Hypercalcemia – clinical syndrome caused by high serum [Ca⁺⁺]

• Defense Against Hypercalcemia – ß PTH, possibly also Ý calcitonin

Signs and Symptoms – severity depends on the rate of rise of serum Ca⁺⁺

• CNS – slow mentation, poor memory, confusion; emotional lability, depression, lethary, coma and death if severe
• GI – anorexia, nausea, vomiting, constipation, peptic ulcers (due to Ý gastrin and gastric acid secretion), pancreatitis
• Renal -nephrogenic diabetes insipidus (ß responsiveness of renal collecting duct cells to ADH Þ ß water reabsorption), kidney stones, nephrocalcinosis (leads to kidney failure)
• Musculoskeletal – Osteitis fibrosa cystica due to Ý PTH (Ý osteoclast activity, ß bone mineralization, fibrosis of trabeculae), generalized muscle weakness, fatigue, proximal weakness, aches in muscles and joints
• Soft Tissue – calcium phosphate deposition in subcutaneous tissues (pruritis), heart (conduction block), outer margins of cornea (band keratopathy – visible to observers, but no vision problems)

• (1) Increased Input of Bone Ca⁺⁺ into Circulation
• (a) Primary Hyperparathyroidism – most common cause of hypercalcemia overall
• Etiology:
• Parathyroid adenoma – 80%
• Diffuse hyperplasia – 20%
• Parathyroid Cancer – rare
• Ectopic secretion – rare (ex. Oat cell carcinoma of the lung)
• Multiple Endocrine Neoplasia (MEN) – Autosomal Dominant disorder with Ý tendency for endocrine tumors
• MEN Type I – Parathyroid hyperplasia, Pituitary tumors, Islet cell tumors (3 P's: parathyroid, pituitary, pancreas)
• MEN Type II – Parathyroid hyperplasia, Pheochromacytomas, Medullary carcinomas of the thyroid
• Action of Ý PTH – PTH does what it normally does
• Ý reabsorption of bone by osteoclasts and Ý release of Ca⁺⁺ from bone
• Ý renal Ca⁺⁺ reabsorption and Ý renal PO₄^2- excretion
• Ý renal bicarbonate excretion Þ Ý in serum chloride and ß in serum bicarbonate
• Ý activity of renal-1-hydroxylase Þ Ý Vit D so Ý Ca⁺⁺ absorption from the gut
• X-Ray Findings in patients with hyperparathyroidism
• resorption of distal phalanx
• gross periosteal absorption
• "Pepper pot Skull" – areas of radiolucent bone in the skull
• "Rugger Jersey Spine" – radiolucent bone in the vertebral bodies
• "Brown Tumor" – cyst seen in Osteitis Fibrosis Cystica
• Treatment – surgery, observation if asymptomatic
• (b) Hypercalcemia due to Malignancy – most common cause of hypercalcemia in hospitalized patients
• Etiology
• Ectopic secretion of true PTH – e.g., oat cell carcinoma of the lung (rare)
• Parathyroid cancers (rare)
• Bone Metastases ("Local Osteolytic Hypercalcemia") – Ý osteoclast activity
• Humoral Hypercalcemia – occasionally seen in solid tumors without bony metastases
• secrete PTH related peptide (PTHRP), homologous to N-terminal PTH
• Treatment – surgery to correct cancer
• Ý renal Ca⁺⁺ excretion: IV saline (Ý GFR), furosemide (Ý Na⁺ in distal tubule interferes with Ca⁺⁺ reabsorption)
• ß bone resorption: Biphosphonates (Pamidronate) incorporate into bone and interfere with osteoclast activity; Plicamycin is toxic to osteoclasts; Calcitonin directly inhibits osteoclasts
• Ý Ca⁺⁺ deposition in soft tissues: Oral phosphate precipitates calcium
• (c) Thyrotoxicosis – Ý thyroid levels can cause bone resorption; occurs in 23% of patients with thyrotoxicosis
• (d) Complete Immobilization in state of rapid bone turnover (adolescence or Paget’s) – Ý Ca⁺⁺ overwhelms kidney
• (2) Increased Intestinal Absorption of Ca⁺⁺
• Etiology
• hypervitaminosis D – increased ingestion of vitamin D
• sarcoidosis and granulomatous diseases – macrophages in granulomas contain 1-hydroxylase
• some lymphomas and leukemias – can produce ectopic 1-hydroxylase enzyme (rare)
• milk-alkali syndrome – due to treatment of peptic ulcer disease with large amounts of milk and bicarb
• Ca⁺⁺ comes from milk; bicarbinate lowers blood pH, inhibiting Ca⁺⁺ excretion
• Treatment – glucocorticoids to antagonize activity of Vitamin D
• (3) Increased Influx of Ca⁺⁺ from abnormal deposits in soft tissue
• usually transient, from resolution of calcium deposition disorder (acute renal failure or acute pancreatitis)
• (4) Decreased Renal Excretion of Ca⁺⁺
• Etiology
• Thiazide diuretics – Ý Ca⁺⁺ reabsorption
• Familial hypocalcuric hypercalcemia – deficit in Ca⁺⁺ receptor in renal tubule and parathyroid glands
• rare autosomal dominant disorder; often mild, not requiring treatment