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Milk-Alkali Syndrome Differential Diagnoses

  • Author: R Hal Scofield, MD; Chief Editor: George T Griffing, MD  more...
 
Updated: Aug 12, 2014
 
 

Diagnostic Considerations

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

  • Hyperthyroidism - Any condition causing hyperthyroidism can cause mild hypercalcemia
  • 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 [33]
  • Familial hypocalciuric hypercalcemia - 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
  • 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
  • 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. 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[6] and 125 patients in series 2[7] ) 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.[40]

Differential Diagnoses

 
 
Contributor Information and Disclosures
Author

R Hal Scofield, MD Professor, Department of Medicine, Section of Endocrinology, University of Oklahoma College of Medicine; Associate Member, Arthritis and Immunology Program, Oklahoma Medical Research Foundation; Staff Physician, Oklahoma City Department of Veterans Affairs Medical Center

R Hal Scofield, MD is a member of the following medical societies: American Association of Immunologists, American College of Physicians, American College of Rheumatology, American Federation for Medical Research

Disclosure: Nothing to disclose.

Coauthor(s)

Thuy-Trang Nguyen University of Louisville School of Medicine

Disclosure: Nothing to disclose.

Shabreen Abdul Sharief, MD Physician, Select Specialty Hospital

Shabreen Abdul Sharief, MD is a member of the following medical societies: American Medical Association, Indian Medical Association

Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, International Society for Clinical Densitometry, Southern Society for Clinical Investigation, American College of Medical Practice Executives, American Association for Physician Leadership, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

Acknowledgements

Romesh Khardori, MD, PhD, FACP Former Professor, Department of Medicine, Former Chief, Division of Endocrinology, Metabolism, and Molecular Medicine, Southern Illinois University School of Medicine

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, and Endocrine Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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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.
Table. Summary of 65 Consecutively Reported Adult Patients With Milk-Alkali Syndrome*
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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