PTH-independent Hypercalcemia Research Articles

A case of combined PTH-dependent and PTH-independent hypercalcemia

A case of combined PTH-dependent and PTH-independent hypercalcemia

A case of hypercalcemia from Pneumocystis jirovecii in an immunosuppressed non-HIV patient

BackgroundThe prevalence of non-HIV related Pneumocystis jirovecii pneumonia (PJP) is increasing with use of immunosuppressive therapies. There are case reports of solid organ transplant recipients on immunosuppressive therapy presenting with mild hypercalcemia, leading to a diagnosis of PJP. Recent studies have shown efficacy of PJP prophylaxis for patients treated with rituximab with a favourable adverse effect profile.Case PresentationA 78-year-old male with a history of PR3-ANCA vasculitis, chronic kidney disease and heart failure with reduced ejection fraction presented to our tertiary care hospital with a two-week history of confusion and non-productive cough. Background immunosuppression with rituximab was completed every six months. The patient was found to have hypercalcemia and new infiltrates and ground glass opacities on cross-sectional imaging. Bronchoscopy was performed that was positive for Pneumocystis jirovecii. He was treated with 21 days of trimethoprim-sulfamethoxazole and prednisone with resolution of symptoms and hypercalcemia.ConclusionsHerein, we present a novel case of PJP in a non-transplant recipient preceded by hypercalcemia. Our case demonstrates the importance for a high suspicion for PJP in chronically immunosuppressed patients on rituximab presenting with PTH-independent hypercalcemia.

Biallelic and monoallelic pathogenic variants in CYP24A1 and SLC34A1 genes cause idiopathic infantile hypercalcemia

ObjectiveIdiopathic infantile hypercalcemia (IIH) is a rare disorder of PTH-independent hypercalcemia. CYP24A1 and SLC34A1 gene mutations cause two forms of hereditary IIH. In this study, the clinical manifestations and molecular aspects of six new Chinese patients were investigated.MethodsThe clinical manifestations and laboratory study of six patients with idiopathic infantile hypercalcemia were analyzed retrospectively.ResultsFive of the patients were diagnosed with hypercalcemia, hypercalciuria, and bilateral medullary nephrocalcinosis. Their clinical symptoms and biochemical abnormalities improved after treatment. One patient presented at age 11 years old with arterial hypertension, hypercalciuria and nephrocalcinosis, but normal serum calcium. Gene analysis showed that two patients had compound heterozygous mutations of CYP24A1, one patient had a monoallelic CYP24A1 variant, and three patients had a monoallelic SLC34A1 variant. Four novel CYP24A1 variants (c.116G > C, c.287T > A, c.476G > A and c.1349T > C) and three novel SLC34A1 variants (c.1322 A > G, c.1697_1698insT and c.1726T > C) were found in these patients.ConclusionsA monoallelic variant of CYP24A1 or SLC34A1 gene contributes to symptomatic hypercalcemia, hypercalciuria and nephrocalcinosis. Manifestations of IIH vary with onset age. Hypercalcemia may not necessarily present after infancy and IIH should be considered in patients with nephrolithiasis either in older children or adults.

Hypercalcemia with the development of chronic kidney disease, nephrolithiasis after intramuscular injection of oil solutions

One of the rare causes of PTH-independent hypercalcemia can be anabolic oil solution, injected intramuscularly by bodybuilders, along with anabolic hormones, in order to make the muscles more prominent. Here is the clinical report of a 43-year-old patient who used Synthol oil solution at the age of 25–30 years is presented. He had long-term undiagnosed hypercalcemia that manifested with nephrolithiasis and progressing chronic kidney disease (CKD). For the first time hypercalcemia was diagnosed at the age of 37, but left omitted. In 2023 (43 years) the laboratory findings sowed extremely high calcium level (4.26 mmol/l) with decreased PTH and CKD C4. Malignancy hypercalcemia was excluded. With this case, the rare cause of hypercalcemia has been proven – intramuscular oil injection resulting in nephrolithiasis, nephrocalcinosis and CKD. Treatment with glucocorticoids has demonstrated positive effect, similar to the ones of granulomatous diseases and hypercalcemia. The mechanisms of PTH-independent hypercalcemia development and differential diagnosis are currently being discussed. The presented clinical case of a rare cause of hypercalcemia may be useful for doctors of various specialties: endocrinologists, therapists, urologists, dermatologists, etc.

O-12 A rare cause of parathyroid hormone independent hypercalcemia: 1,25-(OH)2D-24 Hydroxylase (CYP24A1) deficiency

Abstract Background Common causes of parathyroid hormon (PTH)-independent hypercalcemia in adulthood are malignancy, granulomatous diseases, and endocrinopathies. Loss-of-function mutations of CYP24A1 gene, encoding for 1,25-dihydroxyvitamin D3 24-hydroxylase, can also be a rare cause of supressed intact PTH levels, usually associated with, nephrolithiasis and nephrocalcinosis. This disease, defined as idiopathic infantile hypercalcemia, classically presents with hypercalcemia in infants. However, some individuals have also been reported with late-onset clinical manifestation or late diagnosis in adulthood. Clinical Case A 59-year-old male patient with a known diagnosis of type 2 diabetes mellitus for 30 years. He had a history of recurrent kidney stones since 2006. His blood and urine tests revealed elevated creatinine level, hypercalcemia with normal phosphorus levels, normal 25-hydroxycholecalciferol levels, suppressed intact PTH level and normal 24-hour urinary calcium level (Table 1). Urinary ultrasonography was consisted with medullary nephrocalcinosis and chronic kidney disease. PTH-independent causes of hypercalcemia were investigated. Malignancies, granulomatous diseases and endocrinopathies were ruled out. The 1,25-dihydroxycholecalciferol level was within the normal range. Parathormone related peptide level was determined as 1.60 pmol/L (normal value <4.2). Genetic workup revealed a homozygous loss-of-function mutation p.E143del in the CYP24A1 gene. Thereupon, genetic screening started on the siblings of the patient which not been finalized yet. However, none of them were found to have hypercalcemia in the laboratory evaluation. Treatment was started with low-dose fluconazole, which inhibits enzymes (including 25-hydroxylases and 1-α-hydroxylase) synthesizing vitamin D. After a month of treatment at a dose of 50 mg/day, no change was observed in the patient's calcium values. Follow-up with calcium-restricted diet and adequate oral hydration therapy was planned. Conclusion Idiopathic infantile hypercalcemia may manifest later or diagnosed later in adulthood. Genetic examination should be considered in adult patients in whom other causes of PTH-independent hypercalcemia have been excluded.Table 1.Patient's laboratory parameters

PTH Independent hypercalcaemia in a pregnant patient

PTH Independent hypercalcaemia in a pregnant patient

SAT252 Homozygous CYP24A1 Gene Mutation Induced Hypercalcemia During Pregnancy

Abstract Disclosure: A.R. Ankireddypalli: None. H. Alameddine: None. Introduction: The approach and management of hypercalcemia in pregnancy can be challenging. Pregnancy challenges the calcium homeostasis with physiological increase in 1,25 dihydroxy Vitamin D levels by kidneys and placental 1-alpha hydroxylase, however it rarely causes hypercalcemia. In PTH independent hypercalcemia, disorders in vitamin D metabolism should be considered. Here we report a case of PTH independent hypercalcemia due to autosomal recessive homozygous CYP24A1 gene mutation. Case: A 25-year-old primigravid female presented to the clinic at 26 weeks of gestation for management of hypercalcemia. At 25 weeks gestation, laboratory workup revealed calcium: 13.9 mg/dL, albumin: 2.9 g/dL, PTH: < 6 pg/mL, vitamin D: 45.17ng/mL, creatinine: 1.02 mg/dL, alkaline phosphatase (ALP): 117mcg/L. Since getting pregnant she reported nausea and vomiting. She reported excessive thirst, memory loss, fatigue, exertional dyspnea and 10 lbs weight loss. She denied any personal history of kidney stones or family history of calcium or bone disorders. She stopped her prenatal vitamins at the time of hypercalcemia diagnosis. Her work-up was suggestive of PTH independent hypercalcemia. Differential diagnosis included granulomatous disease, malignancy, benign PTHrP secreting tumors, vitamin D metabolism dysfunction and milk-alkali syndrome. Further work-up revealed ionized calcium: 6.2 mg/dL, PTHrP: 5.3 pmol/L, bone specific ALP: 11.8 mcg/L, 25 hydroxy vitamin D: 132 mcg/L, 1, 25 dihydroxy vitamin D: > 200 pg/mL, 24,25 dihydroxy vitamin D: 1.16 ng/mL, 25-hydroxy vitamin D to 24,25 dihydroxy vitamin D ratio: 75.0, which was indicative of CYP24A1 mutation, an enzymatic defect in vitamin D metabolism. Molecular testing confirmed autosomal recessive homozygous CYP24A1 gene mutation. With elevated 24,25 dihydroxy vitamin D levels, it was unlikely that her 1,25 dihydroxy vitamin D was elevated due to malignancy or granulomatous disease. Treatment with prednisone 60 mg daily for 1 month did not improve her calcium levels. She was recommended to limit her calcium intake, avoid vitamin D supplements or sun exposure. At 38 weeks, she delivered a healthy baby without neonatal complication. Postpartum day 2, her labs revealed calcium: 10.7mg/dL with albumin: 2.7mg/dL. Discussion: Diagnosis of CY24A1 gene mutation associated hypercalcemia is based on increased 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D ratio and confirmed by genetic analysis. Recommendations are adequate hydration, limiting calcium intake, avoiding vitamin D supplements and preventing sun exposure. It is important to monitor for neonatal hypocalcemia and worsening of maternal hypercalcemia during breastfeeding. We report this case to raise awareness of this rare cause of hypercalcemia in pregnancy and the importance of checking calcium and vitamin D levels prior to vitamin D supplementation. Presentation: Saturday, June 17, 2023

Substantially Delayed Maturation of Growth Plate Chondrocytes in "Humanized" PTH1R Mice with the H223R Mutation of Jansen's Disease.

Activating parathyroid hormone (PTH)/PTH-related Peptide (PTHrP) receptor (PTH1R) mutations causes Jansen's metaphyseal chondrodysplasia (JMC), a rare disease characterized by growth plate abnormalities, short stature, and PTH-independent hypercalcemia. Previously generated transgenic JMC mouse models, in which the human PTH1R allele with the H223R mutation (H223R-PTH1R) is expressed in osteoblasts via type Ia1 collagen or DMP1 promoters cause excess bone mass, while expression of the mutant allele via the type IIa1 collagen promoter results in only minor growth plate changes. Thus, neither transgenic JMC model adequately recapitulates the human disease. We therefore generated "humanized" JMC mice in which the H223R-PTH1R allele was expressed via the endogenous mouse Pth1r promoter and, thus, in all relevant target tissues. Founders with the H223R allele typically died within 2 months without reproducing; several mosaic male founders, however, lived longer and produced F1 H223R-PTH1R offspring, which were small and exhibited marked growth plate abnormalities. Serum calcium and phosphate levels of the mutant mice were not different from wild-type littermates, but serum PTH and P1NP were reduced significantly, while CTX-1 and CTX-2 were slightly increased. Histological and RNAscope analyses of the mutant tibial growth plates revealed markedly expanded zones of type II collagen-positive, proliferating/prehypertrophic chondrocytes, abundant apoptotic cells in the growth plate center and a progressive reduction of type X collagen-positive hypertrophic chondrocytes and primary spongiosa. The "humanized" H223R-PTH1R mice are likely to provide a more suitable model for defining the JMC phenotype and for assessing potential treatment options for this debilitating disease of skeletal development and mineral ion homeostasis. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Cinacalcet increases renal calcium excretion in PTHrP-mediated hypercalcemia: a case report

BackgroundIn the acute setting, PTH-independent hypercalcemia is typically treated with anti-resorptive agents such as zoledronic acid or denosumab. When these agents are no longer able to control hypercalcemia, several case reports have shown the utility of cinacalcet. However, it is not known if cinacalcet can be effective in patients naïve to anti-resorptive therapy or how cinacalcet ameliorates the hypercalcemia.Case presentationA 47-year-old male with a history of alcohol-induced cirrhosis was admitted for left cheek bleeding and swelling from an infiltrative squamous cell carcinoma of the oral cavity. On admission, he was found to have an elevated albumin-corrected serum calcium of 13.6 mg/dL, a serum phosphorus of 2.2 mg/dL and an intact PTH of 6 pg/mL (normal 18–90) with a PTHrP of 8.1 pmol/L (normal < 4.3), consistent with PTHrP-dependent hypercalcemia. Aggressive intravenous saline hydration and subcutaneous salmon calcitonin were initiated, but his serum calcium remained elevated. Given tooth extractions scheduled for the next day and possible irradiation to the jaw in the near future, alternatives to antiresorptive therapy were sought. Cinacalcet was initiated at 30 mg twice daily then increased to 60 mg twice daily the following day. The albumin-corrected serum calcium level decreased from 13.2 to 10.9 mg/dL within 48 h. The fractional excretion of calcium increased from 3.7 to 7.0%.ConclusionsThis case demonstrates the utility of cinacalcet for the treatment of PTHrP-mediated hypercalcemia without prior anti-resorptive therapy via increased renal clearance of calcium.

A parathyroid hormone/salt-inducible kinase signaling axis controls renal vitamin D activation and organismal calcium homeostasis.

The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell-derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, elevated serum 1,25-vitamin D, and PTH-independent hypercalcemia. The SIK substrate CRTC2 showed PTH and SIK inhibitor-inducible binding to key Cyp27b1 regulatory enhancers in the kidney, which were also required for SIK inhibitors to increase Cyp27b1 in vivo. Finally, in a podocyte injury model of chronic kidney disease-mineral bone disorder (CKD-MBD), SIK inhibitor treatment stimulated renal Cyp27b1 expression and 1,25-vitamin D production. Together, these results demonstrated a PTH/SIK/CRTC signaling axis in the kidney that controls Cyp27b1 expression and 1,25-vitamin D synthesis. These findings indicate that SIK inhibitors might be helpful for stimulation of 1,25-vitamin D production in CKD-MBD.

POEMS syndrome associated with vitiligo (P13-8.007)

<h3>Objective:</h3> To report a case of POEMS syndrome with vitiligo. This is the second case to be reported and the first in an Afro-American patient. <h3>Background:</h3> POEMS syndrome is a rare plasma-cell disorder with multisystem involvement, characterized by the acronym composing its name: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein (M-protein), and Skin changes. Major criteria include mandatory polyneuropathy and monoclonal plasma cell proliferative disorder in addition to Castleman’s disease, sclerotic bone lesions, or elevated vascular endothelial growth factor (VEGF). Minor criteria, still helpful for diagnosis, include organomegaly, endocrinopathy, papilledema, thrombosis, and skin changes, the most common being hyperpigmentation. <h3>Design/Methods:</h3> Case Presentation <h3>Results:</h3> A 50-year-old Afro-American male presented with 3 years of ascending stocking-glove pattern numbness and skin discoloration in his feet. Other positive history included anhidrosis, heat intolerance and erectile dysfunction suggestive of dysautonomia. Medical history included hypoparathyroidism and idiopathic cirrhosis. He did not have history of alcohol overuse, diabetes, or glucose intolerance. Examination revealed confluent hypopigmented macules in feet, vibratory sensation impairments up to knees, absent temperature sensation in feet, and abnormal Romberg test and tandem gait. Remainder of the neurological examination was normal. Laboratory tests were significant for elevated free kappa and lambda light chains, plasma VEGF levels twice over normal range, and an IgA monoclonal band on serum protein electrophoresis. Other relevant laboratory findings included PTH-independent hypercalcemia and alkaline phosphatase elevation. Radiographs of hands, elbows, shoulders, and knees disclosed non-sclerotic lytic lesions. Nerve conduction studies were consistent with a sensorimotor axonal polyneuropathy. The patient met diagnostic criteria for POEMS syndrome. Autologous stem cell transplantation was recommended but the patient declined. His vitiligo, neuropathy, and monoclonal gammopathy remain stable under surveillance at 4 years without pharmacotherapy. <h3>Conclusions:</h3> POEMS syndrome should be suspected in any patient with new onset of vitiligo in the presence of an underlying polyneuropathy and a monoclonal plasma cell proliferative disorder. <b>Disclosure:</b> Dr. Landman has nothing to disclose. Dr. Escobar-Montealegre has nothing to disclose. Dr. Singh has nothing to disclose. Dr. Morales has nothing to disclose. Dr. Rossi has nothing to disclose.

WHEN TOPHACEOUS GOUT INVOLVES MULTIPLE ORGANS: CHALLENGES AND SOLUTIONS.

Uncontrolled chronic gout can lead to deposition of monosodium urate crystals, better known as tophi. Such depositions can involve several organ systems, including unusual locations such as the vertebrae. Nevertheless, certain complications, such as hypercalcemia, can arise because of tophi. Despite an aggressive intervention, hypercalcemia might not resolve spontaneously, as long as an ongoing inflammatory process secondary to gouty tophi is taking place. Herein, we present the case of a 62-year-old man with a long history of gouty tophi who presented for back pain and was found to have spinal cord involvement with PTH-independent hypercalcemia which only resolved with pegloticase therapy.

LBSAT130 Hypercalcemia In Pregnancy Due To CYP24A1 Mutation

Abstract Background The active form of vitamin D (1,25 OH2 vitamin D) is catabolized by a key enzyme 1,25 OH vitamin D-24 hydroxylase, which is encoded by the CYP24A1 gene. Loss of function mutation in the CYP24A1 leads to elevated levels of active vitamin D, causing PTH independent hypercalcemia with nephrolithiasis and nephrocalcinosis. Two phenotypic variants have been identified: idiopathic infantile hypercalcemia, which is a more severe form presenting in infancy, and a milder form with onset in adulthood as is this case. Pregnancy is known to initiate or worsen the hypercalcemia. Clinical Case A 27-year-old woman presented at 11 weeks gestation with hyperemesis, noted to have hypercalcemia calcium 15.7mg/dl (8.2 to 10.1 pg/ml), low PTH 2pg/ml (24 -85 pg/ml) with high serum 1,25 OHD 309pg/ml (nl 19.9-79.3 pg/ml). She had low PTHrp, normal ACE level, and negative TB testing. Pre-pregnancy calcium was normal (9.8mg/dl). She had a history of hypercalcemia in previous pregnancy (Calcium 13mg/dl) that ended in IUFD. Family history revealed nephrolithiasis in her sister, mother, and paternal aunt as well as a consanguineous marriage in our patient and her parents. Vitamin D metabolites evaluated via liquid chromatography showed low serum 24,25(OH)2D (0.29ng/ml nl N/A) and elevated 25OHD 138 ng/mL (20-80 ng/ml). Ratio of 25 (OH) Vit D to 24,25(OH)2D was 475.86 (values &amp;gt;80 indicate probable bi-allelic CYP24A1 deletion or mutation. Genetic test pending. Conclusion This case highlights the fact that patients with 24 hydroxylase deficiency may be normocalcemic with hypercalcemia unveiled during pregnancy due to increased 1alpha hydroxylase production by the placenta and kidneys as well as intake of prenatal vitamins containing calciferol. An index of suspicion for CYP24A1 mutation is needed in patients with high active vitamin D metabolites, high or normal calcium, low PTH, family history of kidney stones or worsening hypercalcemia in pregnancy. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

ODP110 Parathyroid Hormone Independent Hypercalcaemia Secondary to Granulomatous Inflammation: Could This Be Melioidosis?

Abstract Background Hypercalcemia has been described in patients with most granulomatous disorders, most commonly in sarcoidosis and tuberculosis, but never in melioidosis. Clinical Case A 45-year-old woman presented with two-day history of abdominal pain, nausea, lethargy and intermittent fevers during Darwin's wet season. Medications included daily methadone, diazepam and mirtazapine. On examination she was febrile with stable hemodynamics and left upper quadrant tenderness. Investigations revealed pancytopenia, deranged liver function tests with a cholestatic pattern, raised CRP of 53 (&amp;lt;5mg/L) and normal serum calcium. Blood cultures were negative but melioidosis serology was positive (indirect hemagglutination antibody (IHA) titer 1: 1280). Abdominal computed tomography demonstrated hepatosplenomegaly with peripheral splenic infarcts and a 7mm intrasplenic aneurysm, but no abscesses. PET showed no hypermetabolic lesions. After extensive investigation, she was treated for presumptive culture-negative melioidosis with intravenous meropenem. Clinically she improved despite gradual elevation in serum calcium which peaked at 3.31 (2.1-2.6mmol/L) five weeks after presentation. Initial biochemical investigations revealed suppressed PTH at 0.5 (1.4-9.1pmol/L), low 25-hydroxy-Vitamin D of 26 (50-150nmol/L), elevated phosphate at 2.43 (0.75-1.5mmol/L) and moderate renal impairment (eGFR 34mL/min/1.73m 2). Hypercalciuria was present with urine calcium to creatinine ratio of 812 (100-580mmol/mol). Her 1,25-dihydroxy-Vitamin D (calcitriol) was elevated at 219 (48-190pmol/L) suggestive of PTH-independent hypercalcemia. The patient remained asymptomatic of hypercalcemia and aggressive intravenous hydration produced minimal biochemical improvement. Renal impairment precluded bisphosphonate use. She was commenced on prednisolone 50mg while continuing intravenous meropenem. Serum calcium normalized in 10 days and prednisolone dose was gradually tapered. A liver biopsy was performed due to persistent liver derangement and histology showed granulomatous inflammation. She completed six weeks of antibiotics for melioidosis and was discharged on day 50, with a planned six months of eradication therapy. Outpatient follow-up demonstrated normal serum calcium after cessation of prednisolone with decreasing IHA titer (1: 320). We hypothesize that this case reflects PTH-independent hypercalcemia secondary to granulomatous inflammation, presumptively caused by melioidosis. The rise in calcium after commencement of antibiotics and normalization following initiation of glucocorticoid therapy, with no rebound post cessation, is consistent with successful therapy of an infection with granulomatous inflammation. Activated macrophages within granulomas have unregulated 1-alpha-hydroxylase expression which is thought to increase conversion of 25-hydroxy-Vitamin D to calcitriol and therefore increase intestinal calcium absorption. Treatment with glucocorticoids inhibits calcitriol synthesis leading to quick resolution of hypercalcemia. While use of glucocorticoids are commonplace in the management of granulomatous disease due to sarcoidosis, they have been increasingly recognized as an important risk factor for melioidosis, considered to result from suppression of innate immunity. However, use of glucocorticoids if required is not contraindicated once antibiotic therapy for melioidosis has commenced. Conclusion In areas where melioidosis is endemic, clinicians should be aware of hypercalcemia and the potential risks associated with its treatment. Presentation: No date and time listed

ODP645 A Rare Case of Extrapulmonary Sarcoidosis with Hypercalcemia as the Initial Presentation: A Diagnostic Conundrum

Abstract Introduction Sarcoidosis is a multi-system chronic granulomatous disease of unknown etiology with a wide array of manifestations. It most commonly affects the lungs. About 30% of the patients present with extra pulmonary sarcoidosis along with lung involvement and approximately 8% present with disease at extrapulmonary site without lung involvement. Here we present a case of asymptomatic extrapulmonary sarcoidosis that presented with hypercalcemia, later confirmed with an axillary node biopsy showing non-caseating granuloma. Case Presentation A 56-year-old male with a past medical history of renal insufficiency presented with an elevated Calcium (Ca) of 11mg/dL, asymptomatic otherwise. Further lab testing revealed a suppressed Parathyroid hormone (PTH) level of 2 pg/ml, Parathyroid hormone related protein (PTHrP) of 14pmol/L, normal 25-Hydroxy Vitamin D (27ng/ml), markedly elevated calcitriol (106 pg/ml) and 24-hour urinary Calcium (961mg/day). Patient also had renal insufficiency with a creatinine of 1.58mg/dL and glomerular filtration rate of 49ml/min/1.73m2. Angiotensin-converting enzyme (ACE) was also found to b elevated at 125units/L. Computed Tomography (CT)) chest showed scattered pulmonary nodules measuring as large as 7.9 mm, CT scan of abdomen revealed splenomegaly and bilateral non-obstructing renal calculi. A subsequent NM bone scan and X-ray bone survey were unremarkable. Patient's calcium levels progressively increased to a maximum of 13.3. A flow cytometry showed no immunophenotypic evidence of a lymphoproliferative disorder. Due to concern for malignancy, a PET scan was done which revealed small scattered hypermetabolic lymph nodes in bilateral external iliac chain and upper retroperitoneum. A solitary hypermetabolic 10mm right axillary lymph node was seen which was then biopsied. Biopsy report showed epitheloid non-necrotizing granuloma and fibrosis, thus confirming diagnosis of sarcoidosis. Patient was started on prednisone 10mg daily empirically before the biopsy results and repeat calcium in 2 months came back at 9.6mg/dl. He was then switched to a maintenance dose of 5 mg. Case Discussion Hypercalcemia is a common clinical laboratory abnormality with 90% of cases attributed to PTH-dependent hyperparathyroidism and malignancy. Although rare, chronic granulomatous diseases can cause a PTH-independent hypercalcemia through enhanced conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Sarcoidosis makes up only 1% of cases of hypercalcemia, making it very challenging to diagnose it as an etiology of hypercalcemia. Furthermore, hypercalcemia is rarely the initial presentation as it happened in our case. All cases of hypercalcemia must be thoroughly evaluated with PTH, 1,25-hydroxyvitamin D, and PTHrP to rule out common etiologies. Corticosteroids are the main stay of treatment of hypercalcemia in sarcoidosis. This case aims to shed light on sarcoidosis as an etiology of hypercalcemia, even though rare, for prompt diagnosis and management. Presentation: No date and time listed

ODP096 Hypercalcemia Secondary to Vitamin D Supplementation with Normal 25-Hydroxyvitamin D Level in an Elderly Female - Case Report

Abstract Case presentation A 92-year-old female with a history of heart failure, dementia (alert and oriented to time, place and person at baseline), osteoporosis and hypothyroidism presented to the emergency department with altered mental status and constipation. She was oriented to time and person only. Labs included: WBC count 6.2 (4 - 11k/mm cu), Creatinine 1.23 (0.6 - 1.2 mg/dL), Calcium 12.8 (8.6 - 10.3 mg/dL), Albumin 3.9 (3.5 - 5.7 g/dL) and Glucose 94 (70 - 99 mg/dL). CT head showed no acute abnormality. Medication reconciliation revealed that she was taking Cholecalciferol (Vitamin D3) 2000 units daily, which was held. Intravenous fluids were started and further workup was done: PTH &amp;lt; 6 (12 - 88 pg/mL), serum 25 Hydroxyvitamin D 45.1 (30 - 100 ng/mL), serum 1, 25 Dihydroxyvitamin D 79 (19.9 - 79.3 pg/ml) and PTHrP 2.6 (0 - 3.4 pmol/L). Endocrinology was consulted for management of PTH independent hypercalcemia and recommended Zoledronic acid. Serum calcium levels normalized with bisphosphonate therapy and withholding of Vitamin D3 supplementation in addition to symptomatic improvement. Repeat 1-25-Dihydroxyvitamin D level decreased to 38.3 pg/mL while repeat PTH normalized at 20.8 pg/mL. Subsequently, serum calcium levels remained within normal limits, and she was discharged. Discussion Vitamin D, the "sunshine Vitamin", has claimed much fame and popularity for its varied benefits. With a growing user base, there is concern for potential adverse effects, primarily involving the population with an underlying propensity for hypercalcemia. According to the NIH, the safe upper limit of daily Vitamin D intake is 4000 IU; however, for adults &amp;gt; 70 years of age, 800 IU is the recommended dose. Our patient was taking 2000 IU (almost 2.5 times the recommended dose) of Vitamin D3, the most potent form which raises Vitamin D levels twice as fast as Vitamin D2. In addition, her serum 1,25 Dihydroxyvitamin D levels normalized when supplementation was withheld pointing to a cause - effect relationship and thus, effectively ruling out an endogenous source. Moreover, other factors such as prolonged duration of supplement intake, advanced age, immobility, osteoporosis and hypothyroidism contributed to her hypercalcemia. Current review of literature suggests that serum concentrations of 25-Hydroxyvitamin D at which hypercalcemia arises remains undefined. With this case, we wish to emphasize that a holistic approach should be utilized to advise patients regarding Vitamin D supplementation considering pre-existing risk factors for hypercalcemia, concurrent medical conditions, diet and functional status. Although current guidelines detail the ideal dosage and duration of Vitamin D supplementation therapy for different sectors of population, streamlining and individualizing therapy to mitigate potential harm to patients is pivotal. Presentation: No date and time listed

ODP122 Recurrent Episodes of Hypercalcemia due to Disseminated Mycobacterium Avium Complex Infection-related Immune Reconstitution Inflammatory Syndrome

Abstract Introduction Immune reconstitution inflammatory syndrome (IRIS) may occur in patients with acquired immunodeficiency syndrome (AIDS) following initiation of antiretroviral therapy (ART) due to exacerbation of preexisting infectious process, such as disseminated mycobacterium avium complex (dMAC). This type of inflammatory process may be associated with granuloma formation and 1,25(OH) 2 vitamin D-mediated hypercalcemia. Hypercalcemia typically is controlled with a single dose of intravenous bisphosphonate or a two to four-week course of glucocorticoid, in addition to antibiotics for dMAC and ART. Here we present a case of IRIS-associated hypercalcemia related to dMAC resistant to intravenous bisphosphonate therapy and an extended glucocorticoid course. Case presentation A 30-year-old man with AIDS with CD4 count 4 cells/mm^3 (441-2,156) was admitted with subacute fevers, chills, and cough one month after starting ART. Cultures drawn during admission were positive for MAC and he was started on therapy for dMAC with ethambutol and azithromycin. Seven months after starting ART, he was readmitted with weakness and fatigue and found to have calcium 13.5 mg/dL (8.6-10.4), albumin 3.9 g/dL (3.9-5. 0), creatinine 1.40 mg/dL (0.6-1.3), CD4 count 80 cells/mm3. Further workup revealed intact PTH 2 pg/mL (11-51), 25-OH vitamin D 38 ng/mL (20-50), 1,25(OH) 2 vitamin D 171 pg/mL (19.9-79.3), PTHrP &amp;lt; 2. 0 pmol/L (0. 0-2.3), suggestive of PTH-independent hypercalcemia mediated by 1,25(OH) 2 vitamin D. CT scan of the chest showed multiple cavitary lesions, ground glass nodularity, and diffuse lymphadenopathy. He was treated with intravenous fluids, zoledronic acid 4mg, and continued ART and antibiotics for MAC. On discharge calcium was 9.5 mg/dL. He had recurrence of 1,25(OH) 2 vitamin D-mediated hypercalcemia (calcium 13.6mg/dL) 11 months after starting ART, which was controlled with intravenous fluid and prednisone 60mg tapered over 6 weeks. He then had recurrence of hypercalcemia 13 and 16 months after starting ART, each resolved with intravenous fluids and repeat prolonged prednisone courses. Testing for other infectious causes of granulomatous disease including Cryptococcus, Histoplasma, Mycoplasma tuberculosis was negative during multiple presentations. At 13 months, his CD4 count was 214 cells/mm^3 and repeat CT scan of the chest showed improvement in size of cavitary nodule and ground glass nodularity. Conclusion IRIS related to dMAC is an uncommon cause of 1,25(OH)2 vitamin D-mediated hypercalcemia. Multiple recurrences of hypercalcemia and the need for extended courses of glucocorticoid despite improvement of underlying infectious process has not previously been reported. Presentation: No date and time listed

RF30 | PSAT177 A Case of Hypercalcemia Related to Immune Checkpoint Inhibitor-Induced Sarcoidosis-like Granuloma

Abstract Background Immune checkpoint inhibitor (ICI) is an essential part of the treatment of various advanced cancers, but its use can be associated with a number of side effects, including hypercalcemia. The mechanism through which hypercalcemia arises is not well established. One proposed mechanism is through sarcoidosis-like reactions. Here we present an illustrative case. Clinical Case A 75-year-old female with past medical history notable for stage IV endometrial adenocarcinoma treated with surgery plus adjuvant chemotherapy, presently on pembrolizumab for 9 months, hypertension, and diabetes was admitted with generalized fatigue, difficulty ambulating, slow movements, and slow speech. Stroke was ruled out with negative neurologic imaging. Blood work revealed elevated calcium 13.8 mg/dL (8.6-10.4 mg/dL) and ionized calcium 1.64 mmol/L (1.09-1.29 mmol/L). Additional workup showed suppressed PTH 7 pg/mL (11-51 pg/mL), 25-OH vitamin D 19 ng/mL (20-50 ng/mL), elevated 1,25(OH)2 vitamin D of 114 pg/mL (19.9-79.3 pg/mL), elevated angiotensin converting enzyme (ACE) level 90 U/L (12-69 U/L), and normal PTHrP, suggestive of PTH-independent hypercalcemia mediated by 1,25(OH)2D as seen in sarcoidosis. Two months prior to admission and seven months after starting pembrolizumab, surveillance CT found improvement in tumor burden but new intrathoracic lymphadenopathy. Lymph node biopsy via bronchoscopy identified non-caseating granulomas suggestive of a sarcoidosis-like reaction. The patient's moderate hypercalcemia was treated with intravenous fluids, calcitonin, and zoledronic acid 4 mg with normalization of calcium levels. Glucocorticoid therapy was initially deferred to avoid counteracting the effect of pembrolizumab, however prednisone 10 mg daily was started 1 month after discharge when calcium rose again to 11.1 mg/dL. Prednisone was tapered off over 8 weeks as her calcium and 1,25(OH)2D levels normalized. She then restarted pembrolizumb, but after the third month she had recurrence of hypercalcemia (calcium 10.8 mg/dL) with elevated 1,25(OH)2D (89.5 pg/mL). She was again treated with prednisone 10 mg daily which was tapered off over 6 weeks with resolution of hypercalcemia. Her calcium levels remained normal off pembrolizumab. The temporal correlation in our case strongly suggests that ICI administration caused sarcoidosis-like granulomas and hypercalcemia. Conclusion Immune checkpoint inhibitors are known to occasionally cause hypercalcemia, although the mechanisms are not well established. In our case, moderate hypercalcemia was likely caused by ICI-induced sarcoid-like granulomas that responded promptly to glucocorticoids and interruption of ICI-therapy. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 1:12 p.m. - 1:17 p.m.

Abstract #1161902: A case of 1,25-OH vitamin D mediated hypercalcemia due to extrarenal 1-hydroxylase activity in a patient with disseminated histoplasmosis: challenges in clinical diagnosis and management

Endogenous overproduction of 1,25-OH vitamin D is an uncommon cause PTH-independent hypercalcemia, and extra-renal 1-hydroxylase activity due to disseminated histoplasmosis in a non-endemic location an uncommon cause of 1,25-OH vitamin D mediated hypercalcemia. The case presented several diagnostic and therapeutic challenges. For example, corticosteroids specifically target the pathophysiology of absorptive hypercalcemia, but were contraindicated in disseminated fungal disease. Empiric use of anti-resorptive therapy was ineffective and likely contributed to the development of hypocalcemia subsequent to initiation of anti-fungal therapy.

Approach to Hypercalcemia

Hypercalcemia is a presentation commonly encountered in the clinical setting. Due to its vast differential diagnosis, a systematic approach is necessary when approaching patients with hypercalcemia. This article presents a simple, yet thorough approach to help clinicians determine the etiology of their patients' hypercalcemia. The main components of history taking, physical examination, and laboratory investigations for patients with hypercalcemia are highlighted. Emphasis is put on the importance of determining whether the hypercalcemia is associated with elevated or inappropriately normal parathyroid hormone (PTH) levels or not. The main etiologies of PTH-dependent hypercalcemia and PTH-independent hypercalcemia are explored. Primary hyperparathyroidism and hypercalcemia secondary to malignancy are highlighted as together, they make up 90% of hypercalcemia cases. A presentation of the management principles of hypercalcemia is also provided.