Calcitriol-mediated Hypercalcemia Research Articles

A case of calcitriol-mediated hypercalcemia in a patient with solid tumor

A case of calcitriol-mediated hypercalcemia in a patient with solid tumor

FRI694 Hypercalcemia And Renal Failure As Initial Presentation Of A Rare Case Of Primary Splenic Large B Cell Lymphoma

Abstract Disclosure: N. Ding: None. S.K. Majumdar: None. Background: Hypercalcemia can be seen in patients with malignancy. However, primary splenic large B cell lymphoma presenting with hypercalcemia and renal failure is rare. Clinical Case: A 75-year-old male with PMH of migraine headaches and hearing loss was sent to the hospital by his primary care doctor due to lab abnormalities, including hypercalcemia and renal failure. He also had abdominal pain, weakness, polyuria, and weight loss for several weeks. He took calcium 1000 mg and vitamin D 5000 units daily. Laboratory tests showed creatinine 2.8 (0.4-1.3) mg/dL, calcium 13.8 (8.8-10.2) mg/dL, ionized calcium 6.75 (4.6-5.08) mg/dL, phosphorus 3.6 (2.2-4.5) mg/dL, PTH 12.6 (15-65) pg/mL, PTHrP 23 (14-27) pg/mL, 25-hydroxy vitamin D 53 (30-100) ng/mL, 1,25-dihydroxy vitamin D 171 (18-72) ng/L, CTX collagen C-telopeptide 1137 pg/ml, SPEP without significant abnormality, UPEP with Bence-Jones proteinuria. Skeletal series showed no suspicious lesions, but MRI abdomen revealed an 11 cm splenic mass. Patient underwent splenectomy and pathology revealed diffuse large B-cell lymphoma. Following surgery, his hypercalcemia resolved without additional interventions. 1,25-dihydroxy vitamin D reduced to 25 ng/l and CTX reduced to 451 pg/ml. Further workup, including bone marrow biopsy and imaging, were negative. Patient was subsequently diagnosed with primary splenic large B cell lymphoma. He completed R-CHOP therapy and had no hypercalcemia in follow-up labs. Conclusion: Calcitriol-mediated hypercalcemia occurs in less than 1% of lymphomas, and primary splenic lymphoma constitutes less than 1% of non-Hodgkin lymphomas. The case represents an extremely rare etiology for hypercalcemia. Interestingly, elevated 1,25-dihydroxy vitamin D and hypercalcemia resolved after splenectomy. Clinicians should consider lymphoma as a potential cause of hypercalcemia and renal failure in elderly patients. Presentation: Friday, June 16, 2023

Abstract #1406508: A Rare Case of Calcitriol-mediated Hypercalcemia in a Patient with Pneumocystis Jiroveci Pneumonia and the Role of Steroids in its Management

Calcitriol-mediated hypercalcemia is an uncommon complication of Pneumocystis jiroveci pneumonia (PJP). Some cases of PJP have been reported in patients with solid organ transplants and AIDS. Here we present a case of calcitriol-mediated hypercalcemia due to granulomatous Pneumocystis jiroveci pneumonia in a patient with a history of multiple sclerosis. A 45-year-old man with a medical history of multiple sclerosis, spondyloarthritis, smoking, and bipolar disorder was admitted for the evaluation of fever, fatigue, constipation, confusion, and weight loss of 10 Lbs over three months. His medications include rituximab, methotrexate, vitamin D-4000 IU, lithium, and calcium carbonate-600 mg. Laboratory evaluation showed elevated serum calcium (15 mg/dl) with a suppressed parathyroid hormone (9 pg/mL). Other pertinent findings include mildly elevated 25-hydroxyvitamin D (87 ng/ml), significantly elevated 1,25-dihydroxyvitamin D (381 pg/ml), and normal PTHrP (<2 pmol/L), vitamin A (0.82 mg/L) and TSH (1.31 mU/L). Extensive workup including AFB smear for tuberculosis, ACE level for sarcoidosis, SPEP for multiple myeloma, leukemia-lymphoma flow cytometry, and CT chest and PET-CT for malignancy were unremarkable. Treatment with large-volume intravenous fluids, calcitonin, and zoledronic acid followed by denosumab showed a transient reduction in serum calcium level to 10.5 mg/dl in 2 days and a rebound to a peak of 15.4 mg/dl in a week. Bronchoscopy with bronchoalveolar lavage which was done for persistent fever and new onset hypoxia revealed PJP confirmed by PCR. With this new finding, the diagnosis of PJP-induced calcitriol-mediated hypercalcemia was considered. He was then treated with Bactrim and prednisone 60 mg daily. Due to the severity of hypercalcemia, he required a hemodialysis session while waiting for the medications to take effect. His calcium normalized a week after the initiation of steroids and antibiotics and he was discharged on a slow prednisone taper. Clinic follow-up 4 weeks after discharge showed normal calcium, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D levels. Discontinuation of prednisone was attempted but resulted in rebound elevation of 1,25-dihydroxyvitamin D requiring continuation of low-dose prednisone 5 mg. Our immunocompromised patient developed hypercalcemia induced by PJP infection due to granulomatous production of 1α-hydroxylase resulting in increased calcitriol formation. Steroids unsurprisingly appear to have the best impact on PJP-induced hypercalcemia because of their anti-inflammatory property. In this clinical entity, it inhibits inflammation and granuloma formation leading to a reduction in the release of 1α-hydroxylase and 1,25-dihydroxyvitamin D levels. It is essential to consider PJP as an etiology of hypercalcemia, especially in immunosuppressed patients. Steroid appears to be effective medical therapy in this setting. The timing and duration of treatment, and the efficacy of bisphosphonates and denosumab, require further studies.

ODP627 Hypercalcemia in a Patient With Gastrointestinal Stromal Tumor (GIST): Evaluation and Treatment Strategies

Abstract A 52-year-old African woman was found to have a pelvic mass at the age of 41. Following resection of small bowel tumors at the time, she was diagnosed with GIST and peritoneal metastases were confirmed. Despite treatment with imatinib, her disease progressed and was started on regorafenib. Due to lack of consistent insurance coverage, she took this medication intermittently for several years, and her tumor progressed to develop intra-abdominal peritoneal and pelvic metastases. She underwent debulking surgery, and her disease subsequently remained stable with regorafenib. Unfortunately, she developed hemoptysis which led to discontinuation of regorafenib, and while off treatment, the patient developed altered mentation, extreme lethargy, and poor PO intake. She was found to have a serum calcium of 16 mg/dL and was admitted for treatment of severe hypercalcemia. With intravenous (IV) fluids, calcitonin and zoledronic acid, her calcium improved to 11-12 mg/dL; however, despite additional therapies, including denosumab and repeat zoledronic acid, her calcium did not normalize. Further evaluation revealed: 25-hydroxy-vitamin D3 level 22.2 ng/mL (normal), 1,25-dihydroxy-vitamin D3 107 mcg/mL (elevated), PTH 6. 0 pg/ml (low), and PTHrP 3.3pmol/L (low). She was given a diagnosis of calcitriol-mediated hypercalcemia and started on IV hydrocortisone 100 mg every 12 hours. Her serum calcium started to improve within 48 hours and normalized after eight days to 9.8mg/dL. Her clinical condition improved, and she was discharged with prednisone 20 mg daily. At the time of her post-hospital follow up several days later, her serum calcium remained normal. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Calcitriol-Mediated Hypercalcemia from Hepatic Granulomatosis Following Percutaneous Cholecystostomy Tube

Granulomatous conditions can present with calcitriol-mediated hypercalcemia via increased 1-hydroxylase activity—activity that is not inhibited by calcium or calcitriol—indicating a lack of feedback inhibition. Differential diagnosis of granulomatosis is quite broad and can require extensive workup as highlighted by this case. Our patient is a 69-year-old white female admitted to the hospital with altered mental status and hypotension. Initial evaluation was concerning for infection, due to leukopenia and thrombocytopenia. CT abdomen revealed cholecystitis, percutaneous cholecystostomy tube was placed, and the patient’s mental status improved. One month after discharge, the patient presented to the hospital with a corrected calcium of 15.2 mg/dl. PTH was 22 pg/mL with normal renal function and phosphorus. The patient was treated with intravenous fluids, calcitonin, and zoledronic acid. Calcitriol was 69 pg/ml (18–75 pg/ml) and corrected calcium responded by time of discharge. During outpatient follow up, she was found to have corrected calcium 11.2 mg/dl and calcitriol 166 pg/ml with appropriately low PTH. Additional workup of apparent calcitriol-mediated hypercalcemia with whole-body CT imaging, tuberculosis screening, and flow cytometry only notable for possible right cervical lymphadenopathy on CT. Subsequent lymph node biopsy was benign. The patient completed a 30-day course of prednisone 20 mg daily followed by prednisone taper and her corrected calcium and calcitriol levels normalized. However, after discontinuation of prednisone, lab work demonstrated increase in calcium and liver enzymes. Repeat CT scan showed multiple hypoechoic areas with subsequent biopsy consistent with necrotizing hepatic granulomatosis. PAS-A, Fite, and AFB stains were negative for fungi and mycobacteria. Removal of cholecystostomy tube resulted in complete resolution of hypercalcemia and elevated calcitriol levels. Foreign body-induced granulomatosis is associated with PTH-independent hypercalcemia. Silicone has been implicated in foreign body granuloma. Hepatic granulomatosis is associated with percutaneous tube, especially with prolonged placement (approximately 11 months in this case). Removal of the foreign body is associated with improvement in hypercalcemia. Follow-up liver ultrasound demonstrated complete resolution of hepatic granulomas at three months following removal of the cholecystostomy tube.

Calcitriol Induced Hyper Calcemia in Stroma Uterine Cancer Independent From PTHrp

Case Presentation: A 70-year-old female with a history of breast cancer presented with an intra-abdominal mass. The biopsy of the mass was positive for endometrial stromal sarcoma. During hospital admission, the patient was noted to have hypercalcemia attributable to her malignancy. This hypercalcemia responded positively with IV fluids with calcitonin, and the patient was discharged with oncology follow-up for chemotherapy. The patient was referred back upon repeat labs by oncology showing a calcium of 13.4 mg/dL. The physical exam at this time was unremarkable. However, labs were significant for a RDW of 16.7%, Monocyte count of 17.7 mcg/L, Creatinine of 1.24 mg/dL, Calcium of 12.8 mg/dL, and Globulin of 4.2 g/dL. Special chemistry tests came back significant for a 1,25 Dihydroxy Vitamin D level of 256.8 pg/mL, PTHrP level of 3.7 pmol/L, PTH of 18.6 pg/mL, and free kappa light chains of 47.18 mg/dL. The patient was then placed on Prednisone 20mg daily with Zometa as needed with GYN oncology follow-up. Discussion: Paraneoplastic hypercalcemia is a relatively common finding in malignancy, affecting up to 44% of patients (Mirrakhimov, 2015). However, the etiology behind hypercalcemia ranges from increased PTHrP, osteolytic metastases, parathyroid related tumors, and uncommonly from 1,25 Hydroxy Vitamin D (Mirrakhimov, 2015). The patient presented with hypercalcemia secondary to an endometrial stromal sarcoma. The hypercalcemia was presumed to be related to PTHrP, however, serum levels of PTHrP and PTH were at the upper limits of normal, thus not sufficient to explain hypercalcemia. The elevated Vitamin D level was suspect for a calcitriol mediated hypercalcemia, a rare finding with a few case reports relating to gastrointestinal stromal tumors (Betlachin, Kim, & Oxman, 2020). The diagnosis is further backed up by the patient’s response to prednisone, which reduces 1 alpha hydroxylase activity, reducing the calcium levels. Calcitriol mediated hypercalcemia is a phenomenon that is typical of certain granulomatous diseases, but not as well defined in the literature for cancer (Kallas et al., 2010). Thus, it is important to consider calcitriol related hypercalcemia in malignancies with reduced PTH or PTHrP for proper treatment.Mirrakhimov A. E. (2015). Hypercalcemia of Malignancy: An Update on Pathogenesis and Management. North American journal of medical sciences, 7(11), 483Anna Betlachin, MD, Sarah Sangnim Rhee Kim, MD, Rachael Oxman, MD, MPH, Calcitriol-Mediated Hypercalcemia in a Patient With Metastatic Gastrointestinal Stromal Tumor, Journal of the Endocrine Society, Volume 4, Issue Supplement_1, April-May 2020,Melissa Kallas, Francis Green, Martin Hewison, Christopher White, Gregory Kline, Rare Causes of Calcitriol-Mediated Hypercalcemia: A Case Report and Literature Review, The Journal of Clinical Endocrinology & Metabolism, Volume 95, Issue 7, 1 July 2010, Pages 3111.

Calcitriol-mediated hypercalcemia as an immune-related adverse event in a patient receiving nivolumab and ipilimumab for metastatic renal cell carcinoma, case report

BackgroundSevere hypercalcemia is often associated with uncontrolled malignancy through several mechanisms. However, calcitriol-mediated hypercalcemia is a rare etiology for advanced solid tumors.Case presentationWe report a case of calcitriol-mediated hypercalcemia secondary to immune checkpoint inhibition in a responder with metastatic clear cell renal cell carcinoma (ccRCC). In this case, a 68 year old male with metastatic ccRCC to the liver within 4 months of right radical nephrectomy went on to develop hypercalcemia (12.8 mg/dL) shortly following 2 cycles of nivolumab and ipilimumab. Additional testing showed an elevated calcitriol level (142 pg/mL), low parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) levels, and a normal 25-hydroxyvitamin D level. FDG-PET imaging showed hypermetabolic mediastinal, hilar, and intra-abdominal lymphadenopathy, however the subsequent lymph node biopsy only showed reactive lymphoid cells without malignancy or granuloma. The hypercalcemia was resistant to initial therapy with calcitonin, hydration, and zoledronic acid but quickly responded to high-dose prednisone (1 mg/kg), followed by normalization of calcitriol levels. The patient was rechallenged with nivolumab and ipilimumab which provided a partial response after 4 cycles. He was maintained on low dose prednisone (10 mg daily) leading to a sustained resolution of his hypercalcemia.ConclusionThis case suggests calcitriol-mediated hypercalcemia as a novel immune-related adverse event.

MON-LB69 Calcitriol-Mediated Hypercalcemia in a Patient With Metastatic Gastrointestinal Stromal Tumor

Background: Hypercalcemia is a common complication of advanced malignancy, affecting up to 30% of cancer patients through various mechanisms (1). Hypercalcemia has rarely been described in gastrointestinal stromal tumors (GIST), with fewer than ten case reports as of 2018 (1,2). We describe a case of calcitriol-mediated hypercalcemia in a patient with GIST. Clinical Case: An 80-year-old woman with a history of metastatic GIST and nivolumab-induced type 1 diabetes and thyroiditis presented with dramatic progression of metastatic peritoneal disease and new severe hypercalcemia with acute kidney injury. On hospital admission, calcium (Ca) was 15.1 mg/dL (8.6-10.3 mg/dL), ionized Ca was 1.98 mmol/L (1.09-1.29 mmol/L), and creatinine was 2.56 mg/dL (0.6-1.3 mg/dL, baseline 1.8 mg/dL). She was treated with IV fluids and 45 mg of IV pamidronate with initial Ca improvement to 10.7 mg/dL over the next 48 hours. Additional workup showed that 25-hydroxyvitamin D was 18 ng/dL (20-50 ng/dL), PTH was 9 pg/mL (11-51 pg/mL), PTHrP was 3.1 pmol/L (0.0-3.4 pmol/L), and calcitriol was elevated to 172 pg/mL (19.9-79.3 pg/mL). Prior chest/abdomen/pelvis CT scans had not shown bony metastases or granulomas. After stopping IV fluids, Ca rose to 12.2 mg/dL the next day. Prednisone 20 mg daily was started which stabilized Ca levels and lowered calcitriol to 17.4 pg/mL after two weeks. She also began a new regimen of cabozantinib. Prednisone was tapered to 10 mg daily and she continues to maintain normal Ca levels with the addition of home health IV fluids three times a week. Conclusion: GIST tumors are a rare cause of hypercalcemia of malignancy. Although hypercalcemia of malignancy is most often due to tumor-secreted PTHrP or bony metastases, a small percentage of cases are mediated by excess calcitriol production. There is a growing number of case reports, including this case, to suggest that calcitriol-mediated hypercalcemia is the most common cause of hypercalcemia in GIST tumors (2-4). Glucocorticoids may be used to decrease calcitriol production and help maintain eucalcemia. Definitive therapy for hypercalcemia in these patients involves decreasing tumor burden by treatment of the underlying malignancy (3).

SAT-346 Hypercalcemia Secondary to Calcitriol and PTHrP Cosecretion Only Responsive to Hydroxychloroquine

Background: Hypercalcemia of malignancy mediated by concurrent elevations in both 1,25-dihydroxyvitamin D (calcitriol) and parathyroid hormone (PTH)-related protein (PTHrP) is a rare phenomenon previously only reported with solid tumors. The preferred treatment for calcitriol-mediated hypercalcemia is glucocorticoid therapy and second-line therapy is traditionally ketoconazole. Hydroxychloroquine has previously been reported as efficacious only in cases of calcitriol excess related to sarcoidosis. Clinical case: A sixty-two year-old female with a history of diffuse large B cell lymphoma, complicated by disease progression despite multiple treatment regimens over the preceding five years, developed acute hypercalcemia to a corrected value of 14.7 mg/dL (8.9-10.3). Work-up revealed a suppressed PTH, PTHrP <2.0 pmol/L (0.0-3.4), and calcitriol elevation of 136.0 pg/mL (19.9-79.3). She was treated with zolendronate with rapid normalization of calcium levels. Upon recurrence of hypercalcemia six months later, repeat calcitriol was 176.0 pg/mL with a new PTHrP elevation of 7.0 pmol/L. Repeat dosing of zolendronate was less efficacious. She was prescribed prednisone 60 mg daily with subsequent addition of denosumab 120 mg weekly with continued hypercalcemia. Given rising levels of calcitriol and PTHrP (up to 285.6 pg/mL and 43.5 pmol/L, respectively) and potential drug interactions between ketoconazole and her chemotherapy, she was started on hydroxychloroquine 400 mg daily. Her calcium normalized and calcitriol dropped to 61.1 pg/mL despite imaging evidence of continued lymphoma progression. Three weeks later, she developed septic shock and was transitioned to hospice. Conclusion: In reviewing the literature, this appears to be the first reported case of a hematologic malignancy with pathologic levels of both calcitriol and PTHrP. It is also the first reported efficacy of hydroxychloroquine in malignant hypercalcemia. Interestingly, PTHrP secretion occurred months after the initial development of hypercalcemia. Control of both calcitriol and calcium levels did not occur until initiation of hydroxychloroquine despite preceding use of high-dose glucocorticoids and anti-resorptive therapy. Our case suggests that hydroxychloroquine should be considered in cases of calcitriol-mediated hypercalcemia resistant to glucocorticoids, particularly as it has less drug interactions and a more favorable side effect profile when compared to ketoconazole.

Calcitriol Elevation Is Associated with a Higher Risk of Refractory Hypercalcemia of Malignancy in Solid Tumors.

Hypercalcemia of malignancy (HCM) is a common complication of advanced cancer. PTH-independent HCM may be mediated through different mechanisms: (1) humoral HCM, caused by the secretion of PTH-related peptide (PTHrP), (2) local osteolysis resulting from metastatic lesions, and (3) calcitriol-mediated hypercalcemia. Calcitriol-mediated HCM in patients with nonlymphomatous solid tumors is thought to be rare. We performed a retrospective chart review from 2008 to 2017 to characterize further patients at our institution with solid tumors who had HCM with concomitant elevations in calcitriol. Patients with PTH-dependent hypercalcemia and patients with evidence of granulomatous disease were excluded, as were patients with hematologic malignancies. We hypothesized that patients with HCM and elevated calcitriol levels would respond less favorably to treatment with antiresorptive therapy compared with patients with HCM but without calcitriol elevation. We also aimed to assess mortality and determine if PTHrP and phosphorus levels correlate with calcitriol because both factors may alter calcitriol levels. Of 101 eligible patients, calcitriol was elevated in 45 (45%). PTHrP was elevated in 76% of patients with elevated calcitriol compared with 52% of patients without calcitriol elevation. The mean PTHrP value did not differ between patients with HCM and elevated calcitriol (36.3 ± 22 pg/mL) and those without calcitriol elevation (37.4 ± 19 pg/mL). Those with elevated calcitriol levels generally did not respond completely to antiresorptive treatment (80% incomplete response rate), whereas most patients without an elevation in calcitriol responded well to antiresorptive treatment (78% response rate: P < .001). There was no significant difference in the percentage of patients with metastatic bone disease among the 2 groups (49% vs. 55%, respectively). There was no difference in mortality between the 2 groups (P = .14). A weak but significant negative correlation was found between phosphorus and calcitriol (Pearson r = -0.261, P = .016). This correlation was only significant in patients without calcitriol elevation (Pearson r = -0.4, P = .0082). Also, a significant negative correlation was found between PTHrP and phosphorus, again only in patients without calcitriol elevation. In the setting of HCM, patients with calcitriol elevation are much less likely to respond to antiresorptive therapy than patients without calcitriol elevation. Because calcitriol elevation did not appear to be correlated with hypophosphatemia or elevated PTHrP, it would appear that calcitriol production under these conditions is autonomous, and not subject to normal physiological controls. These observations indicate that calcitriol elevations in patients with HCM have clinical significance.

SAT-496 Symptomatic Hypercalcemia in a Transgender Patient with Silicone-Induced Granulomas

Introduction Despite FDA-issued safety concerns, silicone injections remain legal and are practiced by unlicensed providers. Here we present a case of calcitriol-mediated hypercalcemia secondary to a granulomatous reaction induced by silicone injections. Clinical Case This is a case of a 39-year-old male to female transgender patient who presented with nonspecific symptoms that included myalgias and abdominal pain. The patient’s past medical history includes bipolar 1 disorder, well-controlled HIV, GERD, history of DVT/PE and a history of Hodgkin’s lymphoma treated with chemotherapy and autologous stem cell transplant 3 years prior to presentation. A thorough physical exam revealed infiltrative red plaques involving her buttocks and breasts at sites where, after further questioning, she reported receiving cosmetic silicone injections in Mexico as part of her gender transition 15 years ago. Laboratory evaluation revealed a serum calcium level of 13.5mg/dL (n 8.5-10.1mg/dL) and a serum creatinine level of 1.74mg/dL from a baseline creatinine of 1.1mg/dL. 1,25-dihydroxyvitamin D level was high at 92.5pg/mL (n 19.9-79.3pg/mL) while a 25-hydroxyvitamin D level was low at 16.2ng/mL (n 30-100ng/mL). PTH was undetectably low (<6.5pg/mL) and PTH-related protein level was normal at 3.4pmol/L (n<3.4pmol/L). Contrasted CT imaging of her chest, abdomen and pelvis revealed infiltrative nodular soft tissue hyperdensities throughout the breasts and buttocks likely representing a granulomatous inflammatory process. The patient was initially treated with intravenous fluids and furosemide administration. Dermatology was consulted, and biopsy of the affected plaques was performed. Patient was started on prednisone to target the exuberant 1-alpha hydroxylation thought to be occurring at the site of the granulomatous reaction. Results of the tissue biopsy revealed a foreign body giant cell reaction consistent with silicone injection. Serum calcium levels rapidly normalized after initiating steroid therapy and patient was discharged to follow-up as an outpatient where prednisone was eventually tapered off and she was started on hydroxychloroquine. Conclusion Hypercalcemia is a commonly encountered problem that is often incidentally found in patients presenting with non-specific symptoms. Clinical judgement leads us down a well-learned algorithm to attempt to diagnose the etiology. However, there is growing evidence linking silicone injections to granulomatous disease. It is therefore prudent to consider silicone granulomas as part of the differential of hypercalcemia, particularly within the transgender community. It is of vital importance to directly ask about past cosmetic injections as most patients will not readily volunteer that information.

MON-342 Calcitriol-Mediated Hypercalcemia in Adrenal Diffuse Large B-Cell Lymphoma

Background: Hypercalcemia of malignancy can present with a suppressed intact PTH level in response to various etiologies including elevated PTH-rP, increased calcitriol production via activation of the enzyme 1-alpha hydroxylase, or osteolytic bone lesions. PTH-independent hypercalcemia with elevated 1,25-dihydroxyvitamin D (calcitriol) levels should prompt evaluation for granulomatous disorders including sarcoidosis, tuberculosis, and lymphoma. Here we present a case of calcitriol-mediated hypercalcemia secondary to a rare, adrenal diffuse large B-cell lymphoma. Clinical Case: A 61-year-old female presented with fatigue, myalgias, and generalized weakness. On admission, calcium was 14.1 mg/dL (8.9-10.3), phosphorus 2.4 mg/dL (2.3-4) and iPTH was suppressed to 3.6 pg/mL (8.5-75). CT scan revealed a 30-35 Houndsfield unit, 14 x 9 x 13 cm left adrenal mass. Workup included PTH-rP 0.3 pmol/L (<2.0) and calcitriol 109 pg/mL (18-78). Serum and urine electrophoresis were negative for monoclonal protein spikes. Further hormonal evaluation revealed normal serum and urine metanephrines, 24-hour urine cortisol 64 mcg/24h (3.5-45), 8 AM cortisol 1.9 ug/dL following 1 mg dexamethasone suppression (<1.8), midnight salivary cortisol 87 ng/dL (<100), DHEA-S 16.2 mcg/dL (<15-157), and 11-deoxycortisol 24 ng/dL (10-79). Angiotensin-converting enzyme level was normal at 10 U/L (8-53). Her hypercalcemia improved with intravenous fluids and calcitonin. She was not a surgical candidate as PET/CT revealed multiple para-aortic and mesenteric hypermetabolic lymphadenopathy, left breast soft tissue density, and a lesion in the right posterior pelvis likely indicative of metastatic disease. Nuclear bone scan ruled out bone metastases. Para-aortic biopsy was considered technically difficult in this patient so she underwent CT-guided core needle biopsy of the adrenal mass which confirmed high-grade CD5-positive diffuse large B-cell lymphoma. Immunohistochemical staining was positive for CD20, BCL2, BCL6, MUM-1, and Ki-67 90%. She completed 6 cycles of chemotherapy with rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone (R-CHOP). Repeat PET/CT following completion of chemotherapy showed no residual disease however one month later, she presented with acute encephalopathy with MRI brain showing a large frontal lobe tumor concerning for relapse. She received 1 cycle of intrathecal methotrexate and cytarabine however these were discontinued due to severe deconditioning. She now remains on oral ibrutinib. Conclusions: Primary adrenal lymphomas are a rare cause of non-Hodgkin lymphomas with less than 150 cases noted in the literature. Lymphoma should be included in the differential of patients presenting with PTH-independent hypercalcemia given the aggressive nature of the disease and associated high mortality.

Silicone Granulomatous Inflammation Resulting in Hypercalcemia: A Review of the Literature

Silicone usage for cosmetic enhancement is common, although it is not approved by the U.S. Food and Drug Administration. Granulomatous inflammation leading to hypercalcemia is a rare complication. We present a case of non-parathyroid hormone (PTH), calcitriol-mediated hypercalcemia in a woman with a history of cosmetic injections. Case report and review of the literature. A 48-year-old female with metabolic syndrome was evaluated for severe hypercalcemia (calcium >15 mg/dL). Laboratory tests revealed low-normal PTH, normal 25-hydroxyvitamin D, elevated 1,25-dihydroxyvitamin D, and hypercalciuria. Imaging studies, including a computed tomography (CT) scan of the lungs, was nonrevealing. Positron emission tomography/CT showed symmetric hypermetabolic subcutaneous stranding of bilateral gluteus and proximal thighs. She admitted to silicone injections in the buttocks 10 years prior. Her examination was unremarkable except for an intermittent pruritic rash over the right thigh. Labs revealed total serum calcium 11.3 mg/dL, PTH 18 pg/mL, 24-hour urinary calcium 509 mg, and PTH-related peptide 18 pg/mL. Serum and urine electrophoresis were normal, 25-hydroxyvitamin D was 47 pg/mL, and 1,25-dihydroxyvitamin D was 121 pg/mL. Angiotensin-converting enzyme level was 80 U/mL. A diagnosis of granulomatous inflammation resulting in calcitriol-mediated, PTH-independent hypercalcemia was entertained. Silicone-induced hypercalcemia should be thought of in those with prior cosmetic injections. Tissue biopsy confirms the diagnosis, which is often delayed. We reviewed 19 cases with silicone usage and variable levels of hypercalcemia. Renal injury was common. One death was reported. Glucocorticoids, calcium restriction, and hydration have been used to treat calcitriol-mediated hypercalcemia but are not curative. Ketoconazole and bisphosphonates have been used with variable success. Surgical excision tends to be ineffective due to silicone migration. The treatment of this disorder is difficult and often ineffective.

Mechanisms of Hypercalcemia in Non-Hodgkin Lymphoma and Associated Outcomes: A Retrospective Review

IntroductionThe etiology of hypercalcemia in non-Hodgkin lymphoma (NHL) has been most often attributed to either elevated serum levels of 1,25-dihydroxycholecalciferol (calcitriol) or parathyroid-related protein (PTHrP). In a single-center retrospective review, we evaluated the incidence of, and outcomes associated with, hypercalcemia in NHL. Patients and MethodsThe medical records of patients with a histologically confirmed diagnosis of NHL and ≥ 1 episode of hypercalcemia were evaluated for demographic and lymphoma-specific factors, including the response to therapy and overall survival. ResultsFifty-four patients with NHL met the inclusion criteria. Most patients (57.4%) had diffuse large B-cell lymphoma, of which, 70% were the nongerminal center subtype. Approximately one half (42.6%) of the included patients had undergone serologic investigation into the etiology of hypercalcemia; however, only 17 patients (31.5%) had both a serum PTHrP and a calcitriol level properly collected. Of the 17 cases for which both a serum calcitriol and a PTHrP were collected, most (61.1%) were found to have neither an elevation of serum calcitriol nor an elevation of PTHrP. The degree of calcitriol elevation correlated with worse progression-free survival (P = .04) but not overall survival. ConclusionThe major mechanism by which NHL patients develop hypercalcemia is not mediated by calcitriol or PTHrP. Hypercalcemia is most prevalent in patients with diffuse large B-cell lymphoma of the nongerminal cell subtype. Patients with calcitriol-mediated hypercalcemia showed a trend toward worse outcomes, suggesting that calcitriol might be a marker of high-grade lymphoma, transformation to such, or a surrogate for more advanced disease.

Hypercalcemia in Lung Cancer due to Simultaneously Elevated PTHrP and Ectopic Calcitriol Production: First Case Report

Calcitriol-mediated hypercalcemia has been reported in malignant lymphomas and granulomatous diseases but not in lung carcinoma. We describe a patient with squamous cell lung carcinoma with hypercalcemia and elevated calcitriol levels. A 60-year-old Caucasian male patient with stage IIIB squamous cell lung cancer developed hypercalcemia at 14.8 mg/dL two years after receiving chemotherapy and radiotherapy where labs showed a serum intact PTH: 7 pg/mL, PTHrP: 30 pmol/L, 1,25-hydroxyvitamin D (calcitriol): 76 pg/mL, and 25-hydroxyvitamin D levels: <4 ng/mL. Calcitriol levels were elevated despite undetectable 25-hydroxyvitamin D levels. There are no reported lung cancer cases with elevated calcitriol as an etiology of hypercalcemia. We believe that the elevated calcitriol levels in this case were due to a PTHrP-independent mechanism, possibly from either ectopic production of calcitriol in tumor cells or from increased activity of 1-alpha hydroxylase in the same cells. The patient died before the effects of prednisone therapy could be assessed. Studies are needed to investigate the cellular source of calcitriol and its role in hypercalcemia in patients with lung cancer.

Calcitriol-Mediated Hypercalcemia: Causes and Course in 101 Patients

Hypercalcemia mediated by 1,25-dihydroxy vitamin D (calcitriol) is uncommon, with evidence on etiology limited to small case series or case reports. The objective of the study was to systematically identify a large series of cases of calcitriol-mediated hypercalcemia and document the presentation, demographics, and clinical course across etiologies. The study was a hospital-based, retrospective case series, identifying subjects from 1999 through 2009 across the public hospital system in Queensland, Australia. All patients aged over 18 years were identified that had persistent hypercalcemia associated with elevated or inappropriately normal calcitriol concentration or elevated serum angiotensin-converting enzyme. A total of 101 cases were identified. Sarcoidosis was the most common etiology (49%), followed by hematological malignancy (17%) and infections (8%). Etiologies not previously described include squamous cell carcinoma of the tongue, ovarian cystadenocarcinoma, and chronic lymphocytic leukemia. Median serum angiotensin-converting enzyme was higher in sarcoid patients compared with all other causes [218 U/L (176-277) vs 155 U/L (110-208), P < .001], but a level above the normal range did not discriminate well between cases of sarcoidosis and other causes (specificity at cutoff of 130 U/L was only 31%). However, a value greater than 250 U/L was highly specific (89%) for sarcoidosis but lacked sensitivity (31%). A calcitriol level greater than 300 pmol/L was not seen in sarcoidosis but was seen with other etiologies. Cases with neoplastic etiologies were older (61.4 ± 11.4 y) than all other subjects (51.7 ± 15.0 y, P = .006). Hypercalcemia mediated by calcitriol remains a rare presentation. In almost half the cases, sarcoidosis was the underlying cause, whereas a third of patients had cancer or systemic infections.

Silicone-Induced Granuloma after Injection for Cosmetic Purposes: A Rare Entity of Calcitriol-Mediated Hypercalcemia

Hypercalcemia is often a clue to the presence of unsuspected illness. We present an interesting case of an HIV-positive transgender female with a rare cause of silicone-induced granulomatous hypercalcemia. Although there have been a few case reports of silicone injections in dialysis patients causing hypercalcemia, this metabolic derangement secondary to silicone granulomas continues to be a unique entity with an unclear pathophysiology. We present a 45-year-old transgender HIV-positive female, with extensive silicone injections, who presented with symptomatic hypercalcemia. Workup for malignancy and hyperparathyroidism was negative. 1,25-Dihydroxyvitamin D level and 24-hour urine calcium level were elevated. CT scan showed extensive high-density reticulonodular densities in the buttocks and gluteal muscle fascia extending upwards to the lumbar region, along with prominent external iliac and inguinal lymph nodes. Nuclear imaging showed diffuse heterogeneity and increased uptake in the buttocks, most consistent with granuloma calcifications, and an inguinal lymph node biopsy confirmed a foreign body giant cell reaction. The patient was started on prednisone and this resulted in decrease in serum and urinary calcium levels. Physicians should have a high index of suspicion for silicone-induced hypercalcemia considering the growing prevalence of body contour enhancement with injections, implants, and fillers using this material.

Rare Causes of Calcitriol-Mediated Hypercalcemia: A Case Report and Literature Review

Calcitriol-mediated hypercalcemia resulting from elevated extrarenal 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-hydroxylase) activity has not previously been described in giant cell polymyositis. We report an unusual case of hypercalcemia due to disseminated granulomatous disease in a 62-yr-old woman with profound proximal muscle weakness and weight loss. She was initially diagnosed with vitamin D deficiency myopathy with a low serum 25-hydroxyvitamin D; serum calcium at this time was low-normal. Vitamin D(3) 3000 IU daily was prescribed. One month later, blood work showed new hypercalcemia and hypercalciuria with normalized 25-hydroxyvitamin D. 1,25-dihydroxyvitamin D was high-normal, despite a suppressed PTH, undetectable PTHrP, and essentially normal renal function. Her hypercalcemia resolved, and her strength improved only after prednisone was added to bisphosphonate therapy. Two weeks later, she died from acute congestive heart failure. Autopsy revealed a disseminated giant cell myositis affecting skeletal, cardiac, and gastrointestinal smooth muscle. Immunohistochemistry localized 1alpha-hydroxylase to the inflammatory infiltrates in skeletal and cardiac muscle. A review of English publications in Medline and Embase, including a reference search of retrieved articles, revealed that calcitriol-mediated hypercalcemia has been described in over 30 conditions, most of which are granulomatous in nature, ranging from inflammatory conditions and foreign body exposures to infections and neoplasms. Hypercalcemia resulting from autonomous 1alpha-hydroxylase activity may be unmasked by low-dose vitamin D supplementation and should not be excluded from the differential diagnosis of nonparathyroid causes if the serum calcitriol is inappropriately normal, rather than frankly elevated.

Hypercalcemia of Malignancy

Hypercalcemia of malignancy (HCM) is the most common life-threatening metabolic complication of malignancy and affects 10 to 20% of patients with advanced cancer. In oncology units, its incidence varies between 0.5 and 10.9%. In more than half of the patients, it is associated with pulmonary and mammary cancers. In the presence of hypercalcemia, it is important to recognize co-existing conditions, like primary hyperparathyroidism, that could partially explain the elevation of serum calcium. HCM causes a series of symptoms which decrease quality of life. Constipation, nausea and vomiting, confusion and/or stupor, polyuria and polydipsia, as well as bone pain, are specific to HCM. The normalization of calcemia significantly improves all of these symptoms. However, HCM remains largely underdiagnosed in medical practice. Furthermore, specific treatment of HCM in the hospital is usually late, and patients are rarely given adequate rehydration. HCM should be treated as an emergency upon diagnosis. Patients with normalized calcium levels have a better quality of life and are usually able to return home. Treatments for patients with HCM include: (i) rapid rehydration with isotonic saline intravenously; (ii) intravenous bisphosphonates; and (iii) calcitonin in addition to bisphosphonates for patients whose levels of serum calcium are in the life-threatening range (≥4 mmo1/L). The most currently used bisphosphonates are clodronic acid and pamidronic acid; however, the increased convenience of a 15-minute infusion, greater efficacy (∼90%), and longer duration of response (∼30 days) should make zoledronic acid the new standard of treatment for patients with HCM. Corticosteroids are highly effective agents for the treatment of patients with hematological cancer and calcitriol-mediated hypercalcemia. Promising new treatments for patients with HCM include antibodies to parathyroid hormone-related peptide and osteoprotegrin.