Approach Considerations
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 may be 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 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 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.
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 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.
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
- 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
- Electrocardiography - Potential findings are QT-interval shortening and ventricular arrhythmia
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:
- 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 PTH-RP
- The timing of measurement of PTH is critical
- PTH should always be determined and interpreted with a simultaneous serum calcium or, more correctly, with ionized serum calcium
- An elevated 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. (See the image below.)
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. 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
PTH-RP 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.
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 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.
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.
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| Mean Age | 51 Years (Range, 24-95 y) |
| Sex | 35 men and 43 women |
| Calcium source | Calcium carbonate in all but 1 |
| Ingestion of bicarbonate | In 7 patients |
| Ingestion of milk | In 20 patients (plus one who ate yogurt) |
| Mean serum calcium | 15.1mg/dL (3.75mmol/L) (range, 11.1-27.5mg/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,[6] as well as additional patients reported by Gibbs and Lee, 1992;[9] Nakanishi et al, 1992[10] ; Brandwein and Sigman, 1994[11] ; Campbell et al, 1994[12] ; Duthie et al, 1995[13] ; Spital and Freedman, 1995[14] ; Fiorino, 1996[15] ; Lin et al, 1996[16] ; Muldowney and Mazbar, 1996[17] ; Sulkin and Krentz, 1999[18] ; Camidge and Peaston, 2000[19] ; George and Clark, 2000[20] ; Vanpee et al, 2000[21] ; Liu et al, 2002[22] ; Robertson, 2002[23] ; Morton, 2002[24] ; Kleinig and Torpy, 2004[2] ; Picolos et al, 2005[7] ; Gordon et al, 2005[25] ; Addington et al, 2006[5] ; Verburg et al, 2006[26] ; Ennen and Magann, 2006[27] ; Caruso et al, 2007[28] ; Dinnerstein et al, 2007[29] ; Javid et al, 2007; Kaklamanos and Perros, 2007[30] ; Shah et al, 2007[31] ; Irtiza-Ali et al, 2008[3] ; and Jousten and Guffens, 2008.[4] Two of the patients were pregnant. | |
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