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Transcript

Disorders of Calcium and Phosphorus Regulation of Small Animals

Laura Vega, DVM, MS, DACVECC (Emergency and Critical Care)

  1. Know the forms of calcium in circulation, the main factors that influence their distribution, and the differences between total and ionized calcium measurements
  2. List the main differential diagnosis of hypo- and hypercalcemia in dogs and cats, their mechanism, and expected calcium-phosphorus pattern if applicable
  3. Know the clinical signs associated with hypo- and hypercalcemia
  4. Recognize indications for emergent treatment of hypocalcemia, hypophosphatemia, and hypercalcemia, and the recommended therapies

OBJECTIVES

Protein-bound Ca

iCa

Complexed Ca

HypoAlb

Normal

CALCIUM IN CIRCULATION

tCa

  • iCa or free ionized calcium (55%): biologically active
  • Protein bound calcium (35%): albumin and globulins
  • Complexed calcium (10%): bound to phosphate, bicarbonate, citrate, lactate, oxalate

Largest body stores found in bone (and teeth for Phos) with about 1% in plasma/extracellular fluid

Calcium & Phosphorus

Hyperphosphatemia → "mass law" → hypocalcemia If Phos (mg/dl) x tCa (mg/dl) > 60-70 → tissue mineralization

  • iCa is tighly regulated by interacting feedback loops involving iCa, PTH, calcitriol and calcitonin
  • PTH related protein (PTHrP) binds to PTH receptors in bone and kidneys
  • Phosphorus absorption and excretion are regulated with calcium
  • Interaction of Ca-Phos is important:

Calcium & Phosphorus

Hypocalcemia

Chronic renal failure (early)Decreased renal phosphate clearance resulting in hyperPhos and Ca-Phos precipitation in tissuesDecreased renal synthesis of 1-alpha-hydroxylase leading to decreased calcitriol

HypoalbuminemiaLow tCa, normal iCa; clinically insignificantCan mask hypercalcemia

Acute pancreatitisPrecipitation of calcium in peripancreatic fat +/- hypomagnesemia and calcitonin release

Eclampsia or puerperal tetanyIncreased Ca mobilization for fetal skeletons and milk production+/- poor diet intake or parathyroid atrophy from Ca supplementation

Differential diagnosis (Common)

  • Secondary to hyperphosphatemia from:
    • Phosphate-containing enema
    • Acute kidney injury, urinary tract obstruction
    • Rhabdomyolysis
    • Tumor lysis symdrome
  • Hypoparathyroidism: primary/autoimmune vs iatrogenic
  • Alkali administration (sodium bicarbonate): increased binding to proteins and HCO3-
  • Ethylene glycol intoxication: Ca-oxalate crystalluria and tissue deposits with oxalic acid
  • Malabsorptive gastrointestinal disease
  • Blood transfusions: chelation with citrate
  • Hypocalcemia of critical illness

Differential diagnosis (occasional)

  • Measure serum iCa and PTH if concerns for hypoparathyroidism
  • Abdominal ultrasound/pancreatic lipase (cPLI or fPLI) if concerns for pancreatitis
  • Abdominal ultrasound/endoscopic GI biopsies if concerns for malabsorptive GI disease

Additional diagnostics

If low Ca and high Phos

Chronic kidney disease, acute kidney injury, urinary tract obstruction, hypoparathyroidism, phosphate-containing enema, or other causes of hyperPhos

Diagnostic evaluation

UNCOMMONHypotensionPolyuria or polydipsiaRespiratory arrest or death

OCCASIONALSeizuresTachycardia/arrhythmiasPantingPyrexiaLethargyAnorexiaThird eyelid prolapse (cats)Posterior lenticular cataracts

COMMONMuscle tremors/fasciculationsFacial rubbingTetanyPaw chewingStiff gaitRestlessness or excitationHypersensitivity to stimuliAggressionDisorientation

Clinical signs

Asymptomatic vs signs from hypocalcemia-induced increased neuronal excitabilityOften episodic and worse with exercise, stress, excitement

Goal = resolution of clinical signs, not normalization of Ca levels

*ECG monitoring, stop if concerns for cardiotoxicity

0.5-1.5ml/kg IV over 10-20 minutes

  • Clinical signs of hypocalcemia
  • Severe hypocalcemia (iCa < 0.8mmol/L)
  • Continuous/fast decrease in Ca levels

Calcium gluconate 10%

Acute/emergent:

Calcium supplements

  • Increased substrate for absorption
  • Calcium carbonate (highest % Ca2+ available)

Vitamin D metabolites

  • Upregulate active intestinal transport of Ca2+
  • Calcitriol (most bioavailable), ergocalciferol

Subacute/chronic:

treatment

Hypercalcemia

PATHOLOGIC

  • Primary hyperparathyroidism: excessive PTH from parathyroid gland tumor
  • Hypercalcemia of malignancy
    • Humoral (tumor distant from bone): secretion of PTHrP, calcitriol, and/or cytokines
      • Lymphoma (common), AGASACA (less common), melanoma, thymoma, and carcinomas (uncommon)
    • Local (tumor in bone): secretion of PTHrP and/or cytokines, osteolysis
      • Lymphoma (common), multiple myeloma (less common)
    • Metastatic or primary bone neoplasia (rare)

Differential diagnosis

NON-PATHOLOGIC

  • Young growing animals
  • Hemoconcentration, hyperproteinemia
  • Sampling/laboratory error: lipemia, hemolysis, nonfasting sample

  • Chronic renal failure
    • Renal secondary hyperparathyroidism from decreased calcitriol production and hypocalcemia from Ca-Phos tissue precipitation
  • Hypervitaminosis D
    • Cholecalciferol → calcitriol: rodenticide intoxication, vitamin D supplements
    • Calcipotriol or calcipotriene: anti-psoriasis creams
    • Calcitriol glycoside-containing plants: Lillies, day-blooming jessamine
  • Granulomatous disease
    • Activated macrophages synthesize calcitriol
    • Fungal (blasto-, histo-, or coccidioidomycosis, aspergillosis), parasitic, sterile nodular panniculitis

Differential diagnosis

*HyperCa-induced AKI vs AKI with secondary HyperCa?

  • Idiopathic hypercalcemia (cats)
  • Hypoadrenocorticism
    • Dehydration/hyperproteinemia, decreased GFR
  • Non-malignant osteolytic lesions
    • Osteomyelitis, hyperthrophic osteodystrophy, disuse osteoporosis
  • Acute renal injury
    • Occasional after conversion from oliguria to polyuria, mobilization of Ca salts deposited in tissues
    • Grape/raisin intoxication induced AKI

Differential diagnosis

If concurrent azotemia

CKD, AKI, hypervitaminosis D, hypoadrenocorticism, hyperCa of malignancy, granulomatous disease

If both Ca and Phos are high

Hypervitaminosis D, chronic renal failure, hypoadrenocorticism, hyperCa of malignancy (local, osteolytic)

If high Ca and low-normal Phos

Primary hyperparathyroidism, HyperCa of malignancy (humoral)

  • Idiopathic hypercalcemia
  • Chronic kidney disease
  • Neoplasia (SCC, lymphoma)

Diagnostic evaluation

  • Neoplasia (humoral malignancy)
  • Primary hyperparathyroidism
  • Chronic kidney disease
  • Hypoadrenocorticism

Additional diagnostics

  • FNAs of lymph nodes, anal sac mass, or other palpable peripheral mass
  • Medical imaging of thorax/abdomen (radiographs, ultrasound) and FNA of any lesions found for malignancy or granulomatous disease
  • “Malignancy panel” (iCa, PTH, PTHrP) for primary hyperparathyroidism or cancer you haven’t found
  • Fungal urine antigen testing for granulomatous disease
  • ACTH stimulation test for hypoadrenocorticism
  • 25-hydroxycholecalciferol level for hypervitaminosis D (only detects metabolites of cholecalciferol rodenticide or vitamin D supplements)

Diagnostic evaluation

  • Renal
    • PU/PD (ADH inhibition), tubular damage (mineralization)
  • Neuromuscular (depressed cell membrane excitability)
    • Weakness, twitching, seizures
  • Gastrointestinal (direct effects on chemoreceptor trigger zone)
    • Vomiting, anorexia
  • Cardiac
    • Bradyarrhythmias, cardiac arrest

Non-specific signs from underlying disease if mild, vs related to hypercalcemia if mod-severe

  • Anorexia and lethargy
  • Idiopathic hyperCa: asymptomatic or weight loss and lethargy
  • Polyuria/Polydipsia
  • Anorexia
  • Vomiting

Clinical signs

Avoid steroids prior to definitive diagnosis

  • Furosemide, glucocorticoids
  • Bisphosphonates (decrease osteosclastic activity)

Dilution, calciuresis (↑ with natriuresis)

Ca binding to proteins and HCO3

Calciuresis, inhib bone Ca release

Calciuresis

Sodium bicarbonate

Glucocorticoids

Furosemide

IV fluids (NaCl 0.9% ideal)

Subacute/chronic:

  • Hypercalcemia-induced renal failure
  • High risk of tissue mineralization
  • Clinical signs of hypercalemia

Definitive treatment requires removing the underlying cause, but emergent or palliative therapy may be needed

Acute/emergent:

treatment

CLINICAL SIGNSIf severe (< 1 mg/dl), hemolysis, rhabdomyolysis, respiratory distress, and neurologic abnormalities

Potassium phosphate 0.01-0.06 mmol/kg/h IV CRI

COMMON CAUSES

  • Primary hyperparathyroidism
  • Malignancy-associated hypercalcemia
  • Diabetic ketoacidosis

TREATMENT

  • Prevent with proactive monitoring and supplementation
  • Emergent treatment is indicated for severe symptomatic hypoPhos and asymptomatic animals at risk for developing symptoms

Hypophosphatemia

CLINICAL SIGNSRarely causes clinical signs except from hypocalcemia or tissue mineralization

COMMON CAUSES

  • Chronic or acute kidney injury
  • Hypervitaminosis D
  • Hypoparathyroidism
  • Young growing animals

TREATMENT

  • Emergent treatment is rarely needed
    • IV fluids (NaCl 0.9% ideal)
    • Parenteral glucose +/- insulin
  • Chronic treatment
    • Dietary restriction (low protein diet)
    • Oral phosphate binders (i.e. aluminum hydroxide)

Hyperphosphatemia

lauravega@vt.edu

qUESTIONS?