Calcium/Bone/Parathyroid

HYPOCALCEMIA: Correct for Sodium for Albumin à 2/2 (see reference) à if in doubt check ionized calcium à iPTH, Magnesium, Vitamin D (25-OH), check 1,25-OH Vitamin D only if suspecting vitamin D deficiency or CKD à Rx:

a.     If symptomatic, and severe: IV SLOW infusion of Calcium Gluconate (0.5-1.5 mg elemental calcium/kg/h); switch to oral once symptoms have resolved

b.     If asymptomatic, and mild: Oral is okay (see reference)

Reference:    
1. Differential Diagnosis of Hypocalcemia (MKSAP Endo Table 30)

2. Treatment with Oral Hypoglycemia (MKSAP Endo Table 31)

HYPERCALCEMIA: rule out factitious hypercalcemia (check iCa++ under anaerobic conditions, and in ice) - Once True Hypercalcemia confirmed - check iPTH and iCa++ simultaneously - check PO43- and Vitamin D - DDx. 2/2 (MKSAP Table)  based on if PTH is high or low 
  • Asymptomatic or Symptomatic due to prolonged or severe disease (Nephrolithiasis, CKD, fragility fractures,  bony pain)
  • Treatment: 
    • Short-term interventions based on mild, moderate or severe hypercalcemia: IV Fluid, Furosemide, IV Bisphosphonate, SC Calcitonin, Denosumab (off-lable in CKD patients), Glucocorticoids (if increased intestinal calcium absorption)
    • Longterm treatment based on cause
  • Pathophysiological Classification of Hypercalcemia
    • Humoral Process
      • PTH - via Bone and via Vitamin D via Gut 
      • TSH
      • PTHrp
      • VItaminD
    • Source of Hypercalcemia  
      • GI (Vitamin D, Milk Alkali, Hyperpara via Vitamin D)
      • Kidney
      • Bone (Malignancy, Immobilization, Vitamin D, TSH)
  • Hormonal Axis
    • Calcium - PTH - 2 end-organ 
      • Bone : Multiple actions in bone
        • Direct actions: Increase bone remodeling by increasing number of osteoclasts (do not have PTH receptors) and osteoblasts (have bone receptors) ( this action occurs within hrs)
          • Continuous exposure: Bone resorption
          • Intermittent exposure (few hrs a day): Net effect is bone formation
        • Indirect actions: PTH mediated action on osteoclast is indirect via cytokines released from osteoblasts
      • 3 effect in Kidney 
        • Ca reabsorption: Distal tubule, 
        • PO43- excretion: Proximal tubule, 
        • Increase 1,25 Vitamin D)
    • 25, OH Vitamin D - Increase PTH, and Low PO43- will increase 1, 25 OH - 3 target organ
      • Gut (Increase PO43- and Ca2+)
      • Bone (Resorption at high level, deposition at normal level)
      • Effect on Kidney is questionable
Case 4-2011: A 4-Year-Old Boy with Back Pain and Hypercalcemia
  • Understanding The Mechanism:
    • Calcitonin: (Harrisons 91 e)
      • hypocalcemic activity of calcitonin: is accounted for primarily by inhibition of osteoclast-mediated bone resorption and secondarily by stimulation of renal calcium clearance. These effects are mediated by receptors on osteoclasts and renal tubular cells.
      • Additional effects are through receptors present in the brain, the gastrointestinal tract, and the immune system 
    • Osteoblast and Osteoclast maturation pathways
    • Vitamin A mediated Hypercalcemia:
      • ATRA inhibits cell growth by down regulation of IL-6 R. Subsequent increase in IL 6 activates osteoclasts. See Harrison's  for how osteoclasts are activated. 
    • Multiple Myeloma , other malignancy and Hypercalcemia: IL-1 or TNF mediated osteoclast activation
    • Rhabdomyolysis and Acute Renal Failure: Due to mobilization of Ca++ present in the muscles; Increased PO43- leads to increased PTH - leads to increased Ca2+; Unexplained mechanism leads to increased Vit D which in turn leads to increased Ca absorption. 
    • Li : Increased in the set point at which Ca++ suppresses PTH, which leads to increased PTH release and increase in Calcium level
    • PTH mediated Hypercalcemia: Will have low Phosphorous, and high Cl, with ratio > 33. 

Reference:
       
Etiology of Hypercalcemia (MKSAP Nephro Table 27)
Clinical manifestations of hypercalcemia UpToDate
Diagnostic approach to hypercalcemia UpToDate

Hypercalcemia:
Case 4-2011 (4 yr old Child)

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