---

Calcium Metabolism - Complete Guide

---

The Big Picture: Why Does Calcium Matter?

• Neuromuscular excitability (nerve firing, muscle contraction)
• Cardiac rhythm
• Hormone secretion
• Intracellular signaling

---

The Calcium Homeostasis Diagram

---

1. Blood Calcium: The Three Fractions

---

2. Total Adjusted (Corrected) Calcium

Corrected Ca (mg/dL) = Measured Ca + 0.8 × (4.0 - serum albumin g/dL)

• For every 1 g/dL drop in albumin below 4.0, add 0.8 mg/dL to the measured total calcium
• Similarly, a deficit in immunoglobulins is corrected at 0.5 mg/dL per 1 g/dL deficit

---

3. GI Regulation of Calcium Absorption

A) Passive (Paracellular) Absorption

• Happens throughout the intestine, down a concentration gradient
• Accounts for ~5% of daily intake
• Not regulated - just depends on how much calcium is in the gut lumen

B) Active (Transcellular) Absorption - the regulated route

• Occurs mainly in the duodenum and proximal jejunum
• Calcium enters intestinal cells through the TRPV6 channel on the luminal side
• Transported across the cell bound to calbindin protein
• Pumped out the basolateral side into blood
• This active pathway is switched on by 1,25(OH)₂D (calcitriol) - the active form of Vitamin D
• Normally accounts for 20-70% of dietary calcium absorption

Vitamin D Activation Pathway

Factors Reducing Calcium Absorption

• Achlorhydria (low stomach acid) - calcium carbonate needs acid to dissolve; calcium citrate is better in these patients
• Bariatric surgery
• Pancreatic/biliary insufficiency (calcium binds unabsorbed fats)
• High calcium intake suppresses 1,25(OH)₂D synthesis (negative feedback)
• Low calcium intake does the opposite - stimulates 1,25(OH)₂D

---

4. Calcium-Sensing Receptor (CaSR)

• Parathyroid glands (primary location - controls PTH release)
• Thick ascending limb (TAL) of renal tubule (controls urinary calcium excretion)
• Thyroid C-cells, bone, intestine, and brain

1. Degrades PTH mRNA
2. Promotes cleavage of PTH into inactive fragments
3. Suppresses release of PTH granules

• Loss-of-function mutation (heterozygous) → Familial Hypocalciuric Hypercalcemia (FHH) - the "thermostat" is reset high; mild asymptomatic hypercalcemia with low urinary calcium - benign, no surgery needed
• Gain-of-function mutation (activating) → Autosomal Dominant Hypocalcemia - the "thermostat" is reset low; persistent hypocalcemia with low PTH
• Calcimimetics (e.g., cinacalcet) are drugs that activate the CaSR to suppress PTH in hyperparathyroidism

---

5. Renal Handling of Calcium

Urinary Calcium Excretion

• Normal: 100-300 mg/day in adults
• Hypercalciuria: > 300 mg/day (men), > 250 mg/day (women) - major risk factor for kidney stones
• PTH reduces urinary calcium excretion (increases reabsorption in DCT)
• High serum calcium activates renal CaSR → inhibits TAL reabsorption → increases urine calcium
• Thiazide diuretics reduce urinary calcium (used therapeutically in hypercalciuria/stone disease)
• Loop diuretics (furosemide) increase urinary calcium loss

---

6. Role of PTH in Calcium Metabolism

A) Bone - Release calcium from the skeleton

• Activates osteoclasts (bone breakdown cells) to resorb bone and release Ca²⁺ and phosphate into blood
• Acts quickly (within hours)

B) Kidney - Save calcium, dump phosphate

• Increases Ca²⁺ reabsorption in the DCT (keeps calcium)
• Decreases phosphate reabsorption in the proximal tubule (wastes phosphate in urine) - this is why PTH excess causes hypophosphatemia
• Activates 1-alpha hydroxylase → converts 25-OH-D to active 1,25(OH)₂D → more intestinal calcium absorption (indirect effect, takes hours-days)

C) Intestine (indirect via Vitamin D)

• PTH stimulates renal 1,25(OH)₂D production → 1,25(OH)₂D then increases intestinal calcium absorption

---

7. Hypercalcemia

The Classic Mnemonic: "Bones, Stones, Moans, and Groans"

• Bones - bone pain, pathologic fractures
• Stones - renal calculi, nephrocalcinosis
• Moans - psychiatric: depression, confusion, psychosis
• Groans - GI: nausea, vomiting, constipation, anorexia
• (Plus: polyuria, polydipsia, fatigue, muscle weakness, shortened QT interval)

Causes - Divided into Two Groups:

• Malignancy (most common in hospitalized patients) - either osteolytic bone mets (myeloma, breast cancer) or PTHrP secretion (PTH-related peptide - "humoral hypercalcemia of malignancy"); calcium often >14 mg/dL
• Granulomatous disease (sarcoidosis, TB) - macrophages produce excess 1,25(OH)₂D
• Thyrotoxicosis
• Vitamin D toxicity
• Immobilization
• Milk-alkali syndrome
• Thiazide diuretics
• Familial Hypocalciuric Hypercalcemia (CaSR loss-of-function)

Distinguishing Primary HPT from Malignancy:

• In primary HPT: PTH is elevated (the problem source) - asymptomatic, found incidentally
• In malignancy: PTH is suppressed (osteolysis is the driver) - usually symptomatic, calcium >14

Management of Hypercalcemia:

1. IV normal saline (volume expansion) - first and most important step
2. Loop diuretics (furosemide) - increase urinary calcium loss after volume repleted
3. Bisphosphonates (zoledronate, pamidronate) - inhibit osteoclasts; standard for malignancy-associated hypercalcemia
4. Calcitonin - rapid but short-acting; useful early
5. Steroids - effective for sarcoidosis, vitamin D toxicity, myeloma
6. Cinacalcet (calcimimetic) - activates CaSR; lowers PTH in primary HPT
7. Surgery (parathyroidectomy) - definitive treatment for symptomatic primary HPT

---

8. Hypocalcemia

Symptoms - Due to Neuromuscular Irritability:

• Chvostek's sign - tap the facial nerve just in front of the ear → facial muscle twitching
• Trousseau's sign - inflate BP cuff above systolic for 3 min → carpal spasm (most specific)
• Perioral and fingertip tingling (paresthesias)
• Muscle cramps, tetany
• Seizures (generalized)
• Anxiety, confusion, psychosis
• Prolonged QT interval on ECG → life-threatening arrhythmia
• Hyperactive deep tendon reflexes

Causes:

• Post-surgical (most common) - accidental removal of parathyroids during thyroidectomy or neck dissection
• Autoimmune hypoparathyroidism
• Infiltrative (iron overload, copper, granulomas, tumors)
• Radiation
• CaSR activating mutations (reset thermostat too low)
• Severe hypomagnesemia (Mg is required for PTH secretion AND PTH receptor action)

• PTH is elevated, but end-organs don't respond to it
• Low Ca²⁺ + high phosphate + high PTH

• Inadequate sun exposure, malnutrition, malabsorption
• Most common worldwide cause of hypocalcemia

• After parathyroidectomy for severe HPT - the suddenly PTH-deprived skeleton rapidly takes up calcium from blood

• Renal failure → phosphate retention → calcium-phosphate complexes → less free Ca²⁺

Management:

• Acute/severe symptomatic (tetany, seizures, QT prolongation): IV calcium gluconate (not bolus - can cause cardiac arrest; give slowly)
• Concurrent: Correct hyperphosphatemia, alkalosis, hypomagnesemia
• Chronic: Oral calcium supplements + vitamin D (calcitriol in hypoparathyroidism since the kidney cannot activate vitamin D without PTH)
• Thiazide diuretics - useful adjunct in hypoparathyroidism (reduce urinary calcium loss)

---

Summary: The Calcium Control Loop

Low blood Ca²⁺
      ↓
CaSR on parathyroid glands detects the drop
      ↓
PTH secreted ↑↑
      ↓
THREE simultaneous actions:
  1. Bone → osteoclast activation → Ca²⁺ released from skeleton
  2. Kidney → DCT reabsorbs more Ca²⁺ + wastes phosphate
  3. Kidney → activates 1,25(OH)₂D → gut absorbs more Ca²⁺
      ↓
Blood Ca²⁺ rises → CaSR detects it → PTH suppressed → back to normal

---