Sheehan, Michael T.

Abstract Elevated 1,25-dihydroxyvitamin D (1,25(OH)2D) is a rare cause of non–parathyroid hormone (PTH)–mediated hypercalcemia seen in granulomatous disease, malignancy (most often lymphoma), or genetic mutations. Therapeutic options are limited. We report the case of a 67-year-old White man with nonmalignant, nongranulomatous, 1,25(OH)2D-mediated hypercalcemia treated successfully with cinacalcet. At presentation, he had hypercalcemia, hypercalciuria with recurrent nephrolithiasis, low PTH, elevated 1,25(OH)2D, and normal 25-hydroxyvitamin D. The 1,25(OH)2D levels were inappropriate in the setting of hypercalcemia with low PTH. Evaluations for sarcoidosis, tuberculosis, and malignancy were negative. Genetic testing showed biallelic variants in the CYP24A1 gene. Cinacalcet was trialed and showed normalization of calcium levels. On cinacalcet, biochemical indices showed a slight increase in 1,25(OH)2D and 24-hour urine calcium and mild decrease in PTH. He briefly experienced symptomatic hypocalcemia that resolved after reducing cinacalcet dose. Due to limited symptomatic benefit, he opted to stop cinacalcet. Additional follow-up showed intermittently elevated serum calcium levels after stopping cinacalcet, most recently 10.3 mg/dL. Cinacalcet may be a therapeutic option in nonmalignant, 1,25(OH)2D-mediated hypercalcemia. Further study is necessary to confirm efficacy, understand risks and benefits, and elucidate mechanism(s) of action.

Abstract Disclosure: S. Mohan: None. M.T. Sheehan: None. P.J. Tebben: None. R.A. Wermers: None. Introduction: Elevated 1,25-dihydroxyvitamin D (1,25(OH)2D) is a rare cause of non-parathyroid hormone (PTH) mediated hypercalcemia. An increase in the activating enzyme 1-alpha hydroxylase is seen in granulomatous diseases and lymphoma, while mutations in the CYP24A1 gene leads to reduced catabolism of 1,25(OH)2D. Cinacalcet has been shown to successfully treat 1,25(OH)2D-mediated hypercalcemia of malignancy. Extrapolating this, we report 3 patients with non-malignant 1,25(OH)2D-mediated hypercalcemia treated with cinacalcet. Case Series: The patients (2 male and 1 female) were 55-71 years old. At presentation to our clinic, all had hypercalcemia with serum calcium concentrations between 10.6-11.5 mg/dL (normal, 8.8-10.2 mg/dL). PTH ranged between 16-35 pg/ml (normal 15-65 pg/ml), PTH-related peptide was normal in all patients, 25-hydroxyvitamin D was 32-51 ng/ml, and 1,25(OH)2D was inappropriately normal between 31-77 pg/ml (normal 18-78 pg/mL) in the setting of hypercalcemia and chronic kidney disease in 2 patients with estimated glomerular filtration rates 35-42 ml/min. Other causes of hypercalcemia including sarcoidosis, tuberculosis and malignancy were ruled out. The female patient had hypercalciuria (288 mg/24 hours) without nephrolithiasis and both male patients had severe hypercalciuria (400-660 mg/24 hours) with recurrent nephrolithiasis. One male patient had biallelic variants in the CYP24A1 gene, while the other male patient was suspected to have similar mutations, but not identified on genetic testing. The female patient with a PTH of 35 pg/mL on our initial measurement had documented 1,25(OH)2D level of 82 pg/mL with PTH <20 pg/mL while previously hypercalcemic. Upon cinacalcet initiation all patients demonstrated normalization of calcium levels (8.6-9.5 mg/dl) with doses between 30-90 mg daily. The patient with CYP24A1 gene mutations experienced symptomatic hypocalcemia with calcium of 8.1 mg/dL requiring dose reduction and eventual discontinuation of cinacalcet due to limited clinical benefit. There were no consistent changes in 24-hour urine calcium or fractional excretion of calcium. Levels of 1,25(OH)2D increased and PTH decreased on cinacalcet while serum calcium levels were maintained within normal range, including 2 subjects with continued normocalcemia after 2 years of therapy. Conclusion: Cinacalcet may be a therapeutic option in non-malignant 1,25(OH)2D-mediated hypercalcemia. Further evaluation is needed to confirm efficacy, understand risks and benefits, and elucidate potential mechanisms of action. Mild decrease in PTH may lead to reduced skeletal calcium efflux while the maintenance of normocalcemia despite rising 1,25(OH)2D, which was also seen in our reported patients with malignant 1,25(OH)2D-mediated hypercalcemia, suggests cinacalcet may decrease intestinal calcium absorption. Presentation: Saturday, June 17, 2023

This study examined the plasma FFA, intramuscular long chain acylcarnitine (LCAC) fatty acids and imTG stores during basal and hyperinsulinemic conditions. Methods: Endurance trained (TR, n=8) and sedentary individuals (SED, n=15) were studied under overnight postabsorptive and euglycemic hyperinsulinemic clamp (1.0mU·kg FFM −1 ·min −1 ) conditions. FFA kinetics were measured using a 5‐h infusion of [U‐ 13 C]oleate, for labeling of imTG and LCAC pools. Muscle biopsies were performed to measure imTG and imLCAC enrichment at 1400 h after 5‐h of infusion. imTG concentrations were greater in TR than SED individuals (P<0.01). Table SED Trained Saline** Clamp Saline** Clamp plasma oleate FFA (mpe) 0.210±0.018* 0.271±0.036* 0.189±0.026* 0.361±0.050* imLCAC (mpe) 0.025±0.003 0.005±0.002 0.016±0.005 0.002±0.002 imTG (mpe) 0.018±0.003† 0.011±0.001† 0.024±0.004† 0.013±0.001† P<0.001 saline vs. clamp; *P<0.000 between compartment (plasma vs. imLCAC vs. imTG); †P<0.000 imLCAC and imTG Methods: Endurance trained (TR, n=8) and sedentary individuals (SED, n=15) were studied under overnight postabsorptive and euglycemic hyperinsulinemic clamp (1.0mU·kg FFM −1 ·min −1 ) conditions. FFA kinetics were measured using a 5‐h infusion of [U‐ 13 C]oleate, for labeling of imTG and LCAC pools. Muscle biopsies were performed to measure imTG and imLCAC enrichment at 1400 h after 5‐h of infusion. Conclusion: The imTG contributes more to the imLCAC pools than plasma FFA both in the basal and hyperinsulinemic state, and hyperinsulinemia suppressed oleate FFA entry into the imLCAC pools, more so in trained than untrained adults. Muscle fatty acid oxidation is largely via obligatory cycling of fatty acids through imTG or other intracellular complex lipid pools.

We hypothesized that insulin alters plasma free fatty acid (FFA) trafficking into intramyocellular (im) long-chain acylcarnitines (imLCAC) and triglycerides (imTG). Overnight-fasted adults ( n = 41) received intravenous infusions of [U-13C]palmitate (0400–0900 h) and [U-13C]oleate (0800–1400 h) to label imTG and imLCAC. A euglycemic-hyperinsulinemic (1.0 mU·kg fat-free mass−1·min−1) clamp (0800–1400 h) and two muscle biopsies (0900 h, 1400 h) were performed. The patterns of [U-13C]palmitate incorporation into imTG-palmitate and palmitoylcarnitine were similar to those we reported in overnight postabsorptive adults (saline control); the intramyocellular palmitoylcarnitine enrichment was not different from and correlated with imTG-palmitate enrichment for both the morning ( r = 0.38, P = 0.02) and afternoon ( r = 0.44, P = 0.006) biopsy samples. Plasma FFA concentrations, flux, and the incorporation of plasma oleate into imTG-oleate during hyperinsulinemia were ∼1/10th of that observed in the previous saline control studies ( P < 0.001). At the time of the second biopsy, the enrichment in oleoylcarnitine was <25% of that in imTG-oleate and was not correlated with imTG-oleate enrichment. The intramyocellular nonesterified fatty acid-palmitate-to-imTG-palmitate enrichment ratio was greater ( P < 0.05) in women than men, suggesting that sex differences in intramyocellular palmitate trafficking may occur under hyperinsulinemic conditions. We conclude that plasma FFA trafficking into imTG during hyperinsulinemia is markedly suppressed, and these newly incorporated FFA fatty acids do not readily enter the LCAC preoxidative pools. Hyperinsulinemia does not seem to inhibit the entry of fatty acids from imTG pools that were labeled under fasting conditions, possibly reflecting the presence of two distinct imTG pools that are differentially regulated by insulin.