| | Calcium-Alkali Syndrome Due to Vitamin D Administration and Magnesium Oxide AdministrationReceived 29 July 2008; accepted 4 November 2008. published online 30 January 2009. Milk-alkali syndrome is characterized by the triad of hypercalcemia, metabolic alkalosis, and decreased kidney function and is caused by excessive intake of calcium and alkali.1 This syndrome was first recognized in the 1920s during administration of the then popular “Sippy” regimen for peptic ulcer disease, consisting of large amounts of milk and sodium bicarbonate.2 Although the syndrome became rare after widespread implementation of modern peptic ulcer disease therapies, it has now become increasingly prevalent in elderly patients who use drugs containing calcium (eg, calcium carbonate) for prevention or treatment of osteoporosis.3 Recent data have shown that this condition is the third leading cause of hospital admissions for hypercalcemia, after primary hyperparathyroidism and hypercalcemia of malignancy.4, 5 Therefore, better understanding of this condition is important for clinicians because the diagnosis often is missed.5, 6 Calcium carbonate or other calcium salts that contain organic anion as the source of bicarbonate have replaced milk products as the predominant source of calcium loading in modern cases of this condition, such that the term “milk-alkali syndrome” no longer reflects the etiologic origin. Pathophysiologically, because the triad of hypercalcemia, metabolic alkalosis, and decreased kidney function can occur whenever alkalosis and a calcium load coexist, we suggest that the term “calcium-alkali syndrome,” which broadens the definition of the condition, should replace milk-alkali syndrome, as recommended by several other investigators.6, 7, 8 In this article, we use the term calcium-alkali syndrome to include cases of traditional milk-alkali syndrome. We present a previously undescribed form of calcium-alkali syndrome induced by oral administration of activated vitamin D (alfacalcidol) and an excess of magnesium oxide without calcium-containing drugs or supplements. Case Report  Clinical History An 85-year-old Japanese woman who was receiving treatment for hypertension and osteoporosis developed symptoms of a viral upper respiratory illness and lost her appetite 2 weeks before admission. She gradually became weaker and was referred to the hospital. She presented with nausea, lethargy, and an altered level of consciousness. Physical examination showed blood pressure of 85/45 mm Hg and heart rate of 50 beats/min. Skin turgor was reduced, oral mucosa were dry, and jugular veins were not distended. Neurological examination showed the absence of deep tendon reflexes in the lower extremities. Laboratory data showed severely decreased kidney function (serum creatinine, 4.37 mg/dL [386 μmol/L]; estimated glomerular filtration rate [eGFR], 10 mL/min/1.73 m2 [0.17 mL/s/1.73 m2]), hypercalcemia (serum calcium, 14.5 mg/dL [3.62 mmol/L]), and hypermagnesemia (serum magnesium, 10.2 mg/dL [4.20 mmol/L]). 1,25-Dihydroxyvitamin D level was 24.5 pg/mL (64 pmol/L), which was within the normal range (20.0 to 60.0 pg/mL), and intact parathyroid hormone level was 14 pg/mL (14 ng/L), which was within the lower-normal range (10 to 65 pg/mL). Parathyroid hormone–related peptide was less than the limit of detection. Arterial blood gas analysis confirmed metabolic alkalosis (pH 7.445; serum bicarbonate, 36 mEq/L [36 mmol/L]). Urinalysis showed pH of 8.0 and protein excretion of 0.29 g/d. However, no occult blood or abnormal casts were observed. Other laboratory data were as follows: serum sodium, 133 mEq/L (133 mmol/L); potassium, 4.2 mEq/L (4.2 mmol/L); chloride, 86 mEq/L (86 mmol/L); phosphorus, 4.4 mg/dL (1.42 mmol/L); albumin, 4.1 g/dL (41 g/L); and urea nitrogen, 79.4 mg/dL (28.3 mmol/L). Electrocardiography showed sinus bradycardia at 50 beats/min and first-degree atrioventricular block with a PR interval of 280 milliseconds. The corrected QT (QTc) interval was within the normal range at 0.39 seconds. Abdominal computed tomography did not show notable abnormalities other than mild calcification of the abdominal aorta. Echocardiography showed favorable cardiac function (left ventricular ejection fraction, 78%) and collapse of the inferior vena cava. Tests conducted by the patient's general physician indicated a serum creatinine level of 0.9 mg/dL (80 μmol/L) and eGFR of 64 mL/min/1.73 m2 (1.07 mL/s/1.73 m2) 2 years before admission. The patient presented with volume depletion, decreased kidney function, hypercalcemia, hypermagnesemia, and metabolic alkalosis. Her daily medications included 1.0 μg of alfacalcidol and 6.0 g of magnesium oxide, and these were discontinued upon presentation because it was believed to be the primary cause of the electrolyte disorders. She was initially managed with 3,000 mL of saline solution and 20 mg of furosemide administered intravenously daily. Hemodynamics stabilized and diuresis was achieved with a daily urinary volume of 2,000 to 3,300 mL. The patient showed rapid recovery of consciousness and other symptoms, with improvement in electrolyte disorders and kidney function (Fig 1). Electrolyte levels returned to their normal range within 1 week and kidney function improved, with a serum creatinine level of 1.10 mg/dL (97.2 μmol/L) and eGFR of 50 mL/min/1.73 m2 (0.83 mL/s/1.73 m2) at the time of discharge (hospital day 14). Additional Investigations On further review of the patient's oral medication history, we found that she had begun using 1.5 g/d of magnesium oxide for chronic constipation 4 years before admission and had gradually increased the dosage. One month before admission, she increased the dosage from 3.0 to 6.0 g/d because of persistent constipation. In addition, after experiencing a compression fracture of the lumbar spine 2 years before admission, she had started using 1.0 μg/d of alfacalcidol orally. Despite weakness and decreased appetite, the patient continued to use these drugs. She had not used calcium-containing drugs or supplements and only occasionally consumed milk or yogurt. Diagnosis Calcium-alkali syndrome and hypermagnesemia caused by administration of vitamin D and magnesium oxide. Clinical Follow-up Kidney function remained stable without recurrence of electrolyte or acid-base disorders during follow-up. The patient had a serum creatinine level of 1.0 mg/dL (88.4 μmol/L) and eGFR of 56 mL/min/1.73 m2 (0.93 mL/s/1.73 m2) 6 months after discharge. Discussion The pathophysiological mechanism of calcium-alkali syndrome is complex and involves several interrelated factors. Increased intestinal absorption of calcium, decreased urinary calcium excretion, and decreased kidney function can initiate and maintain hypercalcemia.9, 10 Hypercalcemia can reduce kidney function through vasoconstriction that decreases renal blood flow and GFR, increased sodium and free water excretion, and nausea and vomiting that induce volume depletion.11, 12 Ingestion of an alkali, increased renal tubular bicarbonate reabsorption from volume depletion, direct tubular effects of calcium,13 and suppression of parathyroid hormone in response to hypercalcemia14 can produce and maintain metabolic alkalosis. Once established, hypercalcemia, alkalosis, and decreased kidney function promote and maintain a self-perpetuating cycle. Calcium-alkali syndrome can occur whenever alkalosis and a calcium load coexist, and excessive intake of calcium carbonate, which is both a calcium and an alkali source, is the leading cause of modern cases of calcium-alkali syndrome. The patient in this case was using activated vitamin D (alfacalcidol, 1.0 μg/d) and an excess of magnesium oxide (6.0 g/d, 3 times the normal dose), but neither calcium-containing drugs nor supplements. Magnesium oxide acts as an antacid in the stomach and is converted in the intestinal tract to magnesium carbonate and magnesium bicarbonate, both of which have low absorbability and act as laxatives by osmotically mediating water retention. In this case, ingestion of large amounts of magnesium oxide may have induced significant intestinal absorption of magnesium and bicarbonate. The pathophysiological mechanism in this patient was initiated by a state of volume depletion caused by a viral illness. Excessive magnesium oxide intake and decreased bicarbonate excretion caused by volume depletion resulted in the generation and maintenance of metabolic alkalosis. Alkalosis and volume depletion, in turn, facilitated renal tubular calcium reabsorption9 and activated vitamin D–facilitated intestinal calcium absorption15 with resulting hypercalcemia. Moreover, hypercalcemia and mildly suppressed parathyroid hormone may also contribute to the maintenance of alkalosis.14 Hypercalcemia caused decreased kidney function, and calcium-alkali syndrome was maintained by the interactions described. Hypermagnesemia may have been induced by magnesium intake and decreased urinary excretion caused by decreased kidney function. Calcium-alkali syndrome does not occur in all people who ingest large amounts of calcium and alkali and may occur with even small amounts. In some cases, the amount of ingested calcium carbonate is 2 g or less of elemental calcium daily.5 Differences in susceptibility to the syndrome may be attributed to factors that include age, kidney function, endocrine function, intestinal function, and bone metabolism, which are believed to have an important role in the pathogenesis.10 In addition, metabolic alkalosis from causes other than excessive intake of alkali, such as gastric acid loss,7 can be a causative factor of calcium-alkali syndrome. This background and this case indicate that several factors, including a wide range of calcium loading and alkalosis caused by multiple factors, can lead to calcium-alkali syndrome, and it is not necessarily caused by the ingestion of large amounts of calcium and alkali. As a result of the mechanisms described, this patient had an extremely rare electrolyte disorder in which hypercalcemia and hypermagnesemia coexisted, although calcium-alkali syndrome tends to present as hypomagnesemia.5 Both calcium and magnesium are bivalent cations and show antagonistic activities in the cell membrane,16 and this complicates the effects of combined hypercalcemia and hypermagnesemia. This condition usually is caused by poisoning, and reported cases include dialysis patients using oral magnesium oxide medication17 and near-drowning cases in the Dead Sea, a salt lake that contains high concentrations of electrolytes (ie, cases of Dead Sea water poisoning [DSWP]).18, 19, 20 DSWP causes electrolyte intoxication of combined severe hypercalcemia (maximal reported serum calcium level, 28.8 mg/dL [7.19 mmol/L]20) and hypermagnesemia (maximal reported serum magnesium level, 33 mg/dL [13.58 mmol/L]20) caused by accidental ingestion of large amounts of water from the Dead Sea, and this electrolyte disorder has a significant negative impact on prognosis.18 Electrocardiograms have shown various abnormalities in patients with DSWP, but the QTc interval usually is within the normal range. The QTc interval is expected to shorten in patients with hypercalcemia and lengthen in those with hypermagnesemia, and the normal value may be caused by these effects offsetting each other.20 In our patient, bradycardia and first-degree atrioventricular block improved and the normal QTc interval showed no marked changes during recovery. Hemodialysis therapy is recommended for patients with DSWP lacking deep tendon reflexes because this symptom is predictive of a poor prognosis.19 Although an electrolyte disorder similar to DSWP was recognized and absence of deep tendon reflexes was observed in the lower extremities of our patient, fluid therapy was selected over hemodialysis because her hemodynamics were unstable because of volume depletion. In conclusion, calcium-alkali syndrome can be induced by factors other than ingestion of large amounts of calcium and alkali, and this further broadens the definition of the syndrome. Because the diagnosis may be easily missed, calcium-alkali syndrome should be considered in all patients with hypercalcemia. Acknowledgements Support: None. Financial Disclosure: None. References 1. 1Hardt LL, Rivers AB. Toxic manifestations following the alkaline treatment of peptic ulcer. Arch Intern Med. 1923;31:171–180. 2. 2Sippy BW. Gastric and duodenal ulcer. JAMA. 1915;64:1625–1630. 3. 3Abreo K, Adlakha A, Kilpatrick S, Flanagan R, Webb R, Shakamuri S. The milk-alkali syndrome. Arch Intern Med. 1993;153:1005–1010. MEDLINE 4. 4Beall DP, Scofield RH. Milk-alkali syndrome associated with calcium carbonate consumption (Report of 7 patients with parathyroid hormone levels and an estimate of prevalence among patients hospitalized with hypercalcemia). Medicine (Baltimore). 1995;74:89–96. MEDLINE |
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6. 6Kaklamanos M, Perros P. Milk alkali syndrome without the milk. BMJ. 2007;25:397–398. 7. 7Kleinig TJ, Torpy DJ. Milk-alkali syndrome: Broadening the spectrum of causes to allow early recognition. Intern Med J. 2004;34:366–367. MEDLINE |
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17. 17Matsuo H, Nakamura K, Nishida A, Kubo K, Nakagawa R, Sumida Y. A case of hypermagnesemia accompanied by hypercalcemia induced by a magnesium laxative in a hemodialysis patient. Nephron. 1995;71:477–478. 18. 18Oren S, Rapoport J, Zlotnik M, Brami JL, Heimer D, Chaimovitz C. Extreme hypermagnesemia due to ingestion of Dead Sea water. Nephron. 1987;47:199–201. 19. 19Porath A, Mosseri M, Harman I, Ovsyshcher I, Keynan A. Dead Sea water poisoning. Ann Emerg Med. 1989;18:187–191. Abstract |
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1 Department of Nephrology, Musashino Red Cross Hospital, Tokyo Medical and Dental University, Tokyo, Japan 2 Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan  Address correspondence to Shigeru Hanada, MD, Department of Nephrology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino, Tokyo 180-8610, Japan
PII: S0272-6386(08)01692-2 doi:10.1053/j.ajkd.2008.11.015 © 2009 National Kidney Foundation, Inc. Published by Elsevier Inc All rights reserved. | |
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