AUTHOR AND EDITOR INFORMATION

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• Workup
• Treatment
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• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

Milk-alkali syndrome is caused by the ingestion of large amounts of calcium and absorbable alkali with resulting hypercalcemia. If unrecognized and untreated, milk-alkali syndrome can lead to metastatic calcification and renal failure. This syndrome was originally recognized in the 1920s during administration of the Sippy regimen, consisting of milk and bicarbonate, for treatment of peptic ulcer disease.

With the development of nonabsorbable alkali and histamine-2 blockers for treatment of peptic ulcer disease, milk-alkali syndrome became a rare cause of hypercalcemia; however, with increased use and promotion of calcium carbonate for dyspepsia and as calcium supplementation, a resurgence of milk-alkali syndrome has occurred in the last few years.

Pathophysiology

How oral intake of more than 2 g/d of elemental calcium with absorbable alkali results in hypercalcemia and alkalosis is not completely understood. Adaptation of intestinal calcium absorption to oral intake may play a role and help explain individual variability in the development of milk-alkali syndrome. Some persons maintain a high fractional absorption of calcium even with a high intake, while other persons decrease fractional absorption with a high intake. The former are likely at risk of developing milk-alkali syndrome.

Calcium absorption is completed within 4 hours of intake. Avid absorption of large doses may lead to suppression of parathyroid hormone (PTH), which then produces enhanced bicarbonate retention by the kidney. Continuing ingestion of calcium carbonate and bicarbonate retention leads to alkalosis, which causes increased calcium resorption in the distal collecting system of the kidney. Also, hypercalcemia produces a renal concentrating defect that can be considered a form of nephrogenic diabetes insipidus.

Resultant dehydration and volume depletion may worsen the hypercalcemia. PTH is further suppressed by hypercalcemia. This cyclic pathophysiology maintains hypercalcemia and alkalosis as long as calcium and alkali are taken in by mouth. The data are clear that PTH is suppressed in milk-alkali syndrome. Low PTH levels may be part of the mechanism by which phosphate is either normal or high in many patients, because a low PTH level impairs GI absorption of phosphate.

Chronic milk-alkali syndrome can result in metastatic calcification due to high serum calcium levels and relatively high phosphate levels (calcium times phosphate). Irreversible renal failure may result. However, even severe renal failure may be completely reversible if milk-alkali syndrome is diagnosed early.

Frequency

United States

Among heart transplant patients, Kapsner et al found in a retrospective chart review that 65 of 297 patients had hypercalcemia over a 1-year period. Only 3 of the 65 patients were diagnosed clinically with milk-alkali syndrome, although no alternative diagnoses were made in the other patients. Thus, in this special setting, milk-alkali syndrome was not uncommon. In a 1982 review, milk-alkali syndrome was said to cause less than 1% of hypercalcemia. However, a number of case reports over the last several years have suggested that milk-alkali syndrome is more common than previously observed or appreciated.

More importantly two large studies have been performed. In one study of patients hospitalized for emergent hypercalcemia, milk-alkali syndrome was the underlying cause in 6 (12%) of 49 of patients admitted over a 4-year period (Beall, 1995). The syndrome was third behind hyperparathyroidism and solid malignancy as a cause of hypercalcemia requiring hospitalization, and it was more common than multiple myeloma. A second study of patients hospitalized from 1998-2003 with hypercalcemia found similar results (Picolos, 2005). Of 125 patients without end-stage renal disease, 11 (8.8%) had milk-alkali syndrome. Of those with severely elevated calcium, 9 (25.7%) of 25 had milk-alkali syndrome, which was second only to malignancy among those with severe hypercalcemia.

International

International frequency is not known to be different than that observed in the United States. Occurrence should be related to the number of persons ingesting calcium carbonate.

Mortality/Morbidity

• Milk-alkali syndrome almost never results in death.
• A significant number of patients may be left with permanent renal impairment.
• In recent reports, 19 of 51 patients had a follow-up serum creatinine level of more than 1.5 mg/dL (see the Table).

Race

• No racial predilection is recognized, although Southeast Asians and Indians are potential users of betel nut, which can cause the syndrome.

Sex

• Women are affected more commonly than men and comprise approximately 60% of patients.

Age

• The average age of the last 65 reported patients was 50.3 years, with a range of 24-95 years.



• Older, postmenopausal women taking calcium supplementation may be at particularly high risk.
• 
  Summary of 65 Consecutively Reported Adult Patients With Milk-Alkali Syndrome*
  

  Mean age	50.3 years (range, 24-95 y)
  Sex	29 men and 36 women
  Calcium source	Calcium carbonate in all but one
  Ingestion of bicarbonate	In 6 patients
  Ingestion of milk	In 19 patients (plus one who ate yogurt)
  Mean serum calcium	15.2 mg/dL (3.77 mmol/L) (range, 11.1-27.5 mg/dL)
  High serum phosphorus	In 12 patients
  Permanent renal insufficiency	In 19 of 54 patients eligible for evaluation
  Parathyroid exploration	In 3 patients
  Hypocalcemia with treatment	In 16 patients

  
  *These data are derived from the 7 patients reported, plus the 28 reviewed in Beall and Scofield, 1995, as well as additional patients reported by Gibbs and Lee, 1992; Nakanishi, 1992; Brandwein and Sigman, 1994; Campbell, 1994; Duthie, 1995; Spital and Freedman, 1995; Fiorino, 1996; Lin, 1996; Muldowney and Mazbar, 1996; Sulkin and Krentz, 1999; Camidge and Peaston, 2000; George and Clark, 2000; Vanpee, 2000; Liu, 2002; Robertson, 2002; Picolos, 2005; Gordon, 2005; Kleinig 2004; Morton 2002.

CLINICAL

Section 3 of 11  

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History

• A wide variation of symptoms occurs among individuals, even with similar levels of serum calcium.
  
  
  • Some patients may be completely asymptomatic, with hypercalcemia found incidentally after a multiple chemistry panel.
  
  
  
  • Patients may have severe mental status changes that include obtundation and coma, especially as serum calcium levels rise to higher than 15 mg/dL.
     
• Milk-alkali syndrome can have an acute course with rapid induction of hypercalcemia and acute renal failure soon (within a week) after excess calcium carbonate is begun.



• A more chronic course also is observed. In this form, irreversible renal failure may ensue but many patients have partial recovery with a timely diagnosis.



• The signs and symptoms of milk-alkali syndrome are those of hypercalcemia of any cause.



• Central nervous system symptoms may include the following:
• • Fatigue
  
  
  
  • Depression
  
  
  
  • Malaise
  
  
  
  • Confusion/mental status changes
  
  
  



• Gastrointestinal symptoms may include the following:
• • Nausea
  
  
  
  • Vomiting
  
  
  
  • Constipation
  
  
  



• Genitourinary symptoms may include the following:
• • Urinary frequency
  
  
  
  • Renal tubular defects
  
  
  
  • Renal failure
  
  
  



• Cardiac symptoms may include the following:
  • ECG changes (short QT interval)
  
  
  
  • Arrhythmias

Physical

• No specific or characteristic physical findings are described.
• An altered mental status is common.

Causes

• The cause of milk-alkali syndrome is ingestion of an inappropriately high amount of calcium carbonate. Ingestion of milk and bicarbonate is now rare. One patient has been reported to develop milk-alkali syndrome during prolonged enteral tube feedings containing 2.1 g of calcium per day (Kleinig, 2004).



• Myriad of over-the-counter medicines have calcium carbonate as an ingredient. Patients may be acquiring it from more than one source. For example, a woman might take a 600-mg calcium carbonate tablet twice a day for calcium supplementation and additionally take 200-mg tablets marketed for dyspepsia treatment.



• A careful history of all medicines, including over-the-counter medications, should be obtained. This includes actual inspection of bottles to determine ingredients, when needed.



• While perhaps counterintuitive, the therapeutic index of calcium carbonate is small. The usual prescribed dose is 1200-1500 mg of elemental calcium for postmenopausal supplementation, while 2500-3000 mg of elemental calcium as the carbonate salt can produce milk-alkali syndrome.



• Ingestion of large amounts of milk or milk products is no longer a common feature of milk-alkali syndrome.

DIFFERENTIALS

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Other Problems to be Considered

A summary of the final diagnoses (ie, causing hypercalcemia) in 2 large series, 100 and 125 patients, respectively, admitted for hypercalcemia is as follows:

• Malignancy - 29% in series 1, 33.6% in series 2



• Hyperparathyroidism - 49% in series 1, 29.6% in series 2



• Milk-alkali syndrome - 12% in series 1, 8.8% in series 2



• Multiple myeloma - 4% in series 1, not separated from other malignancies in series 2



• Unknown* - 4% in series 1, 2.4% in series 2



• Vitamin D intoxication - 4% in series 1, 6.8% in series 2

• Hyperthyroidism: Any condition causing hyperthyroidism can cause mild hypercalcemia.



• Hyperparathyroidism: Primary hyperparathyroidism can be caused by an adenoma or hyperplasia. Tertiary hyperparathyroidism is the persistence of high PTH levels and the onset of hypercalcemia after renal transplant in a patient with severe secondary hyperparathyroidism secondary to renal failure. All forms of parathyroid-mediated hypercalcemia should be associated with an inappropriately high serum PTH level. Parathyroid carcinoma is a very rare cause of hypercalcemia.



• Ectopic hormone secretion: Secretion of authentic PTH is rare, but secretion of PTH-related peptide (PTH-RP) by squamous cell malignancies of the lung or head and neck is observed frequently.



• Familial hypocalciuric hypercalcemia



• Hematological malignancies: Almost every type of lymphoma and leukemia can produce hypercalcemia.



• Hypophosphatasia



• Immobilization: Hypercalcemia can occur in the setting of increased bone turnover and immobilization, eg, Paget disease, or paralysis in a teenager.



• Lithium therapy: PTH secretion is stimulated.



• Solid malignancies: Virtually any cancer with metastatic bone lesions can produce hypercalcemia. Squamous cell carcinomas of the lung or head and neck produce a humeral hypercalcemia.



• Vitamin D intoxication

WORKUP

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Lab Studies

• The differential diagnosis of hypercalcemia is wide; many laboratory tests may be indicated in order to eliminate the possibilities. Based on the clinical circumstances, most of the studies may be needed in some patients, while in other patients, only a few are required to secure the diagnosis.



• Serum calcium
  
  
  • An elevated serum calcium level should initiate a workup that includes the possibility of milk-alkali syndrome.
  
  
  
  • Serum calcium levels can range from a mild elevation to a severe life-threatening elevation of higher than 18 mg/dL. Serum calcium levels must be interpreted with regard to serum albumin levels, although the formula for correction of calcium for hypoalbuminemia is only validated in cirrhosis of the liver. Clearly, this correction is not valid during pregnancy or critical illness. Ionized calcium is useful to confirm true, physiologic, elevated calcium.
     
• Serum parathyroid hormone
  
  
  • PTH is suppressed to below normal in patients with milk-alkali syndrome.
  
  
  
  • The 4 important caveats in the measurement of serum PTH are as follows:
    
    
    1. A high-quality, 2-antibody assay for the intact molecule must be used. Many of these assays are based on immunoradiometric techniques. These assays do not crossreact with PTH-RP.
    
    
    
    2. The timing of measurement of PTH is critical. In milk-alkali syndrome, but not in other forms of hypercalcemia, vigorous treatment of hypercalcemia with saline diuresis and loop-diuretics may lead to hypocalcemia. This occurs within the first few days of treatment and is associated with a suppressed PTH. However, with the hypocalcemia, PTH will rise and may reach levels above the reference range. PTH levels should be determined before or at the initiation of treatment. If serum PTH is measured after treatment is started, the levels are unpredictable and the results will be confusing.
    
    
    
    3. PTH should always be determined and interpreted with a simultaneous serum calcium or, more correctly, with ionized serum calcium.
    
    
    
    4. An elevated PTH may be found in the setting of milk-alkali syndrome with renal failure. This is caused by severe secondary hyperparathyroidism. Nonetheless, in general, a high PTH level suggests hyperparathyroidism while a low PTH level is consistent with milk-alkali syndrome or hypercalcemia of malignancy.
        
• Phosphorus
  
  
  • Serum phosphorus concentration can be elevated in milk-alkali syndrome due to a low PTH level, although this finding is less prevalent in the present era than when ingestion of milk and bicarbonate caused the syndrome.
  
  
  
  • The product of serum calcium and phosphorus is an important predictor of the risk of metastatic calcification.
     
• Creatinine/blood urea nitrogen
  
  
  • Kidney function may range from normal to severely compromised in patients with milk-alkali syndrome.
  
  
  
  • Severe renal disease may alter the approach to therapy because intravenous infusion of large amounts of saline may not be possible because of volume overload.
  
  
  
  • The combination of severe renal impairment and a high serum PTH level suggests secondary or tertiary hyperparathyroidism.
     
• Thyroid-stimulating hormone/free levothyroxine and cortisol
  
  
  • Hyperthyroidism can cause elevated serum calcium levels due to high bone turnover.
  
  
  
  • Adrenal failure also can be associated with high serum calcium levels, although the mechanism has not been fully explained.
  
  
  
  • If the clinical and laboratory picture is suggestive, adrenocortical function should be evaluated in a provocative manner such as an adrenocorticotropic hormone stimulation test.
     
• Parathyroid hormone–related peptide
  
  
  • PTH-RP is produced by squamous cell malignancies of the lung or head and neck, resulting in a humeral hypercalcemia. Most of these tumors are clinically apparent, and the hypercalcemia is noted incidentally. No immunological cross reactivity occurs with the use of a high-quality PTH assay; ie, the serum level of PTH is suppressed. PTH-RP is important for lactation and is produced during pregnancy. This may predispose pregnant women to milk-alkali syndrome.
  
  
  
  • Very rarely, an occult malignancy presents with hypercalcemia. In this situation, determination of the serum level of PTH-RP is useful.
     
• Serum albumin and globulin
  
  
  • Approximately 50% of serum calcium is bound to albumin; therefore, the total serum calcium level depends directly on the serum albumin level.
  
  
  
  • In low albumin states, the total serum calcium value may be normal while the ionized calcium value is high. The patient is physiologically hypercalcemic but has a normal total serum calcium value.
  
  
  
  • Total calcium can be corrected for serum albumin. Every change in albumin of 1 g/dL results in a change of 0.8 mg/dL in serum calcium. As noted above, this calculation is known to be accurate in patients with low albumin from liver disease. In other situations, it may not be correct.
     
• Multiple myeloma may cause hypercalcemia. This disorder occasionally is suggested by an elevation in the serum globulin.



• Serum protein electrophoresis helps identify a monoclonal gammopathy.



• Vitamin D
  
  
  • Levels of 1,25-dihydroxyvitamin D are elevated in sarcoidosis and other granulomatous diseases associated with hypercalcemia because of the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Excess vitamin D ingestion is best assessed by measurement of 25-hydroxyvitamin D levels and should be measured in suspected vitamin D toxicity.
  
  
  
  • Serum PTH levels usually are low; therefore, vitamin D–related hypercalcemia may be readily confused with milk-alkali syndrome, although the 1,25-dihydroxyvitamin D level was low in one patient with milk-alkali syndrome.
     
• Complete blood cell count: Other lymphoproliferative diseases, such as leukemia and lymphoma, occasionally induce hypercalcemia.

Imaging Studies

• Chest radiograph: This study is needed in patients with severe renal impairment.

Other Tests

• ECG: Potential findings are QT-interval shortening and ventricular arrhythmia.

TREATMENT

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Medical Care

• Mild hypercalcemia
• • The only care required is discontinuation of calcium carbonate or lowering the dose to no more than 1200-1500 mg of elemental calcium a day.
  
  
  
  • In most patients, calcium supplementation should be changed to a form of calcium other than calcium carbonate. Thus, absorbable alkali is avoided.
     
• Severe hypercalcemia
• • The patient should be admitted to the hospital.
  
  
  
  • A saline diuresis, produced by infusion of large volumes of intravenous isotonic sodium chloride solution, is the treatment of choice.
  
  
  
  • Further calciuresis can be induced by treatment with intravenous loop diuretics.
  
  
  
  • The typical patient is volume depleted; therefore, volume should be replaced with saline prior to institution of diuretic therapy. Care should be taken to not induce volume depletion with the diuretics because this may worsen the hypercalcemia.
  
  
  
  • Calcium carbonate should be stopped to resolve the pathophysiology that produced the hypercalcemia.
  
  
  
  • As stated above, patients with milk-alkali syndrome may become transiently hypocalcemic during treatment with intravenous saline and intravenous diuretics.
  
  
  
  • Because laboratory studies such as PTH measurements will not have returned to normal when therapy is instituted, the serum calcium level must be monitored closely.
  
  
  
  • Pamidronate has been used successfully in the treatment of hypercalcemia secondary to milk-alkali syndrome. However, treatment of milk-alkali syndrome with bisphosphonates was associated with hypocalcemia in one series, where 6 of 11 patients with milk-alkali syndrome had treatment-induced hypocalcemia. Five of these 6 patients received bisphosphonates.

Consultations

• Consultation with a nephrologist may be needed with severe renal disease and/or severe hypercalcemia because dialysis sometimes is required.
• Consultation with an endocrinologist may be needed for interpretation of PTH and other laboratory studies.

Diet

• A low-calcium and low-phosphorus diet is required during hypercalcemia.

Activity

• No activity restrictions are necessary.

MEDICATION

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The primary therapy of hypercalcemia in milk-alkali syndrome is intravenous volume replacement with isotonic sodium chloride solution. When ingestion of calcium carbonate has stopped, the pathophysiologic stimulus for hypercalcemia is no longer present. Hypercalcemia in this setting usually is rapidly corrected. Loss of calcium from urine can be increased with the use of a loop diuretic, but this therapy cannot be started until intravascular volume has been replenished. Renal dialysis has been used in a few patients, as has intravenous infusion of pamidronate.

Drug Category: Diuretics

Induce calciuresis.

Drug Category: Bone resorption inhibitors (antiresorptive)

Decrease movement of calcium from bone to serum.

FOLLOW-UP

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Further Inpatient Care

• Milk-alkali syndrome is a diagnosis of history and one of exclusion; other potential causes of hypercalcemia must be eliminated.



• If hypocalcemia develops in the course of treatment, this usually can be treated with oral calcium supplementation. A calcium source without absorbable alkali, such as calcium citrate, is preferred. Rarely, intravenous calcium might be required to treat severe hypocalcemia.

Further Outpatient Care

• Over-the-counter medications containing calcium carbonate must be eliminated.

In/Out Patient Meds

• Once calcium carbonate is no longer being ingested and hypercalcemia has been treated acutely, further care specifically directed at the milk-alkali syndrome is not necessary.

Transfer

• Occasionally, dialysis may be required with severe renal impairment. With an elevated serum calcium and phosphorus, dialysis may be needed to urgently lower these parameters. This may prevent ectopic calcification.

Deterrence/Prevention

• Avoid excess calcium carbonate.

Complications

• Some patients are left with permanent renal impairment.

Prognosis

• Prognosis usually is good, although this diagnosis is frequently missed.
• Reports indicate that some patients have been admitted with hypercalcemia several times before the diagnosis was made.
• A complete history of all medication use, including over-the-counter medications, should prevent milk-alkali syndrome from escaping detection.

Patient Education

• The proper dose and the potentially harmful dose of calcium carbonate need to be discussed with the patient.



• Attention to ingredients in all medications should be stressed. Multiple over-the-counter (OTC) medications contain calcium carbonate.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to consider the diagnosis is a potential medicolegal pitfall. In the author's experience, this is usually related to a failure to obtain a full history of over-the-counter medications. In a recent series of 11 patients with milk-alkali syndrome, only 5 had the diagnosis made while hospitalized. The remaining 6 were diagnosed only with chart review in retrospect.

• Patients discharged without a specific diagnosis are likely to continue excess intake of calcium carbonate and develop hypercalcemia again.

Special Concerns

• Milk-alkali syndrome has been reported in pregnancy. Pregnant women absorb calcium from the GI tract more avidly than in the nonpregnant state. The serum level of PTH-RP is increased in pregnancy. Furthermore, pregnant women are prescribed calcium supplements and frequently have GI symptoms for which OTC calcium carbonate–containing preparations might be taken.

• The syndrome was induced by ingestion of large amounts of calcium carbonate during hyperemesis gravidarum in one patient.

• Milk-alkali syndrome has been treated with dialysis during pregnancy.

• The newborn of a pregnant woman with milk-alkali syndrome had hypocalcemia in the neonatal period in a recent report.

• Milk-alkali syndrome can be induced by use of betel nut, a recreational drug used in Southeast Asia and India by an estimated 600 million persons a day. The meat of the betel nut is made into a paste (or quid) with dried oyster shell, wrapped in a betel nut leaf, and placed in the lateral buccal pouch. Because the paste contains calcium carbonate from oyster shell, milk-alkali syndrome can result from heavy use. Betel nut is addictive and causes oral cancer. Betel nut and related ingredients are available in areas of the West with large immigrant populations from Asia and India. The lips, tongue, and oral mucosa are stained a characteristic red in long-term users of betel nut.

• Milk-alkali syndrome has recently been reported in children.

• The author has recently seen iatrogenic milk-alkali syndrome in a patient with sepsis and acute renal failure who was given large doses of calcium carbonate as a phosphate absorption blocker. As the renal failure resolved, calcium carbonate was continued and hypercalcemia developed.

MULTIMEDIA

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Media file 1:  The hospital course of a patient with milk-alkali syndrome who developed symptomatic hypocalcemia with a markedly elevated serum parathyroid hormone level (PTH) during treatment. Thirty days after discharge, the calcium and PTH levels were both normal.
	View Full Size Image
Media type:  Graph

REFERENCES

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• Brandwein SL, Sigman KM. Case report: milk-alkali syndrome and pancreatitis. Am J Med Sci. Sep 1994;308(3):173-6. [Medline].
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• Liu SW, Kumar AM, Nadel ES, Brown DF. A young woman with altered mental status. J Emerg Med. May 2002;22(4):405-8. [Medline].
• Morton A. Milk-alkali syndrome in pregnancy, associated with elevated levels of parathyroid hormone-related protein. Intern Med J. Sep-Oct 2002;32(9-10):492-3. [Medline].
• Muldowney WP, Mazbar SA. Rolaids-yogurt syndrome: a 1990s version of milk-alkali syndrome. Am J Kidney Dis. Feb 1996;27(2):270-2. [Medline].
• Nakanishi T, Uyama O, Yamada T, Sugita M. Sustained metabolic alkalosis associated with development of the milk-alkali syndrome. Nephron. 1992;60(2):251. [Medline].
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• Robertson WC. Calcium carbonate consumption during pregnancy: an unusual cause of neonatal hypocalcemia. J Child Neurol. Nov 2002;17(11):853-5. [Medline].
• Sippy BW. Gastric and duodenal ulcer: Medical cure by an efficient removal of gastric juice corrosion. JAMA. 1915;64:1625-30.
• Spital A, Freedman Z. Vignette in clinical pathophysiology: Severe hypercalcemia in a woman with renal failure. Am J Kidney Dis. Oct 1995;26(4):674-7. [Medline].
• Sulkin T, Krentz AJ. Iatrogenic recurrent severe hypercalcaemia and renal impairment. Postgrad Med J. Dec 2000;76(902):800, 807. [Medline].
• Ullian ME, Linas SL. The milk-alkali syndrome in pregnancy. Case report. Miner Electrolyte Metab. 1988;14(4):208-10. [Medline].
• Vanpee D, Delgrange E, Gillet JB, Donckier J. Ingestion of antacid tablets (Rennie) and acute confusion. J Emerg Med. Aug 2000;19(2):169-71. [Medline].
• Wu KD, Chuang RB, Wu FL, et al. The milk-alkali syndrome caused by betelnuts in oyster shell paste. J Toxicol Clin Toxicol. 1996;34(6):741-5. [Medline].

Article Last Updated: Jun 13, 2006