Pathophysiology Rounds 6/24/2010Calcium Regulation: PTH, Vit D, Calcitonin, PTHrp

Calcium Functions of Calcium

o Many intracellular and extracellular fxns and skeletal supporto Coagulation—necessary for activation of factors IX, X, prothrombino Muscle contraction—binds to troponin C which changes its shape and pulls tropomyosin

out of the way so that the myosin head and actin can interdigitateo Cardiac muscle contractiono Stabilizes Na+ channels on axons of nerves and prevents tetanyo Bone formation and resorptiono Control of hepatic glycogen metabolismo Cellular growth and divisiono Essential for release of Ach vesicles at nerve terminalso Involved in many enzymatic reactionso 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 matrixo Almost all non-skeletal calcium resides in the extracellular space

Small and biologically impt quantities are found intracellularly thougho 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 lactateo ~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

iCao Intracellular Calcium

Important secondary messenger in response to biochemical signals (i.e. hormones) transduced through the cell membrane

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

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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 reabsorptiono 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 -αhydroxylation 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

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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 α

Synthesiso Dogs and cats inefficiently photosynthesize vitamin D in their skin and are dependent on

vitamin D in their dieto Vitamin D ingested in the diet is absorbed intact from the intestineo 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

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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 αactive 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 synthesiso Serum PTH, calcitriol, phosphorus, and calcium concentrations are the principal regulators

for renal calcitriol synthesiso Chronic changes in serum calcium regulate the synthesis of calcitriol

These calcium changes can override signals from serum phosphorus and PTHo Deficiencies of phosphorus, calcium, and calcitriol lead to increased calcitriol formation

PTH and hypophosphatemia enhance the activity of 1 -hydroxylaseαo 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

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Renredoxin is the regulatory constituent of the 1 -hydroxylase enzyme system and αis 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 αsynthesis of the enzyme from the renal gene encoding it

Reduced dietary calcium intake can lead to stimulation of renal 1 -hydroxylase in αthe 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 loadingo 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 parathyroidso Importance of calcitriol in a tissue is proportional to the abundance of the VDR in the cells

Actions of calcitriolo 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 boneo Stimulates the kidney to reabsorb both calcium and phosphorus from the glomerular

filtrateo 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 intestineo Enhances the transport of calcium and phosphate from the intestinal lumen to plasma

across the enterocyteo 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

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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 enterocyteo 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 boneo 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 kidneyo Direct inhibition of 25-hydroxyvitamin D 1 -hydroxylase in the renal tubule, preventing α

overproduction of calcitriolo Facilitates calcium and phosphorus reabsorption from the glomerular filtrateo Necessary to work with PTH to reabsorb urinary calcium into blood

Effects of calcitriol on the parathyroid glando 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 glandso The parathyroids synthesize and secrete PTH at a rate that is inversely proportional to the

concentration of extracellular calciumo 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, T½ 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

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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)

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

Inhibitiono 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 hormoneo 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 metabolismo PTH circulates in blood w/ T1/2 of 3-5 mino Removed by macrophages

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o Kidney and bone also participate in destruction of intact PTHo Fragments of PTH are filtered by the glomeruli

Actionso 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 αtubules

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 hourso 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 osteocyte-osteoblast

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 hormoneo Osteoclasts are primarily responsible for the long-term action of PTH

on increasing bone resorption and overall bone remodelingo Increased renal tubular reabsorption of calcium is caused by a direct action on the distal

convoluted tubule

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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 resorptiono 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 milko Fxns as a paracrine factor in many fetal and adult tissue

Skin, mammary gland, endocrine tissue, muscle, lymphoid organs, kidney, bone, brain

o Fxns as an abnormal hormone in an endocrine manner in adults w/ HHM In the Fetus

o Fetuses maintain a higher serum iCa than their damso 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 grows9

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

hypocalcemiao Decreased proportion of PTH that is degraded in the parathyroid chief cells so more is

available for secretion in ~40minuteso Increased PTH leads to renal calcium reabsorption and phosphorus excretion in minuteso Increased PTH leads to bone mobilization of calcium and phosphate in 1-2 hrso After several hrs, increased PTH secretion stimulates the synthesis and secretion of

calcitriolo Increased intestinal transport of calcium and phosphorus into blood follow along w/

internal mobilization from boneo Increased transcription of the PTH gene and synthesis of PTH mRNA, enhancing chief cell’s

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 Hypocalcemiao 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

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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 feceso Renal failure

2nd most common cause Acute or chronic renal dz may cause hypocalcemia through several mechanisms,

including decreased formation of 1, 25-dihydroxycholecalciferol 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 3.7o 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 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/

lactateo 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 hypocalcemiao Phosphate enema

Due to rapid absorption of phosphate and subsequent mass law interaction with serum calcium

o Alkalosis Causes shift of calcium to the protein-bound state resulting in ionized hypocalcemia

o Transfusion of citrate anticoagulated bloodo EDTA contamination of blood

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Hypercalcemia Normal homeostatic response to hypercalcemia

o Opposite of what occurs in hypocalcemiao Decreased PTH secretion, increased intracellular degradation of PTH in chief cells, and

decreased PTH synthesiso Increased calcitonin secretion is stimulated in an attempt to minimize the magnitude of

hypercalcemiao 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 Signso Nervous system depression, decreased reflex activities, weakness, coma/seizureso Decreased QT interval, bradycardia, poor contractilityo Anorexia, nausea, vomiting, constipation, likely 2ndary to depressed GI motilityo 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 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 Hypercalcemiao 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 OAF-like

substanceso OAF is actually thought to reflect the presence of cytokines such as IL-

1, TNFα, TNFß 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 α, TNFß, 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

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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 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 calciuresiso Glucocorticoids increase calciuresis, reduce intestinal absorption, and

inhibit calcium resorption from boneo 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

hypercalcemiao 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

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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 anions—citrate, 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 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 initiationo 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

o 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

o Osteolytic lesions Including septic osteomyelitis and metastatic neoplasia

o Excessive use of intestinal calcium-containing phosphate binderso 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 iCao 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

o Granulomatous disease Blastomycosis, histoplasmosis, schistostomiasis have occasionally been associated

w/ hypercalcemia Nocardia and atypical Mycobacteria may be a cause in cats

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Excessive production of 1, 25-dihydroxycholecalciferol by macrophages has been suggested as the cause

normal macrophages express 1α-hydroxylaseo Non-pathologic

Lab error Lipemia Dehydration secondary to hemoconcentration Increased serum protein due to increased binding of calcium to albumin Young, growing animals

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tCa iCa Phos PTH PTHrP Vit D1° HyperPTH ↑ ↑ ↓ or N ↑ or N N N or ↑Nutritional 2ndary HyperPTH

↓ or N ↓ or N ↑ or N ↑ N N or ↓

Renal 2ndary HyperPTH ↓, ↑ or N ↓ or N ↑ or N ↑ N N or ↓ HHM ↑ ↑ ↓ or N ↓ or N ↑ or N ↓, ↑ or NHypervitaminosis D ↑ ↑ ↑ or N ↓ N N or ↑ (↓ w/

calcipotriene)Addisons ↑ ↑ ↑ or N ↓ or N N N or ↓Idiopathic ↑ ↑ ↑ or N ↓ or N N ↓, ↑ or NRaisin/grape toxicity ↑ unknow

n↑ or N unknown unknown Unknown

1° HypoPTH ↓ ↓ ↑ or N N or↓ N N or ↓Ethylene glycol toxicity

↓ ↓ ↑ or N ↑ N N or ↓

Phosphate enema ↓ ↓ ↑ ↑ N ↓, ↑ or NEclampsia ↓ ↓ ↓ Mild ↑ or N N ↓ or NHypoalbuminemia ↓ ↓ or N N ↑ or N N ↑ or N

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