Milk-Alkali Syndrome

Etiology

Milk-alkali syndrome occurs primarily due to ingesting inappropriately high amounts of calcium carbonate. Increased awareness of the importance of calcium intake and the availability of over-the-counter calcium carbonate preparations for the treatment of osteoporosis and dyspepsia is the most common cause of the milk-alkali syndrome.[4][5] Calcium supplements are also frequently prescribed to patients with chronic kidney disease (to prevent the development of secondary hyperparathyroidism) and patients on treatment regimens that may lead to bone loss, eg, prolonged corticosteroid treatment. Usually, patients with milk-alkali syndrome consume calcium products containing more than 4 g/day of calcium; however, the syndrome has been seen in patients consuming as little as 1.0 g/day.[6] Ingestion of milk products or milk and bicarbonate is no longer considered a significant cause of this syndrome.

Certain other drugs may also contribute to the development of this syndrome. An association between milk-alkali syndrome and thiazide diuretics has been reported.[7] Thiazide diuretics increase calcium reabsorption from the kidney, resulting in contraction alkalosis from volume depletion. Angiotensin-converting enzyme inhibitors and non-steroidal anti-inflammatory drugs also decrease renal calcium excretion by decreasing glomerular filtration rate (GFR).[4] Severe cases of milk-alkali syndrome have been reported in women who are pregnant.[8] Increased gastrointestinal absorption of calcium and amounts of parathyroid-related peptides 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.[9] The syndrome has occasionally also been described in betel nut chewers in India and Southeast Asia. The lime paste mixed with the nut's meat contains high calcium carbonate. Heavy consumption has been reported to give rise to the milk-alkali syndrome.[10]

Epidemiology

Milk-alkali syndrome is a frequent cause of hypercalcemia in the United States. Results from 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 milk-alkali has been reported in places where betel nut chewing is common, such as India and Southeast Asia.[10] 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 women who are post-menopausal due to their increased consumption of calcium carbonate products.[4]

Pathophysiology

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

Hypercalcemia has various effects on the kidney, eventually resulting in hypovolemia. This condition decreases the GFR by causing vasoconstriction and natriuresis by indirectly inhibiting the sodium, potassium, and chloride (Na-K-2Cl) channels in the medullary thick ascending limb of the nephron. Hypovolemia 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 bicarbonate reabsorption.[11] Alkalosis is a net result of increased alkali intake, hypercalcemia-mediated hypovolemia, and decreased GFR. Alkalosis leads to increased calcium reabsorption from the nephron’s distal tubule, leading to hypercalcemia.[4] A vicious cycle develops due to hypercalcemia, alkalosis, and kidney injury.

Certain factors worsen the situation further by increasing calcium levels or causing hypovolemia. These include taking drugs such as thiazide diuretics that decrease calcium excretion and cause natriuresis and vitamin D, increasing 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.[4] Increased calcitriol levels in pregnancy may also contribute to hypercalcemia and the potential worsening of the syndrome if it develops.[12]

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. Currently, it is essential to gain information regarding drug intake, as various over-the-counter preparations contain calcium.[13] Most patients are asymptomatic; 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. Occasionally, patients may also experience palpitations.

On physical exam, hypercalcemia can cause hyporeflexia of the deep tendon reflexes. Decreased muscle strength and tone may also be present. Depression, anxiety, or cognitive impairment may also be noted on psychiatric exams related to hypercalcemia. Metabolic alkalosis can also cause decreased minute ventilation and central respiratory drive, but this effect may be minimal.[14][15] Historically, 3 progressive phases of the syndrome were described when the syndrome developed after the acute or prolonged use of the antacid regimen. Patients presented in the acute, subacute, and chronic stages depending on the duration and time since the exposure.

Acute Toxemic Phase

Patients usually present 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 present with features of acute and chronic hypercalcemia.[16]

Chronic Phase (Brunett syndrome)

Patients treated with the milk and alkali regimen for years generally demonstrated features of chronic hypercalcemia. Symptoms include polyuria, polydipsia, pruritis, tremors, and psychosis. Abnormal calcium deposition in the tissues and organs could be observed in the chronic phase. Band keratopathy and nephrocalcinosis are commonly present. Metastatic calcification in other areas, including the liver, central nervous system, periarticular tissue, subcutaneous tissue, adrenals, bones, and lungs, is also frequently noted.[17][18]

Evaluation

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 must be calculated in patients with hypoalbuminemia. Ionized calcium levels can also be considered to avoid confounding values from hypoalbuminemia. With hypercalcemia, the next step in diagnosis is measuring serum parathyroid hormone levels, which are low in patients with the milk-alkali syndrome.[19][20] 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 high quantities of milk intake. Serum magnesium levels are usually low as hypercalcemia inhibits its reabsorption in the renal tubules; however, renal failure can cause hypermagnesemia due to the inability to secrete magnesium, so this should be considered.[19] Blood urea nitrogen and creatinine can indicate the severity of renal damage.

Various other tests can be done to exclude other causes of hypercalcemia, particularly with low serum parathyroid hormone levels. For example, 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, which is a common cause of hypercalcemia.

Radiological investigations include chest x-rays, which can help exclude malignancy and sarcoidosis. Renal imaging may also be warranted in the case of renal dysfunction. The electrocardiogram in hypercalcemic patients may show QT interval shortening or ventricular arrhythmias.[21] Another frequent abnormality on ECG is the presence of J (Osborn) waves.[22]

Treatment / Management

For mild hypercalcemia, the only intervention needed is to withdraw the offending agent, which in most situations is calcium carbonate. As the source is removed, hypercalcemia and alkalosis are rapidly corrected in milk-alkali syndrome. 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 and to treat hypercalcemia.[23] The initial infusion rate is generally agreed to be 200 to 300 mL/h in those who are non-edematous 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, co-morbid diseases, and 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.[24] 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 with milk-alkali syndrome as they can cause prolonged hypocalcemia.[19] Pamidronate, however, has been used with satisfactory results.(B2)

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.

Diseases causing hypercalcemia and elevated parathyroid hormone levels include these conditions:

• 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:

• Malignancy
• Hyperthyroidism [25]
• Hematological malignancies
• Immobilization
• Hypophosphatasia
• Sarcoidosis and other granulomatous disorders [26]

Hypercalcemia associated with drug use or vitamin intake includes these:

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

Prognosis

The prognosis of milk-alkali syndrome is good, as it can easily be reversed by stopping the ingestion of calcium supplements and absorbable alkalis. The morbidity associated with the disease is highly dependent on the severity and duration of hypercalcemia. If recognized early and treated appropriately, the chances of the development of complications can be significantly reduced, and the prognosis is favorable. However, chronic milk-alkali syndrome can cause permanent damage from systemic calcification, underscoring the importance of early detection and treatment.[18]

Complications

Long-term complications of milk-alkali syndrome are uncommon due to easy reversability of acute milk-alkali syndrome. Withdrawing the offending agent is usually curative. Some studies, however, have reported permanent renal damage, even after the discontinuation of the causative agent in the diet. Several case reports have noted patients with elevated creatinine levels (>1.5 mg/dL) and even renal failure in follow-up investigations.[18] 

Neurological impairment, including obtundation and coma, has 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. There have been reports of status-epilepticus secondary to hypercalcemia in patients with milk-alkali syndrome.[27]