


adequate source of calcium and phophorus from the intestinal tract
Deficiencies in vitamin D lead to impaired bone growth (i.e. rickets,
osteomalacia)
o Necessary for normal bone development and growth b/c it regulates the
production of multiple bone proteins produced by osteoblasts (i.e. ALP,
collagen type I, osteocalcin, and osteopontin)
o Necessary for normal bone resorption b/c it promotes differentiation of
monocytic hematopoietic precursors in the bone marrow into osteoclasts
Effects of calcitriol on the kidney
o Direct inhibition of 25-hydroxyvitamin D 1-hydroxylase in the renal tubule,
preventing overproduction of calcitriol
o Facilitates calcium and phosphorus reabsorption from the glomerular filtrate
o Necessary to work with PTH to reabsorb urinary calcium into blood
Effects of calcitriol on the parathyroid gland
o Inhibits the production of PTH directly and indirectly
Binding of calcitriol to its receptor in parathyroid chief cells directly
inhibits PTH synthesis
Calcitriol stimulates intestinal calcium absorption which indirectly
reduces PTH secretion by increasing serum iCa
o Suppression of PTH synthesis is dose dependent and occurs before serum
iCa concentration is increased by the delayed effects of calcitriol on
intestinal calcium transport
o Considered the primary controlling factor for transcription of PTH gene and
subsequent synthesis of PTH
Suppression of PTH synthesis cannot occur in the absence of calcitriol
even w/ hypercalcemia
PTH secretion decreases 12-24 hrs after exposure to calcitriol

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)
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Calcitriol regulates expression of the calcium receptor gene so it is


considered to exert overall control over PTH synthesis and secretion
o Parathyroid gland has evolved most of its regulatory strategies to prevent
hypocalcemia as most sensitive control occurs at PTH synthesis and
secretion
o High serum iCa increases the rate of degradation of PTH w/in the gland to
protect against hypercalcemia
o PTH secretion is relatively constant (esp during normocalcemia)
Can have a pulsatile pattern in response to minor fluctuations in the
concentration of serum iCa
Relatively low rate of PTH secretion is needed normally to maintain
serum iCa concentration
Basal secretory rate of PTH is ~25% of the maximal rate
o Complete inhibition of PTH secretion is never achieved even in the presence
of severe hypercalcemia
o Stimulators of PTH secretion
Primarily hypocalcemia
Epinephrine
Isoproterenol
Dopamine
Secretin
Prostaglandin E2
Stimulation of nerve endings w/in the parathyroid
Inhibition
o Secretion is inhibited by increased serum iCa
Initial effect to decrease PTH secretion occurs w/in 2-3 minutes
Mediated by the calcium receptor
Slower effects are caused by inhibition of synthesis of PTH mRNA and
its translation to hormone
o Calcitriol also inhibits synthesis and completes a negative feedback loop
from the kidney b/c PTH stimulates renal calcitriol synthesis
The long negative feedback loop is completed when an increased
serum iCa results from PTH stimulation of renal calcitriol production and
subsequent enhanced GI absorption of Ca
Take hours to develop
The short negative feedback loop is mediated by the binding of
calcitriol to VDRs (Vit D Receptors) in parathyroid cells, with inhibition
of transcription of the PTH gene
VDRs are depleted in animals w/ uremia b/c of lack of renal
production of calcitriol
After the VDR binds calcitriol, the VDR-calcitriol complex acts in
the nucleus of the parathyroid chief cells by binding to specific
regions of the PTH gene called vitamin D response elements
(VDREs) and inhibiting transpcription of the PTH gene
Clearance and metabolism
o PTH circulates in blood w/ T1/2 of 3-5 min
o Removed by macrophages

o Kidney and bone also participate in destruction of intact PTH


o Fragments of PTH are filtered by the glomeruli
Actions
o Principal hormone involved in the minute-to-minute fine regulation of blood
calcium concentration
Exerts actions directly by influencing the fxn of target cells in bone and
kidney
Indirectly in the intestine
o Most impt effects on calcium:
(1) increase blood calcium
(2) increase tubular resorption of calcium, resulting in decreased
calcium loss in urine; also increases phosphate excretion
(3) increase bone resorption of calcium and phosphate and increases
#s of osteoclasts on the bone surfaces
(4) accelerate the formation of the principal active vitamin D metabolite
(calcitriol) by the kidney through a trophic effect to both induce
synthesis of and activate the 1-hydroylase in the mitochondria of renal
epithelial cells in proximal convoluted tubules
o Impt action on bone is to mobilize calcium from skeletal reserves into ECF
Increase in calcium results from an interaction of PTH w/ receptors on
osteoblasts that stimulate increased calcium release from bone and
direct an increase in osteoclastic bone resorption
Bone response is biphasic
Immediate effects
o Begins in minutes and increases progressively for several
hours
o Depends on the continuous presence of hormone
o Osteocytic membrane system (formed by connection
between osteocytes and osteoblasts) is believed to provide
a barrier that separates the bone itself from the
extracellular fluid
Between the membrane and bone is a small amount
of bone fluid
o The membrane pumps calcium ions from the bone fluid
into the extracellular fluid creating a calcium ion
concentration in the bone fluid only 1/3 that in the
extracellular fluid
o Osteocytes and osteoblasts have receptor proteins for
binding PTH
PTH is believed to stimulate this osteocyteosteoblast membrane pump by increasing calcium
permeability on the bone-fluid side of the osteocytic
membrane and a calcium pump on the other side of
the cell membrane then transfers the calcium ions
to the extracellular fluid compartment
Late effects
o These are slower, of greater magnitude, and are not
dependent on the continuous presence of hormone
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o Osteoclasts are primarily responsible for the long-term


action of PTH on increasing bone resorption and overall
bone remodeling
o Increased renal tubular reabsorption of calcium is caused by a direct action
on the distal convoluted tubule
PTH may also increase calcium reabsorption in the ascending thick limb
of LOH indirectly by increasing the net positive charge in the nephron
lumen and creating a stimulus for diffusion out of the lumen
o PTH also regulates the conversion of 25-hydroxycholecalciferol to calcitriol
and other metabolites of vitamin D
Calcitonin
Synthesized by C cells in the thyroid gland
Limits the degree of post-prandial hypercalcemia
o Acts to maintain serum iCa concentration w/in a narrow range
Secreted in response to hypercalcemia and also to a calcium-rich meal
Secretion increases during hypercalcemia
Only has minor effects on normal calcium homeostasis
Major target site is bone
o Inhibits osteoclastic bone resorption
o Effects are transitory so limited therapeutic use in hypercalcemia
Effects of calcitonin are much reduced in older animals due to a large reduction in
bone remodeling that occurs with age
Any initial reduction of the calcium ion concentration caused by calcitonin leads
within hours to PTH secretion, which almost overrides the calcitonin effect
PTHrp
Not strictly a calcium-regulating hormone
Produced widely in the body and has numerous actions in developing fetus and
adult animals independent of its role in cancer-associated hypercalcemia
N-terminal region of PTHrP binds and stimulates PTH receptors in bone and kidney
cells with affinity equal to that of PTH
Midregion of PTHrP is responsible for stimulating iCa uptake by the fetal placenta
C-terminal region can inhibit osteoclastic bone resorption
Actions
o Acts as an abnormal systemic calcium-regulating hormone and mimics the
actions or PTH in patients with HHM (humoral hypercalcemia of malignancy)
o Fxns as a hormone in an endocrine manner in the fetus and lactating dams
Necessary for normal endochondral bone formation in fetus and
neonate
Fxns as a calcium-regulating hormone in the fetus and is produced by
the fetal placenta
Produced by lactating mammary gland and is secreted into milk which
likely facilitates mobilization of calcium from maternal bones to
transport into milk
o Fxns as a paracrine factor in many fetal and adult tissue
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Skin, mammary gland, endocrine tissue, muscle, lymphoid organs,


kidney, bone, brain
Fxns as an abnormal hormone in an endocrine manner in adults w/ HHM
Fetus
Fetuses maintain a higher serum iCa than their dams
Fetal parathyroid glands produce low levels of PTH, and PTHrP fxns to
maintain iCa balance in the fetus
PTHrP is secreted by fetal parathyroid chief cells and the placenta
Also produced by the uterus where it is impt in permitting relaxation of
the smooth muscle of the muscularis as the fetus grows

o
In the
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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
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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
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Cause is unclear but likely multifactorial (AKI, transfusions,


hypomagnesemia, sepsis/SIRS all may contribute)
In critically ill people, it is associated w/decreased PTH secretion,
hypercalcitonism, and altered calcium binding to proteins
CPR may result in hypocalcemia in dogs and likely due to complexing of
calcium w/ lactate
Tumor Lysis Syndrome
Rapid destruction of sensitive tumor cells following chemotherapy
usually lymphoid or bone marrow tumors
Release of intracellular products can result in hyperkalemia,
hyperphosphatemia, and hyperuricemia
Hypocalcemia can develop as Ca-Phos salts are deposited into soft
tissues by mass-law effects from markedly increased serum phosphorus
Rare cause of hypocalcemia
Phosphate enema
Due to rapid absorption of phosphate and subsequent mass law
interaction with serum calcium
Alkalosis
Causes shift of calcium to the protein-bound state resulting in ionized
hypocalcemia
Transfusion of citrate anticoagulated blood
EDTA contamination of blood

o
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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
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Decreased tubular reabsorption of electrolytes


Decreased ability to concentrate urine
Necrosis and calcification of renal epithelial cells
Hypercalcemic nephropathy and renal failure
o When marked and accompanied by hyperphosphatemia, may cause
precipitation of calcium phosphate crystals throughout the body
Disease States associated with Hypercalcemia
o Humoral Hypercalcemia of Malignancy (HHM)
Most common cause of hypercalcemia in dogs, 3rd in cats
Possible mechanisms
Ectopic production of PTHrP stimulating osteoclastic resorption of
bone
Osteolysis by prostaglandin E (e.g. PGE2M is a potent mediator of
local bone resorption)
Ectopic production of osteoclast activating factor (OAF) or OAFlike substances
o OAF is actually thought to reflect the presence of cytokines
such as IL-1, TNF, TNF
Direct tumor osteolysis (must be extensive to cause
hypercalcemia)
o May occur with hematologic malignancies and can be
secondary to production of IL-1, TNF , TNF, and PGE2
o Also mets to bone can induction increased calcium by
induction of bone resorption associated with tumor growth,
cytokines, and PGE2
Hypercalcemia persists despite ongoing homeostatic mechanisms to
lower the calcium level (i.e. calcitonin secretion, decreased PTH
secretion, increased renal calcium excretion, and decreased intestinal
calcium absorption)
Neoplasms associated w/ HHM
Lymphoid tumors most common cause in dogs
o LSA, lymphocytic leukemia, thymoma, multiple myeloma
Anal sac apocrine adenocarcinoma
Others include:
o Exocrine pancreatic carcinoma, gastric carcinoma, nasal
adenocarcinoma, primary & metastatic bone tumors,
mammary gland tumors, FSA
o Primary hyperparathyroidism
Autonomous and excessive secretion of PTH causing extreme
osteoclastic activity w/ subsequent hypercalcemia
Most commonly caused by a solitary adenoma of one of the four
parathyroid glands (90%), less commonly secondary to benign
hyperplasia of 1 gland (5%) or malignancy (5%)
Signalment: dogs (5-15yrs), cats (8-15yrs), no sex predisposition
Siamese and Keeshond overrepresented
Clinical signs
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Dogs- PU/PD (isosthenuria), urolithiasis, anorexia, vomiting,


constipation, lethargy, exercise intolerance, muscle weakness,
shivering/twitching, sz
Cats- PU/PD +/- anorexia, vomiting, wt loss, weakness
Serum PTH is high or WNL
o A normal PTH is consistent w/ hyperparathyroidism in a
hypercalcemic, hypophosphatemic dog that is not
azotemic
o PTHrP should be undetectable
Urinary excretion of calcium is increased and excretion of
phosphorus is decreased
Hypophosphatemia can be severe, but serum phos may increase
as renal calcinosis and insufficiency develops
Bone lesions, soft tissue mineralization, and increased ALKP
(dogs)
Urolithiasis (CaOx, CaPhos) in 30% of patients
Cervical U/S helpful but false negatives possible
Radiographs may show extensive decalcification and punched out
cystic lesions in bones
On rare occasions, can develop crystal deposits in alveoli, renal tubules,
thyroid, stomach mucosa, and arterial walls
Treatment
Surgical excision
If severe hypercalcemia, to stabilize pre-op
o Saline diuresis, lasix to promote calciuresis
o Glucocorticoids increase calciuresis, reduce intestinal
absorption, and inhibit calcium resorption from bone
o Bisphophonates decrease osteoclast activity and function
and long-term use can decrease osteoclast #s
Prophylactic Vit D prior to sx may be beneficial in dogs w/ severe
hypercalcemia
o Secondary hyperparathyroidism
Caused by vitamin D deficiency (nutritional) or renal dz
Renal dz may result in increased retention of phosphate, then by law of
mass action (calcium x phosphate= constant value), plasma Ca
decreases, and PTH secretion increases due decreased Ca
Renal dz may result in inadequate fxn of renal tissue to form active Vit
D leading to a decreased calcium absorption from the intestines,
decreased plasma calcium, and increased PTH secretion and a loss of
direct inhibitory effect of calcitriol on PTH production and secretion
In dogs with increased tCa and normal iCa in CKD, elevation is urually
associated with an increase in complexed calcium fraction
Organic anionscitrate, phosphate, lactate, bicarb, or oxalate
If iCa also increased, may be a result of decreased GFR also
Hyperphosphatemia may also directly inhibit conversion to active Vit D
Renal osteodystrophy may result and historically has been the primary
indication for calcitriol administration
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Change in bone density, bone pain, and pathologic fracture


Calcitriol therapy may be indicated in cases of renal osteodystrophy,
with recorded evidence of progressive renal dz and
normophosphatemia (diet, phos binders)
Suppression of PTH should occur w/in 30 days of calcitriol initiation
Hypoadrenocorticism
2nd most common cause of hypercalcemia in dogs
Often accompanied by hypercalcemia (not completely understood)
iCa should be normal
~30% of dogs w/ gluco- and mineralo-corticoid deficiency will have
hypercalcemia
Unknown mechanism
Idiopathic Hypercalcemia (cats)
Most common cause in U.S. cats
46% have no clinical signs, 18% had mild wt loss, 5% had constipation
15% have urolithiasis
Long-haired cats may be over-represented
Osteolytic lesions
Including septic osteomyelitis and metastatic neoplasia
Excessive use of intestinal calcium-containing phosphate binders
Renal failure
Occasionally accompanied by hypercalcemia, in young dogs with
familial renal dz esp
Not a common manifestation of chronic renal failure in aged dogs
Has been associated w/ grape or raisin toxicity (increased tCa and
phos)
Lab findings
Increased phosphorus, normal or increased PTH, decreased or
normal iCa
Vitamin D toxicosis/cholecalciferol-containing rodenticides/Vitamin D
glycoside containing plants/psoriasis creams
Vit D toxicosis is an uncommon cause of hypercalcemia, but can occur
w/ excessive dietary supplementation
Ingestion of cholecalciferol or ergocalciferol containing rodenticides
produces an acute vitamin D toxicosis
Ingestion of plants that contain vit D glycosides (Cestrum sp and
Solanum sp) causes hypercalcemia, parathyroid atrophy, and soft tissue
mineralization
Psoriasis creams contain a vit D analogue (calcipotriene)
Usually develops within 24 hours of ingestion
Granulomatous disease
Blastomycosis, histoplasmosis, schistostomiasis have occasionally been
associated w/ hypercalcemia
Nocardia and atypical Mycobacteria may be a cause in cats
Excessive production of 1, 25-dihydroxycholecalciferol by macrophages
has been suggested as the cause
normal macrophages express 1-hydroxylase
16

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