The calcium-alkali syndrome

Abstract

The milk-alkali syndrome was a common cause of hypercalcemia, metabolic alkalosis, and renal failure in the early 20th century. It was caused by the ingestion of large quantities of milk and absorbable alkali to treat peptic ulcer disease. The syndrome virtually vanished after introduction of histamine-2 blockers and proton pump inhibitors. More recently, a similar condition called the calcium-alkali syndrome has emerged as a common cause of hypercalcemia and alkalosis. It is usually caused by the ingestion of large amounts of calcium carbonate salts to prevent or treat osteoporosis and dyspepsia. We describe a 78-year-old woman who presented with weakness, malaise, and confusion. She was found to have hypercalcemia, acute renal failure, and metabolic alkalosis. Upon further questioning, she reported use of large amounts of calcium carbonate tablets to treat recent heartburn symptoms. Calcium supplements were discontinued, and she was treated with intravenous normal saline. After 5 days, the calcium and bicarbonate levels normalized and renal function returned to baseline. In this article, we review the pathogenesis of the calcium-alkali syndrome as well as the differences between the traditional and modern syndromes.

The milk-alkali syndrome was originally described in the early 20th century when patients developed hypercalcemia, metabolic alkalosis, and renal failure after ingesting large quantities of milk, cream, and absorbable alkali to treat peptic ulcer disease (1, 2). For a period of time after the introduction of histamine-2 blockers and proton pump inhibitors, this syndrome was virtually eliminated. However, a new form of milk-alkali syndrome, that some have proposed should be called calcium-alkali syndrome, has more recently emerged as a relatively common cause for hypercalcemia and metabolic alkalosis (3). The calcium-alkali syndrome is caused in part by the ingestion of large quantities of calcium carbonate, which is available over the counter. The use of calcium carbonate has steadily increased as an antacid and as a calcium supplement to treat or prevent osteoporosis (3). We report a case of calcium-alkali syndrome.

CASE REPORT

A 78-year-old Caucasian woman presented to the emergency department after falling and injuring her right arm. She complained of general malaise, weakness, and dizziness for several days. She denied fevers, chills, weight changes, bone pains, dyspnea, chest pains, palpitations, or urinary symptoms. Her past medical history was significant for chronic obstructive pulmonary disease, hypertension, atrial fibrillation, and chronic kidney disease with a baseline creatinine of 1.3 mg/dL. Her regular medications included verapamil 180 mg twice daily, ramipril 5 mg daily, warfarin 5 mg daily, ibandronate 2.5 mg daily, and calcium with vitamin D over-the-counter supplements. The patient lived in an independent living facility. She had a previous 15 pack-year history of tobacco use but quit 17 years ago. She denied any alcohol or recreational drug use.

On initial examination, her blood pressure was 215/90 mm Hg, pulse 100 beats/minute, respiratory rate 20 breaths/minute, and temperature 97°F. She was alert and oriented to person, place, and time; however, she was irritable, drowsy, and slow to answer questions. She had dry mucous membranes and poor skin turgor. Her chest was clear to auscultation bilaterally. On precordial examination, no murmurs were heard. Her abdomen was soft, nontender, and nondistended. Her extremities had full range of motion and normal strength.

Initial laboratory results included hemoglobin, 16.2 g/dL; hematocrit, 48.2%; sodium, 138 mEq/L; potassium, 4.2 mEq/L; chloride, 96 mEq/L; bicarbonate, 32 mEq/L; blood urea nitrogen, 35 mg/dL; creatinine, 2.9 mg/dL; calcium, 14.4 mg/dL; albumin, 4.0 g/dL; ionized calcium, 1.52 mmol/L; phosphorus, 5.2 mg/dL; intact parathyroid hormone, 21.0 pg/dL; thyroid-stimulating hormone, 2.66 microIU/L; free thyroxine, 1.26 ng/dL; and 25-hydroxy-vitamin D, 11.0 pg/dL. Serum and urine protein electrophoreses did not reveal any monoclonal proteins.

Her chest radiograph was normal. Renal sonography showed bilateral increased echogenicity and cortical thinning, consistent with chronic renal disease.

Upon further questioning, the patient reported that she had ingested about one bottle (>50 tablets) of calcium carbonate tablets (500 mg) over the previous 3 days to treat heartburn symptoms. During this time she also continued taking her regular calcium and vitamin D supplements. The diagnosis of calcium-alkali syndrome was made.

Intravenous normal saline was administered, and all calcium and vitamin D supplements were discontinued. On day 2, the patient was more lucid, awake, and able to readily communicate. Calcium and creatinine levels dropped to 12.8 mg/dL and 2.7 mg/dL, respectively. On day 5, the calcium and bicarbonate levels were normal at 9.6 mg/dL and 27 mEq/L. The creatinine and blood urea nitrogen were at her baseline values of 1.3 mg/dL and 16 mg/dL, respectively.

The patient was educated on the proper use and dosing of all over-the-counter medications, including calcium and vitamin D supplements. She was discharged home on the fifth day of hospitalization.

DISCUSSION

The calcium-alkali syndrome is the third leading cause of hypercalcemia in hospitalized patients after primary hyperparathyroidism and malignant neoplasms (4). The current version of this syndrome has several biochemical and epidemiological differences from the traditional milk-alkali syndromes described in the early to mid 1900s. The historic conditions were more common in middle-aged men with peptic ulcer disease and were due to the hourly ingestion of sodium bicarbonate, magnesium carbonate, and bismuth subcarbonate (“Sippy Powder”) together with cream and milk. In 1949, Burnett et al described a chronic, more persistent variant of this disorder (5). The introduction of histamine-2 receptor blockers (in 1976) and proton pump inhibitors (in 1989) to block acid secretion, as well as treatments directed at eradicating Helicobacter pylori, virtually eliminated the classic acute and chronic forms of the milk-alkali syndrome. Over the last several decades, the “modern” version was recognized. This form more commonly affects postmenopausal women who ingest large amounts of calcium supplements, sometimes together with vitamin D and occasionally with thiazide diuretics to prevent or treat osteoporosis (6–8). It has also occurred in transplant patients taking high doses of calcium carbonate to prevent osteoporosis related to chronic steroid use (6). The use of calcium-containing antacids to treat dyspepsia also may occur, as was the case in the current report. It has been suggested that the modern syndrome be called the calcium-alkali syndrome because it is due to ingestion of soluble calcium salts instead of milk, cream, and the other alkali sources listed above (3).

The calcium-alkali syndrome, similar to the traditional version, is characterized by hypercalcemia, metabolic alkalosis, and renal injury. However, serum phosphorus levels were usually high in the historic forms due to the high phosphorus load from cream and milk and the development of acute and chronic renal injury. The current calcium-alkali syndrome more typically presents with a normal or even low serum phosphorus concentration resulting from the dietary phosphate-binding properties of calcium carbonate (6–8).

Although serum vitamin D is usually suppressed in patients with calcium-alkali syndrome, it may be normal or even increased if vitamin D supplements have contributed to the disorder (8). Serum parathyroid hormone levels, which would be expected to be low, are sometimes normal. This may be due to renal insufficiency or related to a rapid fall in serum calcium soon after initiation of aggressive intravenous saline infusion (7).

The pathogenesis of calcium-alkali syndrome involves the interplay of multiple organ systems, including bone, intestines, and the kidney. The ingestion of large amounts of calcium-containing compounds increases intestinal absorption of calcium and causes hypercalcemia. Hypercalcemia will constrict the renal arterioles, reduce the glomerular filtration rate, and decrease renal calcium excretion (9). Calcium-sensing receptors (CaSRs) are located in many tissues throughout the body, including the renal tubules, the intestines, and the parathyroid and thyroid glands. When high calcium levels activate the CaSRs in the thick ascending loop of Henle, sodium chloride reabsorption at this site is inhibited, causing diuresis and increasing renal calcium excretion (i.e., a loop diuretic-like effect). This effect also contributes to volume depletion and metabolic alkalosis (10). CaSRs are also present on the luminal membrane of the distal convoluted tubules, and activation of these receptors (by high renal tubule calcium concentrations) increases calcium reabsorption via TRVP5 channels (10). In addition, CaSRs are found on the luminal membranes of the collecting duct cells, and their activation reduces expression of aquaporin 2 water channels. This reduces renal tubule water reabsorption and causes the excretion of dilute urine (10). The net effect is a salt and water diuresis with variable impact on renal calcium excretion. Metabolic alkalosis helps to perpetuate this cycle by increasing the affinity of the CaSRs to calcium, which enhances the natriuresis. An alkaline pH also stimulates the activity of an important calcium selective receptor called the transient receptor potential vanilloid member 5 (TRPV5); this enhances calcium reabsorption and leads to worsening hypercalcemia (10, 11). To the extent hypercalcemia suppresses serum parathyroid hormone, renal bicarbonate reabsorption is promoted. Additionally, hypercalcemia may generate nausea and vomiting, which worsens the volume depletion and alkalosis (9).

The diagnosis of calcium-alkali syndrome should be considered when a patient presents with acute renal injury, metabolic alkalosis, hypercalcemia, and a history of excessive calcium (± vitamin D) intake. Generally, the first and most important treatment for calcium-alkali syndrome is extracellular volume expansion with intravenous saline. This will hopefully improve renal function and increase renal calcium and bicarbonate excretion. It is also essential to identify all calcium salt and vitamin D–containing medications that the patient is taking and to provide education about appropriate dosing. It may be difficult to determine the appropriate dose of calcium salts for a given patient. The syndrome has been reported after ingestion of doses as low as 1 g of elemental calcium daily (11). However, most reported cases of the syndrome document ingestion of at least 4 g of elemental calcium per day. Although a daily intake of 2 g of calcium is considered safe for the general population, smaller doses of 1.2 to 1.5 g daily should be used when patients have risk factors that increase their likelihood of developing the calcium-alkali syndrome (3, 8, 9). For example, the elderly and patients with chronic kidney disease are more susceptible because they will have a lower glomerular filtration rate and decreased calcium clearance (9, 11). Additionally, the skeleton of elderly subjects does not buffer calcium loads as well as that of younger subjects (9).

Thiazide diuretic use may also predispose to the development of this condition by enhancing renal tubule calcium absorption and by promoting volume depletion and alkalosis. Furthermore, any medications that reduce glomerular filtration rate, such as nonsteroidal antiinflammatory drugs and angiotensin-converting enzyme inhibitors, can contribute to the development of the syndrome (9).