INTRODUCTION — The milk-alkali syndrome consists of the triad of hypercalcemia, metabolic alkalosis, and acute kidney injury associated with the ingestion of large amounts of calcium and absorbable alkali. The syndrome was originally described in association with the use of milk and sodium bicarbonate for the treatment of peptic ulcer disease . Once a classic cause of hypercalcemia, the milk-alkali syndrome virtually disappeared with the advent of new therapies of peptic ulcer disease and, by 1985, was considered the cause of less than one percent of cases of hypercalcemia .
However, there has since been a resurgence of this disorder, and it may account for up to 12 percent of cases, making it the third leading cause of hypercalcemia behind primary hyperparathyroidism and malignancy [3,4]. (See "Etiology of hypercalcemia".)
Three factors are responsible for this increase in incidence:
●The emphasis on calcium therapy for the prevention and treatment of osteoporosis
●Readily available over-the-counter calcium carbonate preparations
●The use of calcium carbonate to minimize secondary hyperparathyroidism in patients with chronic kidney disease (see "Management of hyperphosphatemia in adults with chronic kidney disease")
This topic reviews the pathogenesis, clinical presentation, diagnosis, and treatment of the milk-alkali syndrome. Other causes of hypercalcemia and alkalosis, and the treatment of these disorders, are discussed elsewhere:
●(See "Etiology of hypercalcemia".)
●(See "Causes of metabolic alkalosis".)
●(See "Treatment of hypercalcemia".)
HISTORICAL PERSPECTIVE — In 1915, Bertram Sippy introduced an antacid regimen designed to neutralize gastric acidity and promote the healing of peptic ulcer disease . The regimen included the hourly administration of milk or cream with Sippy powders (a powder containing 600 mg of magnesium carbonate and 600 mg sodium bicarbonate alternating with a powder containing 600 mg of bismuth subcarbonate and 1200 to 1800 mg of sodium bicarbonate). Toxic reactions characterized by alkalosis and kidney injury were noted shortly thereafter, but the plasma calcium concentration was not measured . In 1936, a report associated hypercalcemia with the alkalosis and kidney injury in patients treated with the Sippy regimen .
Despite these observations, therapy of peptic ulcer disease continued to include the administration of large doses (20 to 60 gm per day) of calcium carbonate, and less acute and more frequent cases were reported. Most cases were middle-aged men, the group with the highest incidence of peptic ulcer disease.
PATHOGENESIS — The milk-alkali syndrome is caused by the ingestion of large amounts of calcium in conjunction with absorbable alkali. However, the fraction of the population at risk who develop sustained hypercalcemia, metabolic alkalosis, and kidney disease is relatively small. In one series of 1350 patients treated with the Sippy regimen, approximately 8 percent were affected . In another study, 297 heart and lung transplant recipients were prescribed large doses of calcium carbonate as prophylaxis for adverse effects of glucocorticoid immunosuppression. Sixty-five patients developed hypercalcemia; 31 were alkalotic at the time of the hypercalcemia, and 37 had an impairment in kidney function .
It is probable that normal kidney function and the suppression of calcitriol production allow maintenance of calcium and acid-base balance in most individuals exposed to large doses of calcium and alkali. Under normal circumstances, the fractional intestinal absorption of filtered calcium declines markedly as calcitriol levels fall, and calcium intakes exceeding 4 grams per day are necessary to achieve normal serum levels in the absence of calcitriol. However, net calcium absorption increases markedly when intake is increased to 10 to 15 grams per day despite suppression of calcitriol . In addition, some individuals may not adequately suppress calcitriol in response to large doses of calcium, resulting sequentially in hyperabsorption of calcium and hypercalcemia . (See 'Possible role of calcitriol' below.)
Although the mechanisms that initiate hypercalcemia are incompletely understood, clinical studies suggest that hypercalcemia underlies the subsequent metabolic derangements including alkalosis and acute kidney injury .
Hypercalcemia produces the following effects in the kidney:
●Vasoconstriction, which decreases the glomerular filtration rate (GFR).
●Activation of the calcium-sensing receptor in the medullary thick ascending limb, which inhibits the Na-K-2Cl cotransporter causing natriuresis. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Urine calcium excretion'.)
●Blockade of antidiuretic hormone (ADH)-dependent water reabsorption in the collecting duct. (See "Clinical manifestations and causes of nephrogenic diabetes insipidus", section on 'Hypercalcemia'.)
The calcium-induced diuresis results in volume depletion, which stimulates the renal tubular absorption of bicarbonate. The combined effects of increased alkali intake, volume depletion, and decreased GFR lead to metabolic alkalosis.
Alkalosis may contribute to the maintenance of both volume depletion (by enhancing the activity of the calcium-sensing receptor) and hypercalcemia (by increasing calcium reabsorption in the distal tubule via the pH-sensitive calcium channel, the transient receptor potential vanilloid member 5 [TRPV5]) [12,13]. Volume depletion due to vomiting or diuretics will also worsen the hypercalcemia and alkalosis.
Marked hypercalcemia can lead to an acute clinical presentation. On the other hand, prolonged or intermittent mild hypercalcemia in conjunction with metabolic alkalosis sets the stage for the development of nephrocalcinosis and chronic kidney disease.
Extrarenal factors — Extrarenal factors that may contribute to the initial development of hypercalcemia include decreased bone buffering and decreased suppression of calcitriol.
Decreased bone buffering — Bone provides the chief reservoir for buffering excess calcium. Older patients have a reduced capacity for bone buffering, which may cause them to be at higher risk for hypercalcemia following the ingestion of calcium-containing supplements .
Possible role of calcitriol — The following observations indicate that some individuals may not suppress calcitriol levels in response to large doses of calcium carbonate:
●Experimental studies show that not all normal individuals fed calcium carbonate suppress calcitriol levels to the same extent, with hormone levels remaining well within the normal range in some .
●The suppression of calcitriol levels by oral calcium carbonate administration in patients with idiopathic hypercalciuria is transient, with the levels returning to the normal range after two weeks of continued ingestion .
The hypothesis that a lack of suppression of calcitriol synthesis is an important determinant of susceptibility to the milk-alkali syndrome has not been formally tested. In published reports describing biochemical parameters in patients presenting with milk-alkali syndrome, plasma calcitriol concentrations appear to be quite variable and demonstrate no consistent pattern [16,17].
This issue assumes more importance in light of the emphasis on calcium carbonate intake for the treatment and prevention of osteoporosis. While recommended doses are only 1.2 g per day, it is likely that some patients, unless otherwise instructed, take higher doses. In the absence of a source of phosphate such as milk, calcium carbonate may produce mild hypophosphatemia, which directly increases the synthesis of calcitriol. Increased intake of calcium and alkali in association with high or even normal levels of calcitriol may predispose certain individuals to mild intermittent hypercalcemia at doses lower than those previously reported. Concurrent therapy with vitamin D, for either osteoporosis or secondary hyperparathyroidism in chronic kidney disease, makes the development of hypercalcemia much more likely. Individuals with mild chronic kidney disease, volume depletion, and those treated with a thiazide diuretic (which directly reduces calcium excretion) are also likely to be at increased risk. (See "Calcium and vitamin D supplementation in osteoporosis" and "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease" and "Management of secondary hyperparathyroidism in adult dialysis patients" and "Diuretics and calcium balance".)
Pregnant women may have elevated calcitriol levels and increased calcium absorption and may also be predisposed to hypovolemia and metabolic alkalosis due to vomiting. Numerous cases of milk-alkali syndrome have been reported in pregnant women [18-20], which suggests that oral calcium carbonate should be used with caution during pregnancy (eg, for the relief of symptoms of reflux).
Risk factors — Patients who appear to be at higher risk for milk-alkali syndrome include older individuals, those susceptible to volume depletion (including patients on thiazide diuretics), and those on medications that reduce the GFR, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or nonsteroidal antiinflammatory drugs . Patients with chronic kidney disease , including patients on dialysis, and pregnant women are also at increased risk. A less common risk factor for milk-alkali syndrome is nicotine-substitute chewing gum, which can provide a significant calcium load when utilized in large quantities .
CLINICAL MANIFESTATIONS — The milk-alkali syndrome can present in a variety of ways that, in part, depend upon the amount and duration of the calcium and alkali ingestion, as well as the presence of risk factors such as thiazide diuretic use and volume depletion.
Most patients with the milk-alkali syndrome are women who take calcium carbonate, often to prevent or treat osteoporosis. They are often asymptomatic and the hypercalcemia, alkalosis, and kidney function impairment are discovered incidentally. (See 'Modern presentation' below.)
The syndrome can also be seen in patients taking calcium-containing over-the-counter antacid medications, and in patients with chronic kidney disease who are prescribed calcium carbonate to treat secondary hyperparathyroidism. (See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)
Historically, patients presented with symptoms of acute or chronic hypercalcemia (eg, nausea, vomiting, weakness, altered sensorium, and pruritus) and, depending upon the duration of hypercalcemia, kidney function impairment that did not always resolve after normalization of the plasma calcium. (See 'Classical presentation' below.)
Modern presentation — The incidence of the milk-alkali syndrome increased during the 1990s [3,4,18,22]. One study found that the milk-alkali syndrome accounted for two percent of hospitalized patients with hypercalcemia between 1985 and 1989, as compared with 12 percent between 1990 and 1993 . In another study, milk-alkali syndrome accounted for 8.8 percent of hypercalcemia cases between 1998 and 2003 .
The majority of patients who now present with milk-alkali syndrome are women, and calcium carbonate is the predominant source of calcium and alkali intake. Betel nut chewing, which occurs in Asia and the South Pacific, can also cause the syndrome [23,24]. Because these nuts are bitter, they are wrapped in a compound containing calcium hydroxide, which is eventually converted to calcium carbonate.
The modern presentation differs from the historical presentation in the following ways:
●Patients are often asymptomatic and the finding of hypercalcemia, alkalosis, and kidney function impairment is an incidental discovery.
●Hypophosphatemia is common, reflecting both the absence of a phosphate load in conjunction with the calcium load and the phosphate-binding properties of calcium carbonate. Historically, milk supplied the calcium load in patients with the milk-alkali syndrome, and milk contains a large amount of phosphate.
●Hypomagnesemia is common at presentation , likely due to the ability of hypercalcemia to inhibit magnesium reabsorption by the renal tubule.
●Intact parathyroid hormone (PTH) levels are generally reduced. This is an important feature that can help distinguish the milk-alkali syndrome from primary hyperparathyroidism [4,25]. In addition, hypocalcemia may develop after therapy of the milk-alkali syndrome, possibly reflecting the combination of PTH suppression with the cessation of the calcium source.
Classical presentation — Three clinical syndromes were recognized in original descriptions . These forms of symptomatic hypercalcemia can still be seen, albeit rarely, in the modern era:
●Acute – The acute or "toxemic" form occurred after approximately one week of treatment . The symptoms were those of acute hypercalcemia and included nausea, vomiting, weakness, and mental changes with psychosis or depressed sensorium (see "Clinical manifestations of hypercalcemia"). There was also severe metabolic alkalosis, a normal to elevated plasma phosphate concentration, and acute kidney injury. Withdrawal of milk and alkali led to rapid relief of symptoms and the return of normal kidney function.
●Chronic – In the chronic form (also called Burnett's syndrome), patients presented after a long history of high milk/alkali intake with symptoms of chronic hypercalcemia, such as polyuria, polydipsia, muscle aches, and pruritus [28-30]. Frequently, there was evidence of metastatic calcifications, including band keratopathy and nephrocalcinosis. Laboratory abnormalities were similar to those in the acute syndrome, but the response to withdrawal of milk and alkali was quite different. The muscle aches and pruritus improved slowly as the plasma calcium concentration slowly normalized. However, there was usually minimal or no improvement in kidney function, as many patients had developed chronic kidney disease.
●Subacute or intermediate – In the subacute form (also called Cope's syndrome), patients were usually seen during therapy with milk and alkali that had been taken intermittently for years . Affected patients had symptoms of both acute and chronic hypercalcemia and responded to medication withdrawal with gradual improvement. Kidney function remained mildly impaired in some cases.
DIAGNOSIS — In a patient with hypercalcemia, alkalosis, and kidney function impairment, the diagnosis of milk-alkali syndrome is based upon the history of ingestion of calcium-rich medications and the exclusion of other causes of hypercalcemia. A thorough history is critical in identifying potential extrinsic sources of calcium or the use of vitamin D preparations that may increase intestinal calcium absorption. The diagnostic approach to hypercalcemia is presented elsewhere. (See "Diagnostic approach to hypercalcemia".)
TREATMENT — Withdrawal of the offending agent (eg, calcium carbonate) and treatment with isotonic saline usually produces clinical improvement and rapid resolution of the hypercalcemia and metabolic alkalosis. In more severe cases, concurrent furosemide therapy can be added to induce further urinary calcium excretion. (See "Treatment of hypercalcemia" and "Treatment of metabolic alkalosis".)
Hypocalcemia often occurs transiently during treatment with furosemide, accompanied by a rebound rise in parathyroid hormone (PTH) to supranormal levels; this phenomenon is unique to the milk-alkali syndrome . This may be because, with other etiologies of hypercalcemia (eg, primary hyperparathyroidism or malignancy), the stimulus to calcium retention persists even after acute treatment of the hypercalcemia. By contrast, in milk-alkali syndrome, cessation of calcium and alkali ingestion immediately removes the hypercalcemic stimulus while suppressed PTH levels are slower to respond. For the same reason, bisphosphonates, which cause a prolonged suppression of the serum calcium, can produce hypocalcemia in patients with the milk-alkali syndrome and should be avoided .
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fluid and electrolyte disorders in adults".)
●The milk-alkali syndrome consists of the triad of hypercalcemia, metabolic alkalosis, and kidney function impairment associated with the ingestion of calcium and absorbable alkali. (See 'Introduction' above.)
●The milk-alkali syndrome starts with the development of hypercalcemia. Hypercalcemia causes a vasoconstriction-induced decline in glomerular filtration rate (GFR) and activation of the calcium-sensing receptor in the medullary thick ascending limb, resulting in natriuresis and volume depletion. The combined effects of increased alkali intake, decreased GFR, and volume depletion lead to metabolic alkalosis. Extrarenal mechanisms that may contribute to hypercalcemia in susceptible individuals include decreased bone buffering capacity and insufficient suppression of calcitriol. (See 'Pathogenesis' above and 'Decreased bone buffering' above and 'Possible role of calcitriol' above.)
●Patients at higher risk for the development of the milk-alkali syndrome include older individuals, those at risk for volume depletion (including patients on thiazide diuretics), and those taking medications that reduce the GFR, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and nonsteroidal antiinflammatory drugs. Pregnant women may also be at higher risk. (See 'Risk factors' above.)
●Most patients with the milk-alkali syndrome are women who take calcium carbonate, often to prevent or treat osteoporosis. They are often asymptomatic and the hypercalcemia, alkalosis, and kidney function impairment are discovered incidentally. The syndrome can also be seen in patients taking calcium-containing over-the-counter antacid medications, and in patients with chronic kidney disease who are prescribed calcium carbonate to treat secondary hyperparathyroidism. Historically, patients presented with symptoms of acute or chronic hypercalcemia (eg, nausea, vomiting, weakness, altered sensorium, and pruritus) and, depending upon the duration of hypercalcemia, kidney function impairment that did not always resolve after normalization of the plasma calcium. (See 'Clinical manifestations' above.)
●The diagnosis of milk-alkali syndrome is based upon the history of ingestion of calcium-rich medications and the exclusion of other causes of hypercalcemia. (See 'Diagnosis' above and "Diagnostic approach to hypercalcemia".)
●Withdrawal of the offending agent (eg, calcium carbonate) and treatment with isotonic saline usually produces clinical improvement and rapid resolution of the hypercalcemia and metabolic alkalosis. In more severe cases, concurrent furosemide therapy can be added to induce further urinary calcium excretion. (See 'Treatment' above and "Treatment of hypercalcemia" and "Treatment of metabolic alkalosis".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Zalman S Agus, MD, who contributed to an earlier version of this topic review.