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Extraosseous calcified masses with hypercalcemia
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A 43-year-old black male presented to his primary care physician with growing nonpainful masses on his right hand and elbow during the previous several months.
Stephanie L. Lee
Approximately 4 months before this presentation, the patient had a small nodule on his finger removed. The pathology showed “cutis calcinosis,” but no further evaluation was performed. During the prior 6 months, he had noticed an increase in thirst and had been drinking four to six cans of cola daily. Physical exam was significant for firm masses in the soft tissues over both hands, elbows, knees and hips. Laboratory studies at that time were significant for elevated levels of calcium (11.3 mg/dL), phosphorus (6.8 mg/dL) and creatinine (7.5 mg/dL).
Sara M. Pietras
He was referred to the endocrine clinic.
Lab results, diagnosis
There were low levels of parathyroid hormone (4 pg/mL) and parathyroid hormone-related protein (PTHrP; <2 pmol/L), with normal levels of 25-hydroxyvitamin D (30 ng/mL) and inappropriately normal 1,25-dihydroxyvitamin D (27 pg/mL).
Radiograph of patient’s right elbow (A, B) and right hand (C,D). Soft tissue calcium deposits are seen in the soft tissue (arrows) over the right elbow and hand. There was resolution of the calcium deposits and soft tissue (yellow line) over his elbow and hand after 4 months of glucocorticoid therapy of sarcoid.
X-rays of his hand and elbow revealed multiple soft tissue calcified masses and soft tissue swelling (Figure 1). Sarcoid was entertained as the cause of the hypercalcemia in this young black male with elevated calcium and low parathyroid hormone and PTHrP.
Ultrasound-guided kidney biopsy showed chronic-active tubulointerstitial nephritis with focal interstitial and intratubular calcium phosphate and calcium oxalate deposits with tubular injury. There was no evidence of granulomatous interstitial nephritis. A CT scan of the chest (Figure 2) showed innumerable pulmonary nodules in a perilymphatic distribution and multiple subcentimeter mediastinal adenopathy in the prevascular, paratracheal and subcarinal areas with renal calcification (medullary calcinosis). The CT scan was consistent with sarcoidosis, lymphangitic spread of tumor and pneumoconiosis. Sarcoid was confirmed by an elevated serum angiotensin-converting enzyme (ACE) level of 104 U/L and a transbronchial pulmonary biopsy showing noncaseating granulomas.
His renal failure prevented the use of bisphosphonates to treat the hypercalcemia. He was initially hydrated gently and treated with sevelamer, an intestinal phosphate binder, and calcitonin to aid in the reduction of serum calcium, but his calcium remained elevated at 12 mg/dL. Once the diagnosis of sarcoid was made, he was treated with a tapering dose of prednisone from 60 mg daily to a maintenance dose of 5 mg daily. Within 48 hours, his serum calcium decreased to 10.8 mg/dL and serum 1,25-dihydroxyvitamin D decreased from 27 pg/mL to 13 pg/mL. After 2 weeks of prednisone therapy, his 1,25-dihydroxyvitamin D decreased further to <2 pg/mL.
His soft tissue calcified masses resolved completely after 4 months of prednisone and sevelamer therapies and cessation of drinking phosphate-containing colas. He has continued on low-dose prednisone therapy for this sarcoid for the last 7 years with normalization of his calcium and resolution of the calcified masses by physical exam and on radiograph (Figure 2). His glucocorticoid therapy has been intermittently stopped. The last trial of glucocorticoid therapy 18 months ago resulted in an elevated 1,25-dihydroxyvitamin D to 102 pg/mL. Prednisone 5 mg daily was resumed with continued normal levels of calcium, 25-(OH)D and 1,25-dihydroxyvitamin D. Renal function has improved, but he continues with chronic renal insufficiency with a creatinine of 3.1 mg/dL. His pulmonary and cardiac functions were not affected by the granulomas, and he continues without respiratory or cardiac symptoms.
The appearance of calcified masses during hypercalcemia of any etiology is unusual. In this case, hypercalcemia was induced by sarcoid. The granulomas of sarcoid contain the enzyme 25-hydroxyl vitamin D 1-hydroxylase (1-hydroxylase), which catalyzes the conversion of the relatively inactive, storage form of 25-(OH)D to the bioactive 1,25-dihydroxyvitamin D. The excess 1,25-dihydroxyvitamin D results in the excess absorption of calcium from the intestines and hypercalcemia. Although this condition may cause severe hypercalcemia and renal calcinosis with renal failure, it is unusual to observe other soft tissue calcification. In this case, the combination of renal failure caused by nephrocalcinosis and elevated phosphorus levels from the renal failure with lack of phosphorus clearance plus excess intake from the increased ingestions of cola resulted in peripheral “metastatic” calcification. His calcium-phosphate product (11.3 x 7.5 =) at 84.8 mg2/dL2 was higher than 65 mg2/dL2, a clinical threshold associated with soft tissue heterotrophic calcification.
Treatment, patient outcome
In chronic renal failure, it is recommended that the serum calcium-phosphorus be maintained at less than 55 mg2/dL2. Hyperphosphatemia is a common biochemical abnormality in advanced renal failure but was worsened by his intake of large quantities of phosphorus-containing cola drinks. Together with the elevated calcium caused by the sarcoid, the resulting increased serum calcium x phosphorus product resulted in the deposition of calcium crystals. This patient demonstrates the efficacy of glucocorticoid therapy to reduce 1-hydroxylase activity by sarcoid granulomas, resulting in unmeasurable levels because his native production of 1-hydroxylase is low due to: 1) reduction of 1-hydroxylase production from his damaged kidneys; and 2) suppression of the enzyme by his elevated phosphorus and suppressed parathyroid hormone levels. His calcium deposits reabsorbed with glucocorticoid therapy because of: 1) reduction in 1-hydrylase activity and lower calcium levels; and 2) reduced phosphorus levels because of his improved renal function and cessation of excess phosphorus intake from colas.
Chest CT scan without contrast. Coronal image shows innumerable small nodules throughout the lung parenchyma (blue arrows). Calcium deposits (medullary calcinosis) are seen in the right kidney (yellow arrows).
Reprinted with permission from: Stephanie L. Lee, MD, PhD
Glucocorticoid therapy is usually maintained for 1 year and then tapered because sarcoid often has spontaneous remissions. In this patient’s case, he has been maintained on low-dose prednisone 5 mg daily because of persistent excess 1-hydroxylase activity and elevated 1,25-dihydroxyvitamin D each time the glucocorticoid was stopped.