What is Milk Alkali Syndrome?

Milk Alkali Syndrome (MAS) is a triad of hypercalcemia, metabolic alkalosis, and acute kidney injury (AKI). It occurs due to the excessive intake of calcium and absorbable alkaline substances, commonly in the form of calcium-based antacids. This syndrome was first described in patients consuming large quantities of milk and antacids for peptic ulcer disease, though it is now more commonly associated with calcium supplementation for osteoporosis or as an adjunct therapy for acid reflux.

Milk-Alkali Syndrome
Risk Factors	Chronic kidney disease Concurrent use of thiazide diuretics (eg, hydrochlorothiazide: promote volume depletion and calcium retention) ACE inhibitors NSAIDs (which decrease glomerular filtration).
Symptoms	Nausea and Vomiting Constipation Polyuria, Polydipsia Neuropsychiatric symptoms
Labs	Hyperclacemia, Metabolic alkalosis, AKI, Decreased PTH, Hypophosphatemia (due to intestinal binding of phosphate by Calcium Carbonate), Hypomagnesemia (decreased renal reabsorption of Magnesium)
Treatment	Discontinue the causative agent followed by Isotonic Saline with Furosemide

Pathophysiology of Milk-Alkali Syndrome

Excessive ingestion of calcium and alkaline salts leads to a cascade of physiological changes:

• Renal Vasoconstriction
  Hypercalcemia induces renal vasoconstriction, reducing renal blood flow and causing a decrease in the glomerular filtration rate (GFR).
• Loop of Henle Dysfunction
  Hypercalcemia activates the calcium-sensing receptor (CaSR) on the basolateral membrane of the thick ascending limb. CaSR activation inhibits the ROM-K channel → this reduces potassium recycling → the Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2) slows due to lack of K⁺. The loss of NKCC2 activity eliminates the normal lumen-positive voltage that drives paracellular Ca²⁺ and Mg²⁺ reabsorption, causing hypercalciuria and magnesiuria. This leads to:
  • Loss of sodium and water (loop-diuretic–like effect)
  • Hypovolemia, which further exacerbates the AKI
• Antidiuretic Hormone (ADH) Resistance
  Hypercalcemia impairs ADH activity in the renal collecting ducts, reducing the kidney’s ability to concentrate urine. This worsens polyuria and aggravates volume depletion.
• Increased Bicarbonate Reabsorption
  The metabolic alkalosis seen in MAS is primarily due to enhanced bicarbonate reabsorption in the proximal tubule
  (driven by volume depletion and decreased GFR).

Risk Factors

Certain conditions and medications can predispose patients to MAS:

1. Chronic Kidney Disease (CKD): Reduced renal clearance of calcium exacerbates hypercalcemia.
2. Thiazide Diuretics (e.g., Hydrochlorothiazide): Promote volume depletion and increased calcium reabsorption..
3. ACE Inhibitors: Impair renal autoregulation, reducing the ability to adapt to hypercalcemia.
4. NSAIDs: Reduce prostaglandin-mediated vasodilation, leading to decreased renal perfusion and worsening GFR.
5. Older adults/postmenopausal women: increased calcium supplement use.

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Clinical Features

The symptoms of MAS result from a combination of hypercalcemia, alkalosis, and renal dysfunction:

• Gastrointestinal Symptoms
  • Nausea and vomiting
  • Constipation

• Urinary Symptoms
  • Polyuria and polydipsia due to ADH resistance and volume depletion

• Neuropsychiatric Symptoms
  • Lethargy, confusion, or irritability

• Other Symptoms
  • Muscle weakness
  • Arrhythmias may occur in severe hypercalcemia

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Laboratory Findings

1. Hypercalcemia: Elevated total and ionized calcium levels
2. Metabolic Alkalosis: Elevated serum bicarbonate
3. Acute Kidney Injury (AKI): Increased serum creatinine due to hypovolemia and vasoconstriction
4. Decreased Parathyroid Hormone (PTH): Due to suppression by hypercalcemia
5. Hypophosphatemia: Calcium carbonate binds phosphate in the intestines, reducing phosphate absorption
6. Hypomagnesemia: Resulting from reduced renal magnesium reabsorption From impaired paracellular magnesium reabsorption in the TAL
7. Hypercalciuria: despite hypercalcemia, CaSR-mediated ROM-K inhibition reduces Ca²⁺ reabsorption.

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Management

The treatment of MAS focuses on removing the precipitating factor and correcting volume depletion and hypercalcemia:

1. Discontinue the Causative Agent: Stop calcium and alkaline salt intake.
2. Restore Volume Depletion: Administer isotonic saline to correct hypovolemia and improve renal perfusion.
3. Promote Calcium Excretion: Use loop diuretics like furosemide after rehydration to enhance calcium excretion.
   • Avoid thiazide diuretics, as they exacerbate calcium retention.

Clinical Pearls

MAS = hypercalcemia + metabolic alkalosis + AKI CaSR → ROM-K inhibition → NKCC2 failure → hypercalciuria Always normalize volume before giving loop diuretics Thiazides worsen MAS Modern cases usually from excessive calcium carbonate, not milk