Calcium-Alkali Syndrome

• Jesse Goldman, M.D.
• Jaime Baynes-Fields D.O., M.P.H.

 Basic Information

Definition

Calcium-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.

Synonyms

1. Milk-alkali syndrome

Presentations

Calcium-alkali syndrome presents in one of three patterns:

1. 1)

   Acute: This stage occurs after approximately 1 week 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. 2)

   Subacute or intermediate (Cope syndrome): Patients typically are encountered after milk and alkali have been ingested intermittently for years. 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. 3)

   Chronic form (Burnett’s 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 similar to 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.

ICD-10CM CODES
E83.52	Disorders of calcium metabolism

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 occurred. 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-leading cause of hypercalcemia (12%) in hospitalized patients from 1990 to 1993, following hypercalcemia of malignancy and primary hyperparathyroidism.

Physical Findings & Clinical Presentation

1. •

   Asymptomatic hypercalcemia:

   1. 1.

      Less than half of all cases are incidental findings of hypercalcemia on random laboratory testing

2. •

   Symptomatic hypercalcemia:

   1. 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.

   2. 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 reducing extracellular fluid volume that further lowers glomerular filtration and increases bicarbonate reabsorption with metabolic alkalosis. Vomiting or diuretic-induced volume depletion worsen hypercalcemia and alkalosis. Elderly individuals experience greater bone loss and are prone to developing hypercalcemia in the presence of excess calcium supplements. Betel nut chewing, a practice in Asia and the South Pacific, is associated with calcium-alkali syndrome. The nuts are bitter and coated with a compound that is converted to bicarbonate, fostering metabolic alkalosis.

Diagnosis

Differential Diagnosis

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

Laboratory Tests

1. •

   Elevated serum ionized calcium (wide variation reported)

2. •

   Elevated BUN and serum creatinine from acute kidney injury or chronic kidney disease

3. •

   Elevated serum bicarbonate and arterial pH from metabolic alkalosis

4. •

   Parathyroid hormone, usually suppressed by hypercalcemia in calcium-alkali syndrome, may be elevated, particularly if evaluated after treatment initiation

5. •

   Serum phosphorus level is variable (historically high with milk ingestion but low with calcium carbonate ingestion due to gut phosphate binding)

6. •

   Hypomagnesemia occasionally

Treatment

Nonpharmacologic Therapy

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

Acute General Rx

1. •

   Discontinuation of all calcium and bicarbonate supplementation

2. •

   Volume repletion by intravenous saline, followed by loop diuretic administration to increase urinary calcium excretion

3. •

   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 for patients whose total serum calcium is >11.5 mg/dl and who may require IV volume repletion and other intensive treatments for hypercalcemia.

Referral

1. •

   Endocrinology

2. •

   Nephrology

Pearls & Considerations

Comments

Detailed history of dietary supplements and over-the-counter medications (see Table E1) can provide important clues. Many patients do not list dietary supplements as a medication.