History of the Milk-Alkali Syndrome

Heard about a case of milk-alkali syndrome at Renal Grand Rounds yesterday. This is an interesting condition whose pathophysiologic mechanism really tests your knowledge of calcium and acid-base homeostasis. I won't attempt to chart the pathway but a really good overview can be found in this 2006 CJASN review by Felsenfeld and Levine. Briefly, patients who have large intakes of calcium and bicarbonate develop hypercalcemia, metabolic alkalosis, and acute renal failure.

The milk-alkali syndrome first rose to prominence when Bertram Sippy in 1915 developed a regimen for the treatment of peptic ulcer disease that involved drinking large volume of milk on an hourly basis along with "Sippy powders" that contained significant amounts of sodium bicarbonate. This provides really an ideal setup of a situation in which hypercalcemia, metabolic alkalosis, and acute renal failure can occur simultaneously, the hallmark of the milk-alkali syndrome.

It was not until 1936 that the toxicities associated with the Sippy protocol were tied to hypercalcemia by a Dr. Cope, who determined that in patients with milk-alkali syndrome the hypercalcemia and metabolic alkalosis could be relatively rapidly reversed by stopping calcium/base input and giving fluids. Although it is seldom used, the moniker "Cope's Syndrome" is occasionally used to refer to the acute- or subacute- forms of milk-alkali syndrome.

In 1949, Burnett et al described a chronic form of milk-alkali syndrome which involved the long-term toxicities of these metabolic derangements, including manifestations such as renal failure secondary to nephrocalcinosis and band keratopathy, in which calcium deposition on the cornea occurs. Fittingly the chronic form of milk-alkali syndrome is sometimes called "Burnett's Syndrome."

With the advent of H2-blockers to more effectively deal with peptic ulcer disease, the milk-alkali syndrome became quite rare for several decades as the general population's intake of popular antacids such as TUMS was greatly reduced. However, there has been a more recent increase in milk-alkali syndrome, particularly in women, with the increased attention to osteoporosis prophylaxis with calcium supplements. Several recent reviews cite milk-alkali syndrome as the third-most-common reason for hypercalcemia requiring hospitalization, after malignancy and primary hyperparathyroidism.