Continuing Education Activity
Milk-alkali syndrome is characterized by a triad of elevated levels of calcium, metabolic alkalosis, and acute kidney injury that commonly occurs due to the combined intake of large amounts of calcium and absorbable alkali. The syndrome can have an acute onset with the rapid development of hypercalcemia and, if left untreated, may progress to the development of acute renal failure and metastatic calcification. This activity reviews the evaluation and treatment of milk-alkali syndrome and highlights the role of the interprofessional team in evaluating and treating patients with this condition.
- Describe the pathophysiology of milk-alkali syndrome.
- Outline the typical presentation of a patient with milk-alkali syndrome.
- Identify the management options available for milk-alkali syndrome.
- Review the importance of improving care coordination amongst interprofessional team members to improve outcomes for patients affected by the milk-alkali syndrome.
Milk-alkali syndrome is characterized by a triad of elevated levels of calcium, metabolic alkalosis, and acute kidney injury that commonly occurs as a result of the combined intake of large amounts of calcium and absorbable alkali. The syndrome can have an acute onset with the rapid development of hypercalcemia and, if left untreated, may progress to the development of acute renal failure and metastatic calcification.
The syndrome was first recognized in the early 20th century when Bertram Sippy introduced a treatment regimen for peptic ulcer disease. The ‘Sippy regimen’ consisted of multiple daily doses of milk and cream combined with an absorbable alkali such as magnesium oxide, sodium bicarbonate, or bismuth subcarbonate to protect the gastric ulcer from further erosion by gastric acid. The results were highly favorable, and it soon became a popular therapy. Soon after, various toxic effects, including hypercalcemia and metabolic alkalosis, were reported. Some cases with acute kidney injury were also reported. With the advent of newer drugs for the treatment of peptic ulcer disease, such as histamine type-2 receptor blockers in the 1980s, the syndrome virtually vanished from the world.
Recently, however, an increased number of cases of the milk-alkali syndrome have been reported. This is likely due to the common use of over-the-counter preparations of calcium for the prevention and treatment of osteoporosis in post-menopausal women. Calcium carbonate is also frequently prescribed to patients with chronic kidney disease for the prevention of secondary hyperparathyroidism. Various scholars have also suggested changing the name of the syndrome to calcium-alkali syndrome due to the changing etiopathology. Milk-alkali syndrome now accounts for more than 10% of the cases of hypercalcemia and is the third most common cause of hypercalcemia in hospitalized patients.
In the present day, Milk-alkali syndrome occurs as a result of the ingestion of inappropriately high amounts of calcium carbonate. Increased awareness of the importance of calcium intake and the increased availability of over-the-counter preparations of calcium carbonate for the treatment of osteoporosis and dyspepsia are major causes of the development of the milk-alkali syndrome. Calcium supplements are frequently prescribed to patients with chronic kidney disease to prevent the development of secondary hyperparathyroidism and also to patients on treatment regimens that may lead to bone loss, e.g., prolonged corticosteroid treatment. Ingestion of milk products or milk and bicarbonate is no longer considered a prominent cause.
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. Thiazide diuretics increase calcium reabsorption from the kidney and also result in contraction alkalosis due to volume depletion. Angiotensin-converting enzyme inhibitors and non-steroidal anti-inflammatory drugs decrease renal calcium excretion.
Severe cases of milk-alkali syndrome have been reported in pregnant women. 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. The syndrome has occasionally been described in betel nut chewers in India and Southeast Asia. The paste mixed with the meat of the nut contains a high amount of calcium carbonate. Heavy consumption has been reported to give rise to the milk-alkali syndrome.
Milk-alkali syndrome (MAS) is a frequent cause of hypercalcemia in the United States. A study on patients hospitalized for hypercalcemia showed that 12% of the cases were due to milk-alkali syndrome, making it the third most common cause after hyperparathyroidism and malignancy. Internationally, the frequency of the condition depends on the amount of calcium carbonate intake. Increased incidence of MAS has been reported in places of the world where betel nut chewing is common, such as India and Southeast Asia. Previously, when the etiology of the syndrome was the consumption of milk and absorbable alkali to treat peptic ulcer disease, more cases were reported in males. Currently, most of the cases are post-menopausal women due to their increased consumption of calcium carbonate products.
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. 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. Increased levels of calcitriol in pregnancy may also contribute to hypercalcemia and the potential worsening of the syndrome if it develops.
History and Physical
Milk-alkali syndrome is a diagnosis of exclusion, and all other conditions causing hypercalcemia need to be excluded. Careful history taking and a detailed physical examination are vital. In current times, it is important to gain information regarding drug intake as various over-the-counter preparations contain calcium. Most patients are asymptomatic and elevated levels of calcium, alkalosis, and renal damage are incidentally discovered. However, some patients may present with acute or chronic signs and symptoms of hypercalcemia. Neurological symptoms of hypercalcemia include altered mental status, headache, vertigo, dizziness, and malaise. Gastrointestinal symptoms include nausea, vomiting, anorexia, and constipation. Genitourinary manifestations include increased urinary frequency and nephrolithiasis. Patients may also experience palpitations. No specific physical signs are seen in milk-alkali syndrome.
Historically, when the syndrome developed after the acute or prolonged use of the antacid regimen, three progressive phases of the syndrome were described. Patients presented in the acute, subacute, and chronic stages depending on the duration of and the time since the exposure.
Acute Toxemic Phase
Patients presented within a month of treatment with the antacid regimen. Symptoms of acute hypercalcemia, including headache, vertigo, dizziness, nausea, vomiting, and anorexia, were reported.
Subacute Phase (Cope syndrome)
Patients presented with features of acute and chronic hypercalcemia.
Chronic Phase (Brunett syndrome)
Patients who had been treated with the milk and alkali regimen for years generally presented with this syndrome with features of chronic hypercalcemia. Symptoms included polyuria, polydipsia, pruritis, tremors, and psychosis. Abnormal deposition of calcium in the tissues and organs was typically observed in the chronic phase. Band keratopathy and nephrocalcinosis were commonly present. Metastatic calcification in other areas, including the liver, central nervous system, periarticular tissue, subcutaneous tissue, adrenals, bones, and lungs, were also frequently noted.
A thorough history and physical examination are required for the diagnosis of milk-alkali syndrome. Elevated serum calcium levels are usually an incidental discovery. Arterial blood gas analysis reveals metabolic alkalosis. Serum albumin levels should be checked in all patients with hypercalcemia, and corrected calcium levels need to be calculated in patients with hypoalbuminemia. Ionized calcium levels can also be considered. With hypercalcemia, the next step in diagnosis is measuring serum parathyroid hormone levels, which are low in patients of milk-alkali syndrome. This finding excludes primary hyperparathyroidism and familial hypocalciuric hypercalcemia during diagnostic evaluation. Serum phosphorus levels are low due to low parathyroid hormone levels but have been reported to be high in the classic syndrome due to the intake of high quantities of milk. Serum magnesium levels are low as hypercalcemia inhibits its reabsorption in the renal tubules. Blood urea nitrogen and creatinine can indicate the severity of renal damage, if any.
Various other tests can be done to exclude other causes of hypercalcemia, particularly with low serum parathyroid hormone levels. Thyroid-stimulating hormone (TSH) and free thyroxine levels can be measured to eliminate hyperthyroidism as a cause of hypercalcemia, and serum protein or urine protein electrophoresis can help exclude multiple myeloma. In addition, normal serum parathyroid-related peptide levels can help exclude malignancy, and normal 1,25 hydroxyvitamin D levels decrease the likelihood of sarcoidosis, both of which are common causes of hypercalcemia.
Radiological investigations include chest x-ray, which can help exclude malignancy and sarcoidosis in the diagnostic evaluation of hypercalcemia. It may also be needed in patients with severe renal impairment. QT interval shortening and ventricular arrhythmias may be seen on an electrocardiogram in hypercalcemic patients. Another abnormality on ECG reported frequently is the presence of J (Osborn) waves.
Treatment / Management
For mild hypercalcemia, the only intervention needed is to withdraw the offending agent, which in most situations is calcium carbonate. Hypercalcemia and alkalosis are rapidly corrected in milk-alkali syndrome as the source is removed. Severe hypercalcemia is managed in the hospital setting. Patients are admitted, and the calcium supplement is discontinued. Intravenous fluids such as normal saline are started to correct hypovolemia. The initial rate of infusion is generally agreed to be 200-300 mL/h in non-edematous patients and then adjusted to maintain a urine output of 100-150 mL/h. The rate, however, is highly variable and needs to be calculated according to the patient’s age, renal status, co-morbid diseases, and, most importantly, the severity of hypercalcemia.
Loop diuretics, like furosemide, can increase urinary calcium excretion. In severe cases of hypercalcemia, they can be started after the intravenous saline infusion is begun and should be continued with caution as hypovolemia can worsen the hypercalcemia. Some patients develop mild hypocalcemia with a rebound rise in parathyroid hormone levels with loop diuretic treatment. Hypocalcemia is transient and generally does not need to be treated, but oral calcium citrate may be considered. Calcium carbonate should be avoided. Bisphosphonates should generally be avoided in patients of the milk-alkali syndrome as they can cause prolonged hypocalcemia. Pamidronate, however, has been used with satisfactory results.
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.
Diseases causing hypercalcemia and elevated parathyroid hormone levels include:
- 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:
- Hematological malignancies
- Sarcoidosis and other granulomatous disorders
Hypercalcemia associated with drug use or vitamin intake include:
- Thiazide diuretics
- Vitamin D
- Vitamin A toxicity
The prognosis of milk-alkali syndrome is good, as it can easily be reversed by stopping the ingestion of the calcium supplement and absorbable alkali. The morbidity associated with the disease is highly dependant on the severity and duration of hypercalcemia and alkalosis. If recognized early and treated appropriately, the chances of development of complications can be greatly reduced, and the prognosis is favorable.
Not many complications have been reported in patients who develop the milk-alkali syndrome. One reason for this is that the syndrome is reversible. Withdrawing the offending agent, which is calcium carbonate in most cases, serves as a cure. Some studies, however, have reported the development of permanent renal damage, even after the discontinuation of the supplement in the diet. Several case reports have mentioned that patients had elevated creatinine levels (more than 1.5 mg/dL) in follow-up investigations. Renal function improvement is variable after treatment. Neurological impairment, including obtundation and coma, have been reported in patients with calcium levels greater than 15 mg/dL. Older age, patients with a history of chronic kidney disease, and patients on dialysis are at high risk of complications.
Deterrence and Patient Education
Increased awareness about the importance of calcium, along with its easy availability, and frequent prescription of calcium-containing supplements, have resulted in a rise in the cases of milk-alkali syndrome in the past few years. The patients should be informed of the pathogenesis of the disorder and the common symptoms of hypercalcemia. The patients should be mindful of the supplements they are taking and their ingredients. Frequently, patients are unknowingly taking calcium through multiple sources. The recommended dose and potentially harmful doses, tailored according to the patient’s requirements, need to be formally discussed with the patient. This is especially important for patients with chronic renal disease because the chances of developing potentially lethal hypercalcemia and metabolic alkalosis are higher in these patients. Patients who develop hypercalcemia also need to be educated about the reversibility of the syndrome with discontinuation of the offending agent.
Enhancing Healthcare Team Outcomes
An increased number of cases of milk-alkali syndrome have been reported in the past decade. Clinicians should keep milk-alkali syndrome high on the differential when dealing with a patient presenting with hypercalcemia. Though generally asymptomatic and discovered incidentally, it can rapidly lead to the development of life-threatening hypercalcemia and alkalosis and may progress to renal failure if left untreated. Clinicians need to be well versed with the causes, pathophysiology, complications, and management of hypercalcemia and alkalosis that develops as a result of this disorder. Being a reversible condition, early management can prove to be life-saving. An interprofessional team approach with effective communication between the members, including internists, endocrinologists, nephrologists, nurses, and pharmacists, is required to enhance patient care and improve outcomes.