Hypercalcemia

  • General
    • Defined as total serum >10.2-10.3 mg/dl if normal albumin
      • Or ionized serum calcium >5.2 mg/dl
        • Only one that is active metabolically - No symptoms usually until >12 mg/dl
  • 1) Calculate Corrected Ca2+ if Albumin is low
    • CCa2+ = (0.8 x (normal albumin-pt albumin)) + serum Ca2+
  • 2) Repeat Serum Calcium + Measure Serum PTH
    • Distinguishes PTH dependent from non-PTH dependent
      • If Low/Normal: Get PTHrP
        • If Normal, Get Vit D (25-OH Vit D)
          • Granulomatous Disease, Exogenous Vitamin D, Acromegaly
      • High: Primary/Tertiary Hyperparathyroidism/FHH
        • Urinary Ca2+
  • Etiology
    • Increased calcium ECF levels and a decrease in renal clearance of calcium
    • 90% from Primary Hyperparathyroidism or Malignancy
  • Common Causes:
    • Parathyroid mediated (outpatients)
      • W/U: 24hr Urinary Calcium
      • A) Primary Hyperparathyroidism
        • MCC of hypercalcemia
        • Normal or elevated urinary calcium
          • (Ca2+ typically within 1mg/dl of normal)
          • 30% hypercalciuria
          • Low or low-normal serum phos
        • Parathyroid adenoma (~85%)
        • Hyperplasia (~15%)
        • Carcinoma (~1%)
          • Ca >14 typically
          • Resection
          • Cinacalcet if refractory to surgery
        • Elevated PTH
        • Diagnosis: PTH
          • If (+), DEXA Scan to characterize (nondominant distal ⅓rd of the radius)
        • Treatment
          • Surgery likely if:
            • Ca2+ >1 above ULN
            • Cr <60 or kidney stones
            • T score <-2.5 almost anywhere
            • Vertebral fracture
          • Limit Ca to 1000mg/day
          • Measure 25-hydroxyvitamin D
            • Replete if <20, goal 20-30 ng/dl
      • B) MEN syndromes, Jaw tumor syndrome
      • C) Familial Hypocalciuric Hypercalcemia (FHH)
        • Mutation in calcium sensing receptor
        • Leads to low urinary calcium excretion
      • D) Tertiary hyperparathyroidism (Renal Failure)
        • Elevated PTH
    • Non-parathyroid mediated
      • W/U: CXR, Serum and Urinary Electrophoresis, PTH-related peptide, Vitamin D
      • Hypercalcemia of Malignancy (hospitalized)
        • MCC of hypercalcemia among hospitalized pts
          • From osteoclast stimulation, PTHrP, or calcitriol production by tumor cells
        • Common Associated Tumors
          • Breast Cancer, Multiple Myeloma, Lymphoma, Squamous cell carcinomas of the lung, head, and neck
        • Parathyroid hormone-related protein (PTHrP)
          • 80% of malignancy-hypercalcemia
          • Humoral Hypercalcemia Malignancy (HHM)
            • Paraneoplastic syndrome related to SCC of the lung
            • Increased bone resorption, and resorption of calcium in the distal renal tubule
            • Increased phosphate excretion (hypophosphatemia)
            • Severe (>14) and rapid-onset hypercalcemia
            • Poor Prognosis, advanced malignancy
          • Squamous cell tumor, Renal and Bladder tumors, Breast and ovarian tumors
          • PTH mimic
          • Decreased PTH, increased PTHrP
        • Bone Metastasis
          • Breast cancer, Multiple Myeloma
          • Increased Osteolysis (stimulation of osteoclasts by local production of cytokines)
          • Phosphorus levels are usually normal, bone pain
          • Decreased PTH, PTHrP, Decreased Vitamin D
        • 1,25-dihydroxyvitamin D
          • Lymphoma
          • Increased calcium absorption
          • Decreased PTH, increased Vitamin D
      • Hypervitaminosis D
        • Hodgkin Lymphoma
        • Chronic Granulomatous Disease
          • If due to sarcoidosis/tuberculosis, excess vitamin D
          • Treatment
            • Only one responsive to corticosteroids (reduce calcitriol)
              • Inhibit VitD formation in mononuclear cells
      • Medications
        • Vitamin D Intoxication (increased GI absorption)
        • Over diuresis
          • Chlorthalidone, Thiazides
          • Hypercalcemia and hypomagnesemia
          • Contraction alkalosis with renal insufficiency
          • Hypokalemia
          • Increased resorption of calcium in distal tubule
          • Hypercalcemia usually mild <12 and rarely symptomatic
        • Milk-Alkali Syndrome
          • Excessive intake of calcium and absorbable alkali
          • Hypercalcemia, metabolic alkalosis and AKI
          • Bicarbonate levels are elevated, decreased renal excretion of bicarbonate
          • Renal vasoconstriction and decreased GFR
          • Renal loss of sodium and water, resorption of bicarbonate
          • Metabolic Acidosis
        • Lithium - Acromegaly, pheo (etc.) - Heart Failure or Renal Insufficiency
        • Loop diuretics CI (will worsen volume depletion)
          • May decrease potassium and magnesium
          • Increases sodium delivery to collecting ducts
            • May lead to ventricular tachycardia
            • Hyperthyroidism
              • Increased bone turnover
  • Symptoms
    • Often Asymptomatic
    • Profound dehydration
      • Fatigue, nausea, vomiting, constipation, pancreatitis
    • Polyuria, polydipsia, nephrolithiasis
      • Hypercalcemia-induced renal disease
    • Neuropsychiatric Symptoms (Anxiety, AMS)
    • Bone pain, Weakness
    • Impaired neuromuscular excitability, leading to weakness, diminished reflexes, decreases GI motility
    • Shortened QT interval, AV Block if severe
    • May induce Nephrogenic Diabetes Insipidus leading to polyuria and fluid loss
      • Decreased oral intake and polyuria cause volume depletion
  • Labs
    • Hypercalcemia ± hypophosphatemia/hypomagnesemia
      • (Intestinal binding, decreased renal reabsorption)
    • Metabolic alkalosis
    • Acute Kidney Injury
    • Suppressed PTH
  • Complications
    • Osteitis Fibrosa Cystica
  • Testing: PTH unless malignancy is suspected (Primary PTH is the MCC)
    • If (-) 2nd MCC is malignancy (Higher levels of calcium usually)
  • Differential Diagnosis
  • Treatment
    • 1) Discontinuation of causative agent
      • Isotonic saline followed by furosemide if due to HF/hypovolemic
      • Glucocorticoids if granulomatous or lymphomas
    • Asymptomatic or mild (<12)
      • No immediate treatment
      • Avoid thiazides, lithium, hypovolemia, bed rest
    • Moderate (12-14)
      • Treat only if symptomatic
      • Similar to severe
      • Bisphosphonates may be used
    • Severe (>14) or Symptomatic
      • Immediate
        • 1) Aggressive IVF with Normal saline (several liters, promotes urinary excretion)
        • 2) Intranasal Calcitonin (tone down, prevent resorption, inhibits osteoclast mediated bone resorption) + Bisphosphonates (take time to work)
      • Avoid loop diuretics unless volume overload (HF) exists - Long-term
      • Bisphosphonates (Zoledronic Acid, pamidronate)
        • Inhibit bone resorption and provide a sustained reduction in calcium levels
        • Takes 2-4 days, delayed effect
          • Renal Insufficiency or Heart Failure where hydration is unsafe
      • Hemodialysis - Due to Excessive Vitamin D, Granulomatous Disease, Certain Lymphomas
      • Glucocorticoids (Inhibit formation of 1,25-OH Vitamin D) - Gallium Nitrate = Bisphosphonates
      • Nephrotoxic, CI: >2.5 mg/dl