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Item Clinical utility of simultaneous quantitation of 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D by LC-MS/MS involving derivatization with DMEQ-TAD(The Endocrine Society, 2014-07) Kaufmann, Martin; Gallagher, J. Christopher; Peacock, Munro; Schlingmann, Karl-Peter; Konrad, Martin; DeLuca, Hector F.; Sigueiro, Rita; Lopez, Borja; Mourino, Antonio; Maestro, Miguel; St-Arnaud, René; Finkelstein, Joel S.; Cooper, Donald P.; Jones, Glenville; Department of Medicine, IU School of MedicineCONTEXT: The discovery of hypercalcemic diseases due to loss-of-function mutations in 25-hydroxyvitamin D-24-hydroxylase has placed a new demand for sensitive and precise assays for 24,25-dihydroxyvitamin D [24,25-(OH)2D]. OBJECTIVE: We describe a novel liquid chromatography and tandem mass spectrometry-based method involving derivatization with DMEQ-TAD {4-[2-(6,7-dimethoxy-4-methyl-3,4-dihydroquinoxalinyl)ethyl]-1,2,4-triazoline-3,5-dione} to simultaneously assay multiple vitamin D metabolites including 25-hydroxyvitamin D (25-OH-D) and 24,25-(OH)2D using 100 μL of serum with a 5-minute run time. DESIGN: The assay uses a newly synthesized internal standard d6-24,25-(OH)2D3 enabling the quantitation of 24,25-(OH)2D3 as well as the determination of the ratio of 25-OH-D3 to 24,25-(OH)2D3, a physiologically useful parameter. SETTING: We report data on more than 1000 normal and disease samples involving vitamin D deficiency or hypercalcemia in addition to studies involving knockout mouse models. RESULTS: The assay showed good correlation with samples from quality assurance schemes for 25-OH-D (25-OH-D2 and 25-OH-D3) determination (-2% to -5% bias) and exhibited low inter- and intraassay coefficients of variation (4%-7%) and lower limits of quantitation of 0.25-0.45 nmol/L. In clinical studies, we found a strong correlation between serum levels of 25-OH-D3 and 24,25-(OH)2D3 (r(2) = 0.80) in subjects over a broad range of 25-OH-D3 values and a marked lack of production of 24,25-(OH)2D3 below 25 nmol/L of 25-OH-D. The ratio of 25-OH-D3 to 24,25-(OH)2D3, which remained less than 25 in vitamin D-sufficient subjects (serum 25-OH-D < 50 nmol/L) but was greatly elevated (80-100) in patients with idiopathic infantile hypercalcemia. CONCLUSIONS: The new method showed good utility in clinical settings involving vitamin D deficiency; supplementation with vitamin D and idiopathic infantile hypercalcemia, as well as in animal models with ablation of selected cytochrome P450-containing enzymes involved in vitamin D metabolism.Item Disorders of Calcium Metabolism: Hypocalcemia and Hypercalcemia(Cureus, 2021-01-01) Tinawi, Mohammad; Medicine, School of MedicineCalcium (Ca+2) is a divalent cation that plays a critical role in numerous body functions such as skeletal mineralization, signal transduction, nerve conduction, muscle contraction, and blood coagulation. Ca+2 metabolism is linked to magnesium (Mg+2) and phosphate metabolism. Ca+2 homeostasis is dependent on intestinal absorption, bone turnover, and renal reabsorption. The hormonal regulators of these processes are the parathyroid hormone (PTH), calcitriol {1,25-dihydroxyvitamin D [1,25(OH)2D]}, and serum ionized Ca+2. Cloning of the Ca+2-sensing receptor (CaSR) has greatly advanced the understanding of Ca+2 metabolism. Disorders of Ca+2 metabolism are easily recognized because Ca+2 is included in routine chemistry panels. Measurement of ionized Ca+2 is the preferred way to ascertain the diagnosis of hypocalcemia and hypercalcemia.Item Parathyroid hormone-related peptide induced hypercalcemia of pregnancy due to mammary hyperplasia(Oxford University Press, 2024-06-20) Jodeh, Wade; Sparks, Payton J.; Higgins, Jasmine M.; Tom, Alan; Anilovich, Natanie; Moit, Harley; Korff, Lisa; Hadad, Ivan; Wang, Xiaoyan; Imel, Erik A.; Donegan, Diane M.; Surgery, School of MedicineMaternal Parathyroid Hormone-related Protein (PTHrP) is involved in the placental transport of calcium. Autonomous overproduction of PTHrP is a rare cause of hypercalcemia in pregnancy. Prior cases of PTHrP-induced hypercalcemia in pregnancy have been managed with either dopamine agonists, fetal delivery, termination of pregnancy, or mastectomy. However, PTHrP level normalization following mastectomy has not previously been documented. Herein, we present a 39-year-old female hospitalized at 19 weeks of gestation for acute encephalopathy due to PTHrP induced hypercalcemic crisis (calcium 15.8 mg/dL, PTHrp 46.5 pmol/L [normal 0-3.4]). Mammary hyperplasia resulting in gigantomastia significantly impaired her ability to ambulate and perform activities of daily living. She remained hypercalcemic during hospitalization despite aggressive hydration, calcitonin, and 2 weeks of dopamine agonist treatment. Bisphosphonate therapy was not administered due to pregnancy and potential effects on the fetus. Our patient underwent bilateral mastectomy along with excision of a large axillary mass. The pathology of all three specimens revealed mammary stromal hyperplasia. PTHrP was undetectable on post-op day 2 and calcium normalized by post-op day 3. At discharge, she was able to ambulate independently. To our knowledge, this is the first reported case of PTHrP induced hypercalcemia related to gigantomastia, documenting resolution of hypercalcemia, and PTHrP levels following mastectomy. Mastectomy is a potential option in the second trimester for pregnant patients with PTHrP induced severe hypercalcemia due to gigantomastia, refractory to treatment with dopamine agonist therapy.Item Relation of hyperparathyroidism and hypercalcemia to bipolar and psychotic disorders(Taylor & Francis, 2022-04-08) Enyi, Chioma O.; D’Souza, Brendan; Barloon, Linda; Ilonze, Onyedika J.; Chacko, Ranjit; Medicine, School of MedicinePrimary hyperparathyroidism (PHPT) is characterized by hypercalcemia and an elevated level of serum parathyroid hormone. PHPT leads to hypercalcemia and presents with renal, skeletal, and neuropsychiatric symptoms. Neuropsychiatric manifestations of PHPT such as psychotic, depressive, and anxiety disorders are rare. Delirium may also be present in patients with PHPT. Parathyroidectomy is the treatment of choice for patients with physically symptomatic PHPT, but it remains unclear if parathyroidectomy is indicated for its psychiatric manifestations. It is unclear if parathyroidectomy should be performed as a treatment for medication-refractory psychiatric symptoms or deferred until psychiatric symptoms have been better controlled. We present two cases of hyperparathyroidism (HPT)-associated hypercalcemia-one with lithium-associated HPT-in which psychiatric manifestations resolved with parathyroidectomy.