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 (-) 2^nd 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