2.6 Hypercalcemia, Hypocalcemia & Disorders of Mineral Metabolism

Calcium and bone homeostasis is governed by the coordinated actions of parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (calcitriol), fibroblast growth factor 23 (FGF-23), and calcitonin across the kidneys, intestines, and skeleton. The ABIM examination heavily emphasizes distinguishing benign from malignant hypercalcemia, managing metabolic bone diseases (osteoporosis and Paget disease), and mastering antiresorptive and anabolic drug safety profiles.

1. Hypercalcemia: Etiologies & Differential Diagnosis

Calcium Correction Formula

Total serum calcium reflects both free ionized calcium (physiologically active, ~50%) and protein-bound calcium (~40–45% bound to albumin): $\text{Corrected Total Calcium (mg/dL)} = \text{Measured Total Calcium} + 0.8 \times (4.0 - \text{Serum Albumin [g/dL]})$

Algorithmic Etiologic Discrimination

Over 90% of all hypercalcemia cases are caused by either Primary Hyperparathyroidism (outpatient setting) or Malignancy (inpatient setting).

+-------------------------------------------------------------------------------------------------------------+
| ETIOLOGY                     | INTACT PTH | PTHrP      | 1,25-(OH)2-D | 24-HR URINE Ca & CLINICAL PEARLS    |
+------------------------------+------------+------------+--------------+-------------------------------------+
| Primary Hyperparathyroidism  | ELEVATED / | SUPPRESSED | NORMAL /     | HIGH (CCCR > 0.02); 85% single      |
| (PHPT)                       | INAPPROPR. | (< 10)     | ELEVATED     | adenoma, 15% 4-gland hyperplasia;   |
|                              | NORMAL     |            |              | Low serum phosphate, normal/high Cl-|
+------------------------------+------------+------------+--------------+-------------------------------------+
| Malignancy: Humoral (HHM)    | SUPPRESSED | MARKEDLY   | LOW /        | HIGH; Squamous cell lung, head/neck,|
|                              | (< 10)     | ELEVATED   | NORMAL       | renal cell, bladder, ovarian cancer |
+------------------------------+------------+------------+--------------+-------------------------------------+
| Malignancy: Osteolytic Bone  | SUPPRESSED | NORMAL /   | LOW /        | HIGH; Breast cancer, Multiple       |
| Metastases                   | (< 10)     | LOW        | NORMAL       | Myeloma (local osteolysis via IL-6) |
+------------------------------+------------+------------+--------------+-------------------------------------+
| Malignancy: Lymphoma /       | SUPPRESSED | LOW        | MARKEDLY     | HIGH; Macrophage 1-alpha-hydroxylase|
| Granulomatous (Sarcoid/TB)   | (< 10)     |            | ELEVATED     | converts 25-OH-D -> active calcitriol
+------------------------------+------------+------------+--------------+-------------------------------------+
| Familial Hypocalciuric       | ELEVATED / | SUPPRESSED | NORMAL       | LOW (CCCR < 0.01; < 100 mg/24h);    |
| Hypercalcemia (FHH)          | NORMAL     |            |              | Inactivating CaSR mutation; BENIGN; |
|                              |            |            |              | No surgery indicated                |
+------------------------------+------------+------------+--------------+-------------------------------------+
| Medication-Induced           | SUPPRESSED | SUPPRESSED | VARIABLE     | Thiazides (decreased urine Ca);     |
| (Thiazides, Lithium, Milk-Alk| (Lithium:  |            |              | Lithium (shifts CaSR setpoint);     |
|                              | norm/high) |            |              | Milk-alkali: High Ca, low PTH, alk  |
+-------------------------------------------------------------------------------------------------------------+

Calculating the Calcium-to-Creatinine Clearance Ratio (CCCR)

To distinguish Primary Hyperparathyroidism from Familial Hypocalciuric Hypercalcemia: $\text{CCCR} = \frac{\text{Urine Calcium (mg/dL)} \times \text{Serum Creatinine (mg/dL)}}{\text{Serum Calcium (mg/dL)} \times \text{Urine Creatinine (mg/dL)}}$

• CCCR < 0.01: Strongly diagnostic of Familial Hypocalciuric Hypercalcemia (FHH).
• CCCR > 0.02: Consistent with Primary Hyperparathyroidism (PHPT).

Primary Hyperparathyroidism: Surgical Indications in Asymptomatic Patients

Definitive treatment is parathyroidectomy. For asymptomatic PHPT, surgery is indicated if ANY of the following international criteria are met:

1. Age < 50 years.
2. Serum Calcium > 1.0 mg/dL (0.25 mmol/L) above the upper limit of normal.
3. Skeletal Involvement: DEXA T-score <= -2.5 at lumbar spine, femoral neck, total hip, or distal 1/3 (33%) radius (cortical bone site), OR history of fragility fracture / asymptomatic vertebral compression fracture.
4. Renal Involvement: eGFR < 60 mL/min/1.73m2, OR 24-hour urine calcium > 400 mg/day (>10 mmol/day), OR presence of nephrolithiasis or nephrocalcinosis on imaging.

2. Acute Hypercalcemia & Hypocalcemia Management

Acute Severe Hypercalcemia (Serum Calcium > 14 mg/dL or Altered Sensorium)

1. Aggressive Volume Expansion (First-Line Immediate Intervention): IV 0.9% Normal Saline at 200–300 mL/hr, titrated to maintain urine output at 100–150 mL/hr. Reverses severe volume contraction and induces renal calciuresis. Loop diuretics (Furosemide) are strictly withheld until full euvolemia is achieved, reserved only for managing volume overload/CHF.
2. Calcitonin (Salmon Calcitonin, 4–8 IU/kg SC or IM every 12 hours): Rapid onset (lowers calcium by 1–2 mg/dL within 4–6 hours). Exhibits tachyphylaxis within 48 hours due to receptor downregulation; serves as a vital bridge until bisphosphonates exert their effect.
3. Intravenous Bisphosphonates (Zoledronic Acid 4 mg IV over 15 min or Pamidronate 60–90 mg IV): Potent inhibition of osteoclastic bone resorption. Onset is delayed (24–48 hours), with peak efficacy at 4–7 days. Dose reduce or avoid in severe renal impairment (eGFR <30–35 mL/min).
4. Denosumab (RANKL Inhibitor, 120 mg SC): Drug of choice for bisphosphonate-refractory hypercalcemia of malignancy and for hypercalcemia in severe renal failure.
5. Glucocorticoids (Prednisone 40–60 mg/day PO/IV): Highly effective specifically for 1,25-(OH)2-D-mediated hypercalcemia (Sarcoidosis, Lymphoma) by downregulating macrophage 1-alpha-hydroxylase.
6. Hemodialysis (Low/Zero Calcium Bath): Indicated for life-threatening hypercalcemia (>18 mg/dL) complicated by oliguric acute kidney injury or congestive heart failure.

Hypocalcemia: Etiologies, Signs & Emergency Management

• Etiologies: Hypoparathyroidism (post-thyroidectomy/parathyroidectomy, autoimmune APS-1, DiGeorge syndrome; low Ca, high Phos, low PTH); Hypomagnesemia (causes both PTH resistance and impaired PTH secretion; calcium will not correct until magnesium is normalized!); Severe Vitamin D deficiency; Chronic Kidney Disease; Acute Pancreatitis (retroperitoneal calcium saponification); Citrate Toxicity (massive blood transfusion); Hungry Bone Syndrome (post-parathyroidectomy).
• Neuromuscular Manifestations: Perioral numbness, digital paresthesias, carpopedal spasm, bronchospasm, hyperreflexia, and prolonged QT interval on ECG predisposing to Torsades de Pointes.
  • Chvostek Sign: Tapping facial nerve 2 cm anterior to ear tragus produces ipsilateral twitching of facial/lip muscles.
  • Trousseau Sign: Inflating blood pressure cuff to >20 mmHg above systolic BP for 3 minutes induces painful carpal spasm (flexion of wrist and MCP joints, extension of IP joints; "main d'accoucheur"). More sensitive/specific than Chvostek.
• Emergency Treatment: For acute symptomatic hypocalcemia (ionized Ca <0.9 mmol/L), administer 1–2 g IV Calcium Gluconate in 50–100 mL D5W over 10–20 minutes (calcium gluconate is preferred over calcium chloride due to reduced risk of tissue necrosis if extravasation occurs). Simultaneously replete magnesium with IV Magnesium Sulfate. Chronic hypoparathyroidism is managed with oral calcium (1–3 g/day) + active Calcitriol (0.25–1.0 mcg/day) targeting a low-normal serum calcium (8.0–8.5 mg/dL) to prevent hypercalciuria and nephrolithiasis.