Calcium-Alkali Syndrome Due to Vitamin D Administration and Magnesium Oxide Administration

Abstract

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.1Hardt L.L. Rivers A.B. Toxic manifestations following the alkaline treatment of peptic ulcer.Arch Intern Med. 1923; 31: 171-180Crossref Scopus (66) Google Scholar 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.2Sippy B.W. Gastric and duodenal ulcer.JAMA. 1915; 64: 1625-1630Crossref Scopus (82) Google Scholar 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.3Abreo K. Adlakha A. Kilpatrick S. Flanagan R. Webb R. Shakamuri S. The milk-alkali syndrome.Arch Intern Med. 1993; 153: 1005-1010Crossref PubMed Google Scholar Recent data have shown that this condition is the third leading cause of hospital admissions for hypercalcemia, after primary hyperparathyroidism and hypercalcemia of malignancy.4Beall D.P. Scofield R.H. 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: 89-96Crossref PubMed Scopus (110) Google Scholar, 5Picolos M.K. Lavis V.R. Orlander P.R. Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients.Clin Endocrinol (Oxf). 2005; 63: 566-576Crossref PubMed Scopus (77) Google Scholar Therefore, better understanding of this condition is important for clinicians because the diagnosis often is missed.5Picolos M.K. Lavis V.R. Orlander P.R. Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients.Clin Endocrinol (Oxf). 2005; 63: 566-576Crossref PubMed Scopus (77) Google Scholar, 6Kaklamanos M. Perros P. Milk alkali syndrome without the milk.BMJ. 2007; 25 (335): 397-398Crossref Scopus (14) Google Scholar 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.6Kaklamanos M. Perros P. Milk alkali syndrome without the milk.BMJ. 2007; 25 (335): 397-398Crossref Scopus (14) Google Scholar, 7Kleinig T.J. Torpy D.J. Milk-alkali syndrome: Broadening the spectrum of causes to allow early recognition.Intern Med J. 2004; 34: 366-367Crossref PubMed Scopus (5) Google Scholar, 8Sulkin T. Krentz A.J. Iatrogenic recurrent severe hypercalcaemia and renal impairment.Postgrad Med J. 2000; 76: 800-807Crossref PubMed Google Scholar 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. 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). 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. Calcium-alkali syndrome and hypermagnesemia caused by administration of vitamin D and magnesium oxide. 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. 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.9Sutton R.A. Wong N.L. Dirks J.H. Effects of metabolic acidosis and alkalosis on sodium and calcium transport in the dog kidney.Kidney Int. 1979; 15: 520-533Crossref PubMed Scopus (205) Google Scholar, 10Felsenfeld A.J. Levine B.S. Milk-alkali syndrome and the dynamics of calcium homeostasis.Clin J Am Soc Nephrol. 2006; 1: 641-654Crossref PubMed Scopus (67) Google Scholar 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.11Zeffren J.L. Heinemann H.O. Reversible defect in renal concentrating mechanism in patients with hypercalcemia.Am J Med. 1962; 33: 54-63Abstract Full Text PDF PubMed Scopus (40) Google Scholar, 12Benabe J.E. Martinez-Maldonado M. Hypercalcemic nephropathy.Arch Intern Med. 1978; 138: 777-779Crossref PubMed Scopus (58) Google Scholar Ingestion of an alkali, increased renal tubular bicarbonate reabsorption from volume depletion, direct tubular effects of calcium,13Liu F.Y. Cogan M.G. Effects of intracellular calcium on proximal bicarbonate absorption.Am J Physiol. 1990; 259: F451-F457PubMed Google Scholar and suppression of parathyroid hormone in response to hypercalcemia14Nordin B.E. The effect of intravenous parathyroid extract on urinary pH, bicarbonate and electrolyte excretion.Clin Sci. 1960; 19: 311-319PubMed Google Scholar 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 reabsorption9Sutton R.A. Wong N.L. Dirks J.H. Effects of metabolic acidosis and alkalosis on sodium and calcium transport in the dog kidney.Kidney Int. 1979; 15: 520-533Crossref PubMed Scopus (205) Google Scholar and activated vitamin D–facilitated intestinal calcium absorption15Norman A.W. Vitamin D metabolism and calcium absorption.Am J Med. 1979; 67: 989-998Abstract Full Text PDF PubMed Scopus (43) Google Scholar with resulting hypercalcemia. Moreover, hypercalcemia and mildly suppressed parathyroid hormone may also contribute to the maintenance of alkalosis.14Nordin B.E. The effect of intravenous parathyroid extract on urinary pH, bicarbonate and electrolyte excretion.Clin Sci. 1960; 19: 311-319PubMed Google Scholar 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.5Picolos M.K. Lavis V.R. Orlander P.R. Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients.Clin Endocrinol (Oxf). 2005; 63: 566-576Crossref PubMed Scopus (77) Google Scholar 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.10Felsenfeld A.J. Levine B.S. Milk-alkali syndrome and the dynamics of calcium homeostasis.Clin J Am Soc Nephrol. 2006; 1: 641-654Crossref PubMed Scopus (67) Google Scholar In addition, metabolic alkalosis from causes other than excessive intake of alkali, such as gastric acid loss,7Kleinig T.J. Torpy D.J. Milk-alkali syndrome: Broadening the spectrum of causes to allow early recognition.Intern Med J. 2004; 34: 366-367Crossref PubMed Scopus (5) Google Scholar 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.5Picolos M.K. Lavis V.R. Orlander P.R. Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients.Clin Endocrinol (Oxf). 2005; 63: 566-576Crossref PubMed Scopus (77) Google Scholar Both calcium and magnesium are bivalent cations and show antagonistic activities in the cell membrane,16Iseri L.T. French J.H. Magnesium: Nature's physiologic calcium blocker.Am Heart J. 1984; 108: 188-193Abstract Full Text PDF PubMed Scopus (693) Google Scholar 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 medication17Matsuo 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: 477-478Crossref PubMed Google Scholar 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]).18Oren S. Rapoport J. Zlotnik M. Brami J.L. Heimer D. Chaimovitz C. Extreme hypermagnesemia due to ingestion of Dead Sea water.Nephron. 1987; 47: 199-201Crossref PubMed Scopus (18) Google Scholar, 19Porath A. Mosseri M. Harman I. Ovsyshcher I. Keynan A. Dead Sea water poisoning.Ann Emerg Med. 1989; 18: 187-191Abstract Full Text PDF PubMed Scopus (18) Google Scholar, 20Mosseri M. Porath A. Ovsyshcher I. Stone D. Electrocardiographic manifestations of combined hypercalcemia and hypermagnesemia.J Electrocardiol. 1990; 23: 235-241Abstract Full Text PDF PubMed Scopus (11) Google Scholar DSWP causes electrolyte intoxication of combined severe hypercalcemia (maximal reported serum calcium level, 28.8 mg/dL [7.19 mmol/L]20Mosseri M. Porath A. Ovsyshcher I. Stone D. Electrocardiographic manifestations of combined hypercalcemia and hypermagnesemia.J Electrocardiol. 1990; 23: 235-241Abstract Full Text PDF PubMed Scopus (11) Google Scholar) and hypermagnesemia (maximal reported serum magnesium level, 33 mg/dL [13.58 mmol/L]20Mosseri M. Porath A. Ovsyshcher I. Stone D. Electrocardiographic manifestations of combined hypercalcemia and hypermagnesemia.J Electrocardiol. 1990; 23: 235-241Abstract Full Text PDF PubMed Scopus (11) Google Scholar) caused by accidental ingestion of large amounts of water from the Dead Sea, and this electrolyte disorder has a significant negative impact on prognosis.18Oren S. Rapoport J. Zlotnik M. Brami J.L. Heimer D. Chaimovitz C. Extreme hypermagnesemia due to ingestion of Dead Sea water.Nephron. 1987; 47: 199-201Crossref PubMed Scopus (18) Google Scholar 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.20Mosseri M. Porath A. Ovsyshcher I. Stone D. Electrocardiographic manifestations of combined hypercalcemia and hypermagnesemia.J Electrocardiol. 1990; 23: 235-241Abstract Full Text PDF PubMed Scopus (11) Google Scholar 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.19Porath A. Mosseri M. Harman I. Ovsyshcher I. Keynan A. Dead Sea water poisoning.Ann Emerg Med. 1989; 18: 187-191Abstract Full Text PDF PubMed Scopus (18) Google Scholar 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. Support: None. Financial Disclosure: None.