Correct!
2. Coccidioidomycosis serology

A coccidioidomycosis serology was markedly positive making a presumptive diagnosis of Valley Fever. A bone biopsy is not necessarily wrong but given a positive coccidioidomycosis serology and a compatible clinical situation is probably not necessary. Serum ACE is often elevated in sarcoidosis but it is unclear how this would have helped in this situation. The patient was begun on fluconazole in addition to her hydration and bisphosphonate therapy. Her serum calcium rapidly returned to the normal range (Figure 3).

Figure 3. Calcium levels during admission. The two normal levels are from previous testing done prior to admission.

Clinically the patient's pseudo-obstruction resolved at a calcium level 8.3 mg/dL and she was eventually discharged. After discharge her calcium levels gradually rose again, so she given chronic bisphosphonates (IV) therapy every 3 months and her calcium levels remained controlled.

Reports of hypercalcemia have been described associated with sarcoidosis, tuberculosis and other granulomatous disorders (4-6). Coccidioidomycosis is a an endemic granulomatous fungal infection found in southwestern United States and known to cause hypercalcemia when the infection is disseminated and involves bone (7-9).

The mechanisms for a granulomatous disease to cause hypercalcemia are not well defined. The overproduction of 1, 25-dihydroxy vitamin D, does occur in sarcoidosis and has been generalized to other granulomatous diseases (8). Calcitriol mediated bone resorption and the production of parathyroid related protein (PTHrP) may also play a role. PTHrP is expressed in most granulomatous lesions but does not necessarily cause hypercalcemia. Fierer, et al. (10) hypothesized that the number of fungal lesions that make PTHrP and the amount produced by each lesion likely plays a role in causing hypercalcemia in coccidioidomycosis. Nearly all the reported cases of infection associated hypercalcemia are the result of disseminated infections. Therefore, an important variable causing this form of hypercalcemia is the number of granulomas able to produce measurable serum levels of PTHrP and this was documented in our patient.

It has been recommended that patients with hypercalcemia due to disseminated coccidioidomycosis should be treated with antifungal therapy and hydration (10,11). Patients with very high levels of calcium such as 15.1 mg/dL may benefit from intravenous hydration and bisphosphonates (11). Symptomatic hypercalcemia causing Ogilvie Syndrome needs to be corrected aggressively because the condition can be very serious and the mortality rate as high as 30% (11).   

References

  1. Di Lorenzo C. Pseudo-obstruction: current approaches. Gastroenterology. 1999 Apr;116(4):980-7. [CrossRef] [PubMed]
  2. Gardner EC Jr, Hersh T. Primary hyperparathyroidism and the gastrointestinal tract. South Med J. 1981 Feb;74(2):197-9. [CrossRef] [PubMed]
  3. Agraharkar M. Hypercalcemia. Medscape. June 23. 2015. Available at: http://emedicine.medscape.com/article/240681-overview (accessed 4/25/16).
  4. Fuss M, Pepersack T, Gillet C, Karmali R, Corvilain J. Calcium and vitamin D metabolism in granulomatous diseases. Clin Rheumatol. 1992 Mar;11(1):28-36. [CrossRef] [PubMed]
  5. Deniz O, Tozkoparan E, Yonem A, et al. Low parathormone levels and hypercalcaemia in patients with pulmonary tuberculosis: relation to radiological extent of disease and tuberculin skin test. Int J Tuberc Lung Dis. 2005 Mar;9(3):317-21. [PubMed]
  6. Shrayyef MZ, DePapp Z, Cave WT, Wittlin SD. Hypercalcemia in two patients with sarcoidosis and Mycobacterium avium intracellulare not mediated by elevated vitamin D metabolites. Am J Med Sci. 2011 Oct;342(4):336-40. [CrossRef] [PubMed]
  7. Lee JC, Catanzaro A, Parthemore JG, Roach B, Deftos LJ. Hypercalcemia in disseminated coccidioidomycosis. N Engl J Med. 1977 Aug 25;297(8):431-3. [CrossRef] [PubMed]
  8. Westphal SA. Disseminated coccidioidomycosis associated with hypercalcemia. Mayo Clin Proc. 1998 Sep;73(9):893-4. [CrossRef] [PubMed]
  9. Caldwell JW, Arsura EL, Kilgore WB, Reddy CM, Johnson RH. Hypercalcemia in patients with disseminated coccidioidomycosis. Am J Med Sci. 2004 Jan;327(1):15-8. [CrossRef] [PubMed]
  10. Fierer J, Burton DW, Haghighi P, Deftos LJ. Hypercalcemia in disseminated coccidioidomycosis: expression of parathyroid hormone-related peptide is characteristic of granulomatous inflammation. Clin Infect Dis. 2012 Oct;55(7):e61-6. [CrossRef] [PubMed]
  11. Legrand SB. Modern management of malignant hypercalcemia. Am J Hosp Palliat Care. 2011 Nov;28(7):515-7. [CrossRef] [PubMed]

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