Calcium Alkali Syndrome

Introduction

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

Milk alkali syndrome
Sippy syndrome
Cope disease
Burnett disease

Clinical Presentation

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. ¹ ^,²
2.Subacute or intermediate (Cope syndrome): Patients have typically ingested milk and alkali intermittently for years. ¹ 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. ¹ Physical evidence of metastatic calcification is detectable as nephrocalcinosis and band keratopathy. Metastatic calcification in other areas, including the liver, central nervous system, periarticular tissue, subcutaneous tissue, adrenals, bones, and lungs, were also frequently noted. ³ 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.

ICD-10–CM CODE
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. ¹ ^, 2
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. ⁴
In chronic kidney disease patients, the use of calcium carbonate instead of aluminum hydroxide as a phos-phate-binder produced the “calcium-alkali” syndrome. ²
This updated term supplants “milk-alkali syndrome,” as milk is no longer the predominant source of calcium.
In a single-center study, the calcium-alkali syndrome was the third-most leading cause of hypercalcemia (12%) in hospitalized patients from 1998 to 2003, following hypercalcemia of malignancy and primary hyperparathyroidism. ⁵

PHYSICAL FINDINGS

•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, as well as shortened QT segment interval.

What causes Calcium Alkali Syndrome?

Overconsumption of supplemental calcium of 3 to 20 g daily, in association with volume depletion, resulting in renal impairment 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. ⁵ ^, 6
Vomiting or diuretic-induced volume depletion aggravates hypercalcemia and alkalosis. Certain other drugs may also contribute to the development of this syndrome. An association between the development of the milk-alkali syndrome and the use of thiazide diuretics has been reported. ⁷
Thiazide diuretics increase calcium reabsorption from the kidney and also result in contraction alkalosis due to volume depletion. Angiotensin-converting enzyme inhibitors and nonsteroidal antiinflammatory drugs decrease renal calcium excretion. ⁸

Severe cases of milk-alkali syndrome have been reported in pregnant women. ⁹ Increased gastrointestinal absorption of calcium and increased amounts of parathyroid-related peptide in pregnant women are thought to play a role. Calcium carbonate is also commonly used for symptoms of reflux in pregnancy.

A rare cause is the use of large amounts of nicotine-substitute chewing gum, which may deliver high quantities of calcium. ¹⁰ Betel nut chewing, prevalent in Asia and the South Pacific, is associated with calcium-alkali syndrome. ⁵ The paste mixed with the meat of the nut contains a high amount of calcium carbonate.

The demographic paradigm has shifted from young men 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 older individuals who experience greater bone loss and are prone to development of hypercalcemia when ingesting excessive calcium supplements. ⁵

Pathogenesis

An established prerequisite for developing this syndrome is the co-ingestion of large amounts of calcium and absorbable alkali. The mechanism of the development of hypercalcemia remains unclear. Increased absorption of calcium from the small intestine, an effect strongly influenced by calcitriol levels, plays an important role. In addition, increased intake of vitamin D may contribute to the development or worsening of the condition.

Hypercalcemia has various effects on the kidney, all of which eventually result in hypovolemia. It decreases glomerular filtration rate (GFR) by causing vasoconstriction and natriuresis by indirectly inhibiting the Na-K-2Cl channels in the medullary thick ascending limb of the nephron. It also decreases water reabsorption by inhibiting the antidiuretic hormone receptors (V2 receptors) in the basolateral membrane of collecting tubules in the kidney.

The resultant hypovolemia contributes to the development of alkalosis by increasing the reabsorption of bicarbonate. Alkalosis is a net result of the increased alkali intake, hypercalcemia-mediated hypovolemia, and decreased glomerular filtration rate. Alkalosis itself leads to increased reabsorption of calcium from the distal tubule of the nephron, leading to hypercalcemia. ⁸ A vicious cycle, hence, develops with the result of hypercalcemia, alkalosis, and kidney injury.

Certain factors worsen the situation further by increasing calcium levels or causing hypovolemia. These include the intake of drugs such as thiazide diuretics that decrease calcium excretion and cause natriuresis and vitamin D that increases calcium absorption from the gut. Older individuals are at a higher risk of developing hypercalcemia and subsequent alkalosis following the intake of calcium supplements due to decreased bone buffering of the excess calcium. ⁸ Increased levels of calcitriol in pregnancy may also contribute to hypercalcemia and the potential worsening of the syndrome if it develops. ¹¹

Differential Diagnosis

As stated previously, the milk-alkali syndrome is a diagnosis of exclusion. Multiple diseases and conditions result in hypercalcemia and need to be considered when diagnosing a suspected case of milk-alkali syndrome. ³

Diseases causing hypercalcemia and elevated parathyroid hormone levels include the following ³ :

•Hyperparathyroidism (primary or tertiary)
•Familial hypocalciuric hypercalcemia
•Acquired hypocalciuric hypercalcemia

Diseases causing hypercalcemia with a normal level of parathyroid hormone, similar to the milk-alkali syndrome, include the following ³ :

•Malignancy
•Hyperthyroidism
•Hematological malignancies
•Immobilization
•Hypophosphatasia
•Sarcoidosis and other granulomatous disorders

Hypercalcemia associated with drug use or vitamin intake include the following ³ :

•Thiazide diuretics
•Lithium
•Vitamin D
•Vitamin A toxicity

LABORATORY TESTS

•Elevated serum ionized calcium (wide variation reported)
•Elevated blood urea nitrogen (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 (Traditional MAS was caused by the Sippy diet, which leads to hyperphosphatemia due to phosphate-rich milk and cream in the Sippy diet. As no extra milk and cream are taken in the modern CAS, hypophosphatemia or normal phosphorus levels are found, caused by phosphate binding capacity of calcium carbonate, which decreases absorption of phosphate from the gut. ¹² )
•Hypomagnesemia
•TSH (to rule out hyperthyroidism as a cause of hypercalcemia)
•SPEP and UPEP to rule out multiple myeloma
•Parathyroid-related protein (to rule out malignancies)
•1,25 Hydroxyvitamin D level (normal levels rule out sarcoidosis)
•ECG (QT prolongation and J Osborn waves)
•Chest x-ray (to rule out sarcoidosis and malignancy)

TREATMENT

NONPHARMACOLOGIC THERAPY

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

ACUTE GENERAL Treatment

•Discontinue all calcium and bicarbonate supplementation.
•Volume repletion by intravenous saline, followed by loop diuretic administration to increase urinary calcium excretion. The initial rate of infusion is generally agreed to be 200 to 300 mL/h in nonedematous patients and then adjusted to maintain a urine output of 100 to 150 mL/h. The rate, however, is highly variable and needs to be calculated according to the patient’s age, renal status, comorbid diseases, and, most important, the severity of hypercalcemia. ³
•Transient hypocalcemia may occur when patients are treated with loop diuretic followed by rebound elevation of parathyroid hormone, a unique feature of the calcium-alkali syndrome that occurs upon sudden cessation of hypercalcemia. Hypocalcemia is transient and generally does not need to be treated, but oral calcium citrate may be considered. Calcium carbonate should be avoided. ³
•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 (e.g., TUMS) and antacids containing calcium carbonate (e.g., Calcarb, CitraCal, Caltrate).

Prognosis

Hypercalcemia and associated symptoms resolve with withdrawal of excess calcium supplementation and treatment of hypercalcemia. Renal function generally returns to normal if calcium-alkali syndrome is diagnosed early. Irreversible kidney damage may occur and require renal replacement therapy. ²

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 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 ( Table E1 ) 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.

TABLE E1

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 soda. Potassium 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

References

1.Medarov B.I.: Milk-alkali syndrome . Mayo Clin Proc 2009; 84: pp. 261-267.

2.Zayed R.F., et al.: Calcium-alkali syndrome: historical review, pathophysiology and post-modern update . Cureus 2021; 13: pp. e13291.

3.Ali R., Patel C.: Milk-alkali syndrome . StatPearls 2022;

4.Arroyo M., et al.: The calcium-alkali syndrome . Case Reports: Proc (Bayl Univ Med Cent) 2013; 26: pp. 179-181.

5.Patel A.M., et al.: Calcium-alkali syndrome in the modern era . Nutrients 2013; 5: pp. 4880-4893.

6.Felsenfeld A.J., Levine B.S.: Milk alkali syndrome and the dynamics of calcium homeostasis . Clin J Am Soc Nephrol 2006; 1: pp. 641-654.

7.Parvez B., et al.: Milk alkali and hydrochlorothiazide: a case report . Case Rep Med 2011 2011; pp. 729862.

8.Patel A.M., Goldfarb S.: Got calcium? Welcome to the calcium-alkali syndrome . J Am Soc Nephrol 2010; 21 (9): pp. 1440-1443.

9.Addington S., et al.: Milk-alkali syndrome in pre-eclamptic pregnancy: report of a patient and evaluation of albumin-corrected calcium in pre-eclamptic pregnancies . J Okla State Med Assoc 2006; 99 (9): pp. 480-484.

10.Swanson C.M., et al.: Nicotine-substitute gum-induced milk alkali syndrome: a look at unexpected sources of calcium . Endocr Pract 2013; 19 (6): pp. 142-144.

11.Kolnick L., et al.: Hypercalcemia in pregnancy: a case of milk-alkali syndrome . J Gen Intern Med 2011; 26 (8): pp. 939-942.

12.Muldowney W.P., Mazbar S.A.: Rolaids-yogurt syndrome: a 1990s version of milk-alkali syndrome . Am J Kidney Dis 1996; 27: pp. 270-272.

Calcium Alkali Syndrome