Milk-Alkali Syndrome

Indigestion
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Diagnosis and reasoning

This elderly gentleman has presented with polydipsia, polyuria and and generalized fatigue for several weeks; he also looks ill and is moderately dehydrated. This constellation of symptoms should prompt immediate consideration of uncontrolled diabetes mellitus; however, this is excluded by the recent normal fasting plasma glucose study, forcing us to consider other potential etiologies. While the differential diagnosis of polydipsia and polyuria is fairly broad, encompassing metabolic, endocrine, and renal causes, this patient's history provides us with a potential clue - the history of consumption of large volumes of antacids and baking soda. Note that antacids are typically composed of a calcium (Ca), magnesium (Mg), or aluminum (Al) cation and a carbonate (CO3), bicarbonate (HCO3), citrate or hydroxide (OH) anion; baking soda is of course, sodium bicarbonate (NaHCO3). Consumption of large amounts of these substances might potentially result in solute overload, giving rise to his symptoms; thus, a serum electrolyte assay is a good next step; this should be combined with an arterial blood gas assay (ABG) to detect any acid-base derangements. Confirming our suspicion, the electrolyte assay reveals the presence of severe hypercalcemia (> 14 mg/dL), while the ABG demonstrates a partially compensated metabolic alkalosis; note that these findings are suggestive of milk-alkali syndrome (MAS) - a consequence of excessive ingestion of calcium with absorbable alkali. As MAS is typically associated with renal impairment, further evaluation in this direction is essential; this reveals elevated serum creatinine levels. It is important to appreciate that while MAS is the most probable etiology here, it is a diagnosis of exclusion; in particular, both primary hyperparathyroidism and malignancies (such as multiple myeloma) must be ruled out in patients of this age group. Regardless of the final diagnosis, the immediate priority is management of the severe hypercalcemia (which is a medical emergency). Rehydration with intravenous (IV) fluids should be the cornerstone of his management - but should proceed with caution, given the renal insufficiency. Further calciuresis should be induced via an IV bisphosphonate (such as pamidronic acid); note that these drugs take 24 to 48 hours to act and are not an alternative for rapid rehydration. Hemodialysis is indicated in patients with refractory hypercalcemia, and should not be attempted immediately. In addition, the alkalosis associated with MAS resolves spontaneously following correction of hypercalcemia; thus, acetazolamide is not indicated. Following management of his hypercalcemia, this patient was extensively investigated; his parathyroid hormone (PTH) levels were diminished (showing them to be reactive to the calcium levels), while parathyroid hormone-related peptide (PTHrP), alkaline phosphatase, serum calcitriol, a myeloma screen, and skeletal survey were all normal. Thus, given the exclusion of hypercalcemia of malignancy and primary hyperparathyroidism, the diagnosis of MAS was finally confirmed.


Discussion

Milk-alkali syndrome (MAS) is characterized by the triad of hypercalcemia, alkalosis and renal insufficiency; it is a consequence of excessive ingestion of calcium with absorbable alkali, and may occur acutely, sub-acutely, or chronically. The condition was initially described in patients who had ingested large amounts of antacids and/or baking soda for relief of peptic ulcer disease; over time, this has diminished in importance as a cause, due to the advent of other drugs for the condition. Nevertheless, MAS is still considered to be one of the most common causes of hypercalcemia; this is attributed to the increasing number of individuals undergoing calcium supplementation - particularly, postmenopausal women on treatment or prophylaxis for osteoporosis and occasionally, pregnant women on calcium supplements. Cases have also been reported in children who consume large amounts of milk, and in patients administered calcium carbonate for the treatment and prevention of hyperphosphatemia in chronic kidney disease. MAS occurs when intestinal absorption of calcium exceeds the ability of the kidneys to excrete the ion. The resulting hypercalcemia leads to a decrease in the glomerular filtration rate, thus compelling the kidneys to retain bicarbonate; this gives rise to the alkalosis seen in the condition, which is further exacerbated by the alkali consumed. Note also that the hypercalcemia gives rise to a form of nephrogenic diabetes insipidus resulting in polyuria, with subsequent volume depletion. This worsens the hypercalcemia, giving rise to a vicious cycle terminating in irreversible renal damage and nephrocalcinosis. An oral intake of ≥2 grams of elemental calcium per day, along with with an absorbable alkali is believed to be sufficient to give rise to MAS; note however, that lesser amounts may also give rise to the condition, depending on individual susceptibility. The symptoms and signs of MAS are essentially the same as those of hypercalcemia and its complications. A detailed history of the medications the patient is on, including over-the-counter (OTC) drugs and home remedies, is key to suspecting the condition. Investigations typically show raised serum calcium levels, although the degree of elevation varies widely; arterial blood gas analysis often demonstrates metabolic alkalosis. Serum parathyroid hormone (PTH) levels are usually suppressed (an important distinguishing factor, as in PTH is elevated in most other differential diagnoses for hypercalcemia); serum phosphate may be elevated, secondary to the low PTH. Depending on the severity of the disease, renal impairment may or may not be seen. It should be appreciated that MAS is a diagnosis of exclusion; thus, a workup to exclude malignancies may be indicated (including serum parathyroid hormone-related peptide levels); endocrinopathies may need to be excluded via thyroid function tests, serum 25-hydroxyvitamin D3 levels, etc. The treatment of MAS depends on the severity of the hypercalcemia. Severe hypercalcemia (>14 mg/dL or 3.5mmol/L) or symptomatic moderate hypercalcemia (>12 mg/dL or 3 mmol/L) requires urgent treatment and possible referral to a nephrologist. Aggressive intravenous rehydration is the first line treatment; both volume repletion and diuresis can be achieved by using isotonic saline. Note that in patients who have severe renal disease, the potential complication of volume overload should be cautiously addressed. Further calciuresis can be achieved via the use of loop diuretics such as furosemide and bisphosphonates; note that these agents are complementary to rehydration, and are not a replacement. Parenterally administered zoledronic acid or pamidronate are the most widely used bisphosphonates; if used, loop diuretics should be administered in low doses, and only when intravascular volume is replenished. These supportive measures are generally sufficient to successfully manage most patients; refractory cases are likely to be benefited by hemodialysis. Note that the offending agent that caused hypercalcemia should be identified and withdrawn as soon as possible; patients who developed MAS while on supplemental calcium should be switched to form of calcium without an absorbable alkali; furthermore, a low calcium and low phosphorous diet is recommended until the state of hypercalcemia resolves. If left untreated, the acute form of MAS can rapidly progress to metastatic calcinosis and renal failure; however, with treatment, a satisfactory recovery is expected within 24 to 48 hours. In the chronic form of MAS, the process of recovery is slower and hypercalcemia may persist for as long as 6 months.


Take home messages

  1. Milk-alkali syndrome (MAS) is caused by excessive ingestion of calcium with absorbable alkali.
  2. MAS is a diagnosis of exclusion; symptoms and signs are essentially those of hypercalcemia in general.
  3. If left untreated, MAS can have an acute course with rapid progression to metastatic calcinosis and renal failure.
  4. The management of MAS generally comprises conservative treatment with intravenous rehydration and removal of the offending agent.

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