milk alkali syndrome

Milk-alkali syndrome

Milk-alkali syndrome is a condition in which there is a high level of calcium in the body (hypercalcemia). This causes a shift in the body’s acid/base balance toward alkaline (metabolic alkalosis). As a result, there can be a loss of kidney function.

Milk-alkali syndrome is almost always caused by taking too many calcium supplements, usually in the form of calcium carbonate.

Contact your health care provider if:

  • You take a lot of calcium supplements or you often use antacids that contain calcium, such as Tums. You may need to be checked for milk-alkali syndrome.
  • You have any symptoms that might suggest kidney problems.

Milk alkali syndrome causes

Milk-alkali syndrome is almost always caused by taking too many calcium supplements, usually in the form of calcium carbonate. Calcium carbonate is a common calcium supplement. Calcium carbonate is often taken to prevent or treat bone loss (osteoporosis). Calcium carbonate is also an ingredient found in antacids (such as Tums).

A high level of vitamin D in the body, such as from taking supplements, can worsen milk-alkali syndrome.

Calcium deposits in the kidneys and in other tissues can occur in milk-alkali syndrome.

Milk alkali syndrome prevention

If you use calcium-containing antacids often, tell your provider about digestive problems. If you are trying to prevent osteoporosis, do not take more than 1.2 grams of calcium per day unless instructed by your doctor.

Milk alkali syndrome symptoms

In the beginning, milk alkali syndrome usually has no symptoms (asymptomatic). When symptoms do occur, they can include:

  • Back, middle of the body, and low back pain in the kidney area (related to kidney stones)
  • Confusion, strange behavior
  • Constipation
  • Depression
  • Excessive thirst and urination. Excess calcium in your blood means your kidneys have to work harder to filter it. This can cause excessive thirst and frequent urination.
  • Fatigue
  • Irregular heartbeat (arrhythmia). Rarely, severe hypercalcemia can interfere with your heart function, causing palpitations and fainting, indications of cardiac arrhythmia, and other heart problems.
  • Nausea or vomiting
  • Other problems that can result from kidney failure

Hypercalcemia can cause stomach upset, nausea, vomiting and constipation.

Hypercalcemia can interfere with the way your brain works, resulting in confusion, lethargy and fatigue. It can also cause depression.

Milk alkali syndrome complications

Milk alkali syndrome complications can include:

  • Calcium deposits in tissues (calcinosis)
  • Kidney stones. If your urine contains too much calcium, crystals may form in your kidneys. Over time, the crystals may combine to form kidney stones. Passing a stone can be extremely painful.
  • Kidney failure. Severe hypercalcemia can damage your kidneys, limiting their ability to cleanse the blood and eliminate fluid.
  • Nervous system problems. Severe hypercalcemia can lead to confusion, dementia and coma, which can be fatal.
  • Abnormal heart rhythm (arrhythmia). Hypercalcemia can affect the electrical impulses that regulate your heartbeat, causing your heart to beat irregularly.

Milk alkali syndrome diagnosis

Because milk alkali syndrome can cause few, if any, signs or symptoms, you might not know you have the disorder until routine blood tests show a high level of blood calcium.

Calcium deposits within the tissue of the kidney (nephrocalcinosis) may be seen on:

  • X-rays
  • CT scan
  • Ultrasound

Other tests used to make a diagnosis may include:

  • Electrolyte levels
  • Electrocardiogram (ECG)
  • Electroencephalogram (EEG)
  • Glomerular filtration rate (GFR)
  • Blood calcium level

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 use of the formula for correction of calcium for hypoalbuminemia is validated only 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.

Phosphorus

Serum phosphorus concentration can be elevated in milk-alkali syndrome due to a low parathyroid hormone (PTH) level, although this finding is less prevalent in the present era than it was 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.

Serum Parathyroid Hormone

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:

  • 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 cross-react with parathyroid hormone-related protein (or PTHrP)
  • The timing of measurement of PTH is critical
  • Parathyroid hormone (PTH) should always be determined and interpreted with a simultaneous serum calcium or, more correctly, with ionized serum calcium
  • An elevated parathyroid hormone (PTH) may be found in the setting of milk-alkali syndrome with renal failure.

As mentioned in the above list, the timing of measurement of PTH is critical, because 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 level. With hypocalcemia, however, 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 has started, the levels will be unpredictable and the results will be confusing.

The elevated PTH that may occur in the setting of milk-alkali syndrome with renal failure is caused by severe secondary hyperparathyroidism. In general, however, a high PTH level suggests hyperparathyroidism, while a low PTH level is consistent with milk-alkali syndrome or hypercalcemia of malignancy.

Parathyroid hormone-related peptide

Parathyroid hormone-related peptide (PTHrP) is produced by squamous cell malignancies of the lung or head and neck, as well as by renal cell cancers, resulting in a humeral hypercalcemia. Most of these tumors are clinically apparent, and the hypercalcemia is noted incidentally. No immunologic cross-reactivity occurs with the use of a high-quality PTH assay; ie, the serum level of PTH is suppressed.

Parathyroid hormone-related peptide (PTHrP) 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 parathyroid hormone-related peptide (PTHrP) 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. That is, 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 1g/dL results in a change of 0.8mg/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; the calculation has been proven to be inaccurate during pregnancy and critical illness.

Multiple myeloma may cause hypercalcemia. This disorder occasionally is suggested by an elevation in the serum globulin.

Creatinine/blood urea nitrogen

Kidney function can 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 due of volume overload.

The combination of severe renal impairment and a high serum parathyroid hormone (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 with an adrenocorticotropic hormone stimulation test. A single serum cortisol level is rarely useful in the diagnosis of adrenal insufficiency.

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 by cells in granulomatous tissue. 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.

Other tests

Additional tests used in determining or excluding the presence of milk-alkali syndrome include the following:

  • Serum protein electrophoresis – Serum protein electrophoresis helps to identify a monoclonal gammopathy characteristic of multiple myeloma
  • Complete blood count (CBC) – Other lymphoproliferative diseases, such as leukemia and lymphoma, occasionally induce hypercalcemia
  • Chest radiography – This study is needed in patients with severe renal impairment. Lung cancer may be preliminarily or presumptively identified by this test
  • Electrocardiography (ECG) – Potential findings are QT-interval shortening and ventricular arrhythmia

Milk alkali syndrome treatment

In severe milk alkali syndrome cases, treatment involves giving fluids through the vein (by IV). Otherwise, treatment involves drinking fluids along with reducing or stopping calcium supplements and antacids that contain calcium. Vitamin D supplements also need to be reduced or stopped.

Mild hypercalcemia

The only care required is discontinuation of calcium carbonate or reduction of the dose to no more than 1200-1500mg of elemental calcium daily. 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. 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, although the utility of loop diuretics for hypercalcemia has been questioned 1.

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 previously, however, 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; 6 of 11 patients with milk-alkali syndrome developed treatment-induced hypocalcemia, with 5 of the 6 patients having received bisphosphonates 2, while in the author’s series of 6 patients, none of whom received bisphosphonate, only 1 developed hypocalcemia 3.

Treatment-related hypocalcemia

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.

Diet and activity

A low-calcium, low-phosphorus diet is required during hypercalcemia. No activity restrictions are necessary.

Milk alkali syndrome prognosis

Milk alkali syndrome is often reversible if kidney function remains normal. Severe prolonged cases may lead to permanent kidney failure requiring dialysis. 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 (OTC) medications, should prevent milk-alkali syndrome from escaping detection.

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.

Morbidity

Milk-alkali syndrome almost never results in death, but a significant number of patients may be left with permanent renal impairment. That is, chronic renal disease may result from milk-alkali syndrome. In reports from the last several years, 20 of 57 patients studied had a follow-up serum creatinine level of more than 1.5 mg/dL (see the Table below). Patients may have severe mental status changes that include obtundation and coma, especially as serum calcium levels rise higher than 15 mg/dL.

References
  1. LeGrand SB, Leskuski D, Zama I. Narrative review: furosemide for hypercalcemia: an unproven yet common practice. Ann Intern Med. 2008 Aug 19. 149(4):259-63.
  2. Picolos MK, Lavis VR, Orlander PR. Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients. Clin Endocrinol (Oxf). 2005 Nov. 63(5):566-76.
  3. Beall 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(2):89-96
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