Milk-Alkali Syndrome Differential Diagnoses

Updated: Aug 09, 2017
  • Author: R Hal Scofield, MD; Chief Editor: George T Griffing, MD  more...
  • Print
DDx

Diagnostic Considerations

Conditions other than milk-alkali syndrome that can cause hypercalcemia include the following:

  • Hyperthyroidism - Any condition causing hyperthyroidism can cause mild hypercalcemia

  • Primary or Tertiary Hyperparathyroidism

  • 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; about 15% of renal cell carcinomas secrete PTH-RP, with hypercalcemia found in some of these patients [41]

  • Familial hypocalciuric hypercalcemia (FHH) - The hypercalcemia is mild and serum PTH is usually in the high-normal range or slightly above normal; fractional excretion of calcium is low in the autosomal dominant disease

  • Acquired hypocalciuric hypercalcemia – There are recent reports of autoantibodies binding the calcium receptor, a G-coupled receptor, and inducing a constellation of findings that mimic FHH. [42, 43]  The frequency of this disorder is not known.

  • 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, such as in Paget disease or in 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 via PTH-RP production

  • Vitamin D intoxication

With regard to hyperparathyroidism, mentioned in the list above, 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 hyperparathyroidism secondary to renal failure. All forms of parathyroid-mediated hypercalcemia are associated with an inappropriately high serum PTH level for the elevated level of serum calcium, but serum PTH may be in the reported normal range. Parathyroid carcinoma is a very rare cause of hypercalcemia.

Rate of occurrence of differentials

A summary of the final diagnoses (ie, of conditions causing hypercalcemia) in 2 large series of patients (100 patients in series 1 [12] and 125 patients in series 2 [13] ) 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

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

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

With regard to the last item above, a diagnosis was not made in these patients, in whom hypercalcemia resolved. In addition, no diagnosis was made in a retrospective review of the chart. However, the use of OTC medicines was not well recorded in these patients. They may have had milk-alkali syndrome, but the diagnosis clearly was not considered during the admission.

Soyfoo et al retrospectively studied in a cancer center all consecutive hypercalcemic (Ca > 10.5 mg/dL) patients over an 8-year period. Of 699 evaluated patients, 642 were analyzed after exclusion of patients whose hypercalcemia resolved after rehydration or who had a normal calcium level after correction for protein concentrations. Clinical information was gathered on the type of cancer, its histology, whether the disease was active or in complete remission, and on the presence of bone metastases. Biochemical data included serum Ca, Pi, proteins in all patients, PTH in most patients, and PTHrP, 25OH-Vitamin D, 1,25(OH)2 –Vitamin D, TSH, and T4 in selected cases.

By order of decreasing frequency, the main causes of hypercalcemia were cancer (69.0%), primary hyperparathyroidism (24.6%), hyperthyroidism (2.2%), milk-alkali syndrome (0.9%), and sarcoidosis (0.45%). In cancer-related causes, bone metastases accounted for 53.0% of the cases, humoral hypercalcemia of malignancy (HHM) for 35.3% of cases, and 11.7% of cases were apparently due to both HHM and bone metastases. Hypercalcemia was not due to cancer in 97% (84/87) of the patients who were in complete remission. Even in patients with active neoplastic disease, the number of patients whose hypercalcemia was not due to cancer remained clinically relevant (115/555 = 20.5%). In the 158 patients with primary hyperparathyroidism, 92 patients were in complete remission and 66 patients had active neoplastic disease. [44]

Differential Diagnoses