Milk Alkali Syndrome

Milk Alkali Syndrome

Milk Alkali syndrome is the triad of hypercalcemia, metabolic alkalosis, and renal insufficiency due to consumption of large amounts of calcium and absorbable alkali. For conventional diagnostic purposes, only hypercalcemia with an appropriate history of ingestions must be present.

The milk alkali syndrome consists of hypercalcemia, hyperphosphatemia (although with use of calcium supplements such as calcium carbonate, phosphate binding in the gastrointestinal tract may produce hypophosphatemia), metabolic alkalosis, and kidney failure.

It was most commonly observed years ago in patients who were treated for peptic ulcer disease with large doses of sodium bicarbonate or calcium carbonate antacids and milk. Kidney failure was mediated by metastatic calcification of the kidney resulting from excessive calcium and phosphorus absorption.

Kidney failure accounted for impairment of bicarbonate excretion. Currently it results from the use of calcium supplements in patients seeking to enhance bone formation, such as postmenopausal women with osteoporosis.

Synonym

Calcium Alkali Syndrome 

Presentations

Calcium-alkali syndrome presents in one of three patterns:

• 1.Acute: This stage occurs after approximately 1 wk of excessive calcium and alkali intake. Symptoms are attributable to hypercalcemia and may include nausea, vomiting, weakness, mental status depression, and confusion. Metabolic alkalosis is present with a normal or elevated serum phosphorus level. An elevated serum creatinine reflects acute kidney injury. Cessation of exogenous calcium and alkali leads to resolution of signs and symptoms.
• 2.Subacute or intermediate (Cope syndrome): Patients have typically ingested milk and alkali intermittently for yrs. Affected patients demonstrate symptoms of acute and chronic hypercalcemia and respond to medication withdrawal with gradual improvement. Kidney function is often mildly and chronically impaired.
• 3.Chronic form (Burnett disease): Symptoms of chronic hypercalcemia present after prolonged high calcium and alkali intake and include polyuria, polydipsia, myalgias, and pruritus. Physical evidence of metastatic calcification is detectable as nephrocalcinosis and band keratopathy. Laboratory findings are like those of the acute syndrome. Muscle aches and pruritus improve slowly as the plasma calcium concentration gradually improves. Minimal or no improvement in kidney function occurs due to irreversible damage.

Epidemiology & Demographics

In the early twentieth century, the calcium-alkali syndrome was associated with the Sippy antacid regimen for peptic ulcer disease that entailed ingestion of large amounts of calcium salts, particularly from milk and absorbable bicarbonate compounds. Kidney injury and alkalosis were followed by hypercalcemia. Following the developments of type 2 histamine receptor blockers and proton pump inhibitors, the syndrome virtually disappeared. However, since the 1980s, a resurgence of hypercalcemia associated with calcium-containing product use for osteoporosis prevention took place. In chronic kidney disease patients, calcium carbonate use as a phosphate-binder instead of aluminum hydroxide produced the “calcium-alkali” syndrome. This updated term supplants “milk-alkali syndrome,” as milk is no longer the source of calcium. The calcium-alkali syndrome was the third-most cause of hypercalcemia (12%) in hospitalized patients from 1990 to 1993, following hypercalcemia of malignancy and primary hyperparathyroidism.

Physical Findings & Clinical Presentation

• •Asymptomatic hypercalcemia:
  • 1.Less than half of all cases are incidental findings of hypercalcemia on random laboratory testing
• •Symptomatic hypercalcemia:
  • 1.Symptoms: Nausea, vomiting, anorexia, fatigue, vague abdominal pain, nephrolithiasis- and pancreatitis-related pain, constipation, myalgia, confusion, and psychosis. In chronic cases, polyuria and polydipsia may be reported (i.e., acquired nephrogenic diabetes insipidus)
  • 2.Physical examination and other testing: Mental status changes include anxiety, depression, and cognitive dysfunction; also shortened QT segment interval

Etiology

Overconsumption of supplemental calcium of 3 to 20 g daily, in association with volume depletion, renal impairment, or thiazide diuretic use, is the most common etiology. The resulting hypercalcemia reduces glomerular filtration of calcium and induces salt-wasting that further reduces the extracellular fluid volume, which lowers glomerular filtration more and increases bicarbonate reabsorption with metabolic alkalosis. Vomiting or diuretic-induced volume depletion aggravate hypercalcemia and alkalosis. The paradigm of demographics has shifted from young males with peptic ulcer disease in the nineteenth century to postmenopausal women, solid organ transplant recipients, bulimic patients, pregnant women, end-stage kidney patients who require dialysis, and elderly individuals who experience greater bone loss and are prone to development of hypercalcemia when ingesting excessive calcium supplements. Betel nut chewing, prevalent in Asia and the South Pacific, is associated with calcium-alkali syndrome.

Pathogenesis

The calcium-alkali syndrome has a generation and maintenance phase. The generation phase of hypercalcemia is due to the increased calcium absorption, decreased renal excretion, and saturation of bone buffering of calcium. The maintenance phase is promoted by hypercalcemia-induced volume depletion from diuresis and natriuresis by activation of the calcium-sensing receptor in the thick ascending loop of Henle, a decrease in glomerular filtration rate that reduces the filtration of calcium, and an increase in renal absorption of calcium as a result of volume depletion and metabolic alkalosis.

 Diagnosis

Differential Diagnosis

Hypercalcemia from other causes includes primary hyperparathyroidism, certain malignancies, and granulomatous disorders, including tuberculosis, sarcoidosis, silicosis, and granulomatous polyangiitis.

Laboratory Tests

• •Elevated serum ionized calcium (wide variation reported)
• •Elevated BUN and serum creatinine from acute kidney injury or chronic kidney disease
• •Elevated serum bicarbonate and arterial pH from metabolic alkalosis
• •Parathyroid hormone, usually suppressed by hypercalcemia in calcium–alkali syndrome, may be elevated, particularly if evaluated after treatment initiation
• •Serum phosphorus level is variable (historically high with milk ingestion but low with calcium carbonate ingestion due to gut phosphate-binding)
• •Hypomagnesemia

 Treatment

Nonpharmacologic Therapy

Hemodialysis is rarely required for severe renal dysfunction or markedly symptomatic hypercalcemia.

Acute General Rx

• •Discontinue all calcium and bicarbonate supplementation.
• •Volume repletion by intravenous saline, followed by loop diuretic administration to increase urinary calcium excretion.
• •Transient hypocalcemia may occur when patients are treated with loop diuretic followed by rebound elevation of PTH, a unique feature of the calcium-alkali syndrome that occurs upon sudden cessation of hypercalcemia.
• •Bisphosphonates are avoided due to prolonged suppression of serum calcium in calcium–alkali syndrome.
• •Patient education to limit future calcium supplementation from over-the-counter calcium supplements (TUMS) and antacids containing calcium carbonate (Calcarb, CitraCal, Caltrate).

Prognosis

Hypercalcemia and associated symptoms resolve with withdrawal of excess calcium supplementation and treatment of hypercalcemia. Acute cases typically resolve in 1 to 2 days, while chronic cases take longer. Patients initially presenting with kidney failure may incur residual kidney damage.

Disposition

Treatment is determined by degree of hypercalcemia and symptoms. Hospitalization is required for symptomatic patients or forpatients whose total serum calcium is >11.5 mg/dl and who may require intravenous saline volume repletion and other intensive treatments for hypercalcemia.

Referral

• •Endocrinology
• •Nephrology

 Pearls & Considerations

Comments

Detailed history of dietary supplements and over-the-counter medications can provide important clues. Many patients do not list calcium-containing dietary supplements as a medication. These supplements may also include vitamin D, thereby facilitating hypercalcemia.

Potential Sources of Alkali

From Johnson RJ, Feehally J: Comprehensive clinical nephrology, ed 2, St Louis, 2000, Mosby.

Alkali/Alkali Precursor	Source
Bicarbonate	Sodium bicarbonate: Pills, intravenous solutions, proprietary brands, e.g., Alka-Seltzer baking sodaPotassium bicarbonate: Pills, oral solutions
Lactate	Lactated Ringer solution, peritoneal dialysis solutions
Acetate, glutamate, propionate	Parenteral nutrition
Citrate	Blood products, plasma exchange, potassium supplements, alkalinizing agents
Calcium compounds (alkalinizing effect minimal when given by mouth), acetate, citrate, and carbonate	Calcium supplements, phosphate-binders