Steroid Resistant Hypercalcemia in Sarcoidosis: A Treatment Dilemma

Introduction:
Sarcoidosis induces hypercalcemia via increased macrophage 1-α hydroxylase activity causing enhanced production of 1,25-dihydroxy vitamin D. Steroids inhibit 1-α hydroxylase and hence, are the mainstay of treatment. We present a case of hypercalcemia as a presenting symptom of sarcoidosis with resistance to steroid treatment.

Case Description:
A 53-year-old African American female with a past medical history of chronic kidney disease presented to the hospital with an elevated calcium level of 13.6 mg/dL. Other laboratory data was pertinent for creatinine 1.6 mg/dL, phosphorus 3.1 mg/dL, and alkaline phosphatase level 251 U/L. She complained of constipation, diffuse pain in extremities, and a history of osteoporosis. Workup was consistent with non-PTH dependent hypercalcemia with a low PTH level (6.9 pg/mL). 25-hydroxy vitamin D was low (19.6 ng/mL), thyroid function was normal and workup for multiple myeloma was negative. Generalized (mediastinal, hilar, abdominal and pelvic) lymphadenopathy, pulmonary interstitial thickening, and hepatosplenomegaly were noted on imaging. Further testing showed elevated 1,25-dihydroxy vitamin D (123 pg/mL), normal PTHrP, and elevated ACE level (140 U/L). Finally, granulomatous inflammation was seen on the FNA of a cervical lymph node, confirming the diagnosis of sarcoidosis. Preceding the workup, the patient had received IV hydration with normal saline and IV zoledronic acid 4 mg. Calcium levels improved partially to 10.5 mg/dL however, up trended again in 2 weeks. Eventually, prednisone 20 mg, hydroxychloroquine 200 mg, and azathioprine 50 mg daily were initiated for sarcoidosis treatment. Ten days later, the calcium level remained between 12 and 13 mg/dL. A nuclear medicine bone scan ruled out bone lesions as a cause of treatment resistance. Use of methotrexate and ketoconazole was excluded due to renal dysfunction and transaminitis respectively. Prednisone was then increased to 30 mg daily and denosumab 120 mg was given. When calcium levels remained persistently elevated, infliximab infusion 5 mg/kg was administered in an effort to curb the steroid resistant hypercalcemia. Calcium levels finally improved to 9.4 mg/dL. Nonetheless, a repeat infusion of infliximab was required in 2 weeks for hypercalcemia recurrence.

Discussion:
Sarcoidosis causes PTH independent hypercalcemia via enhanced extrarenal conversion of 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D in macrophages. Hypercalcemia is the presenting symptom in only 3% cases. Steroids are the first line treatment that suppress 1-α hydroxylase activity in macrophages. Ketoconazole (inhibits cytochrome P450 hence, decreasing 1-α hydroxylase activity), infliximab (binds to excess tumor necrosis factors resulting in granuloma resolution), and methotrexate (possibly via reduction in disease burden) can be used in steroid refractory hypercalcemia of sarcoidosis. A good response to denosumab 60 mg SQ was seen in a case of sarcoidosis related hypercalcemia allowing weaning off steroids.