Introduction
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.1
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 the increased use and promotion of calcium carbonate for dyspepsia and for calcium supplementation, a resurgence of milk-alkali syndrome has occurred. (See image below for the hospital course of a patient with milk-alkali syndrome who during treatment developed symptomatic hypocalcemia with a markedly elevated serum parathyroid hormone level [PTH].)
The hospital course of a patient with milk-alkali syndrome who during treatment developed symptomatic hypocalcemia with a markedly elevated serum parathyroid hormone level (PTH). Thirty days after discharge, the calcium and PTH levels were normal.
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 × 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.2 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.3 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.4 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. Areas of the world in which betel nut chewing is common may have an increased incidence of milk-alkali syndrome (see Special Concerns).
Mortality/Morbidity
- Milk-alkali syndrome almost never results in death.
- A significant number of patients may be left with permanent renal impairment.
- In reports, 20 of 57 patients studied had a follow-up serum creatinine level of more than 1.5 mg/dL (see the table under Age).
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*Open table in new window
Table
| Mean age | 51.0 years (range, 24-95 y) |
| Sex | 35 men and 43 women |
| Calcium source | Calcium carbonate in all but one |
| Ingestion of bicarbonate | In 7 patients |
| Ingestion of milk | In 20 patients (plus one who ate yogurt) |
| Mean serum calcium | 15.1 mg/dL (3.75 mmol/L) (range, 11.1-27.5 mg/dL) |
| High serum phosphorus | In 12 patients |
| Permanent renal insufficiency | In 20 of 57 patients eligible for evaluation |
| Parathyroid exploration | In 3 patients |
| Hypocalcemia with treatment | In 16 patients |
| Mean age | 51.0 years (range, 24-95 y) |
| Sex | 35 men and 43 women |
| Calcium source | Calcium carbonate in all but one |
| Ingestion of bicarbonate | In 7 patients |
| Ingestion of milk | In 20 patients (plus one who ate yogurt) |
| Mean serum calcium | 15.1 mg/dL (3.75 mmol/L) (range, 11.1-27.5 mg/dL) |
| High serum phosphorus | In 12 patients |
| Permanent renal insufficiency | In 20 of 57 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; Morton 2002; Kleinig 2004; Picolos, 2005; Gordon, 2005; Addington et al, 2006; Verburg et al, 2006; Ennen and Magann, 2006; Caruso et al, 2007; Dinnerstein et al, 2007; Javid et al, 2007; Kaklamanos and Perros, 2007; Shah et al, 2007; Irtiza-Ali et al, 2008; and Jousten and Guffens, 2008. Two of the patients were pregnant.
Clinical
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.5
- Myriad of over-the-counter medicines have calcium carbonate as an ingredient.6,7 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.
More on Milk-Alkali Syndrome |
 Overview: Milk-Alkali Syndrome |
| Differential Diagnoses & Workup: Milk-Alkali Syndrome |
| Treatment & Medication: Milk-Alkali Syndrome |
| Follow-up: Milk-Alkali Syndrome |
| Multimedia: Milk-Alkali Syndrome |
| References |
| Further Reading |
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Keywords
milk-alkali syndrome, calcium carbonate, hypercalcemia, calcium absorption, furosemide, pamidronate, Burnett's syndrome, Burnett syndrome, metastatic calcification, calcium supplementation, parathyroid hormone, PTH, Sippy regimen
