Uric Acid in Primary Hyperparathyroidism: Marker, Consequence, or Bystander?
Abstract
1. Introduction
2. Uric Acid Metabolism, Excretion, and Definition of Hyperuricemia
2.1. Uric Acid Metabolism and Excretion
2.2. Definiton of Hyperuricemia
2.3. Clinical Manifestations Associated with Hyperuricemia
3. Primary Hyperparathyroidism
3.1. Primary Hyperparathyroidism Definition and PTH Actions
3.1.1. PTH Actions in the Kidney
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- Promoting the expression and activity of apical channel TRPV5 (transient receptor potential vanilloid member 5), increasing calcium entry into tubular cells;
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- Regulating Claudin-14, a tight junction protein, involved in calcium paracellular transport in the ascending limb of Henle’s loop (TAL) [46];
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- Reducing sodium reabsorption by the Na/Cl cotransporter (NCC) in the proximal tubule, indirectly promoting the TRPV5 activity [47];
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3.1.2. PTH Actions in Bone
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- Activating PTH1R on the osteoblastic surface stimulates RANKL (receptor activator of nuclear factor kappa-Β ligand) production and inhibits OPG (osteoprotegerin), thereby stimulating differentiation and osteoclastic activity [51].
3.1.3. PTH Actions in the Gut
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- -
3.2. Clinical Manifestation Associated with Primary Hyperparathyroidism
4. Clinical Evidence of the Association Between Primary Hyperparathyroidism and Uric Acid
5. Possible Mechanisms of Hyperuricemia in Primary Hyperparathyroidism
5.1. Interaction Between PTH and Uric Acid
5.2. Interaction Between Serum Calcium and Uric Acid
5.3. Chronic Inflammation in Hyperuricemia and Hypercalcemia
5.4. Uric Acid and Bone Turnover
6. Clinical Implications and Future Perspectives
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
PHPY | Primary hyperparathyroidism |
BMD | Bone mineral density |
UA | Uric acid |
CKD | Chronic kidney disease |
MSU | Monosodium urate |
GLUT9 | Glucose transporter 9 |
OAT1/3 | Organic transporter 1/3 |
URAT1 | Urate anion transporter 1 |
ABCG2 | ATP-binding cassette super-family G member 2 |
TRPV5 | Transient receptor potential cation channel subfamily V member 5 |
NCX1 | Sodium/calcium exchanger 1 |
PMCA1b | Plasma membrane calcium ATPase 1b |
TAL | Ascending limb of Henle’s loop |
NCC | Na/Cl cotransporter |
NaPi-II | Sodium-dependent phosphate transport protein 2 |
RANKL | Receptor activator of nuclear factor kappa-Β ligand |
OPG | Osteoprotegerin |
RANK | Receptor activator of nuclear factor κ B |
TRPV6 | Transient receptor potential vanilloid subfamily member 6 |
LVH | Left ventricular hypertrophy |
NHANES | National Health and Nutrition Examination Survey |
BMI | Body mass index |
ROS | Reactive oxygen species |
CaSR | Calcium-sensing receptor |
NF- κB | Nuclear factor kappa-light-chain-enhancer of activated B cells |
MAPK | Mitogen-activated protein kinases |
IL-1β | Interleukin-1β |
IL-6 | Interleukin-6 |
IL-8 | Interleukin-8 |
TNF-α | Tumor necrosis factor-alpha |
IL-1Ra | Interleukin-1 receptor antagonist |
References
- Bilezikian, J.P.; Bandeira, L.; Khan, A.; Cusano, N.E. Hyperparathyroidism. Lancet 2018, 391, 168–178. [Google Scholar] [CrossRef]
- Cipriani, C.; Bilezikian, J.P. Three Generational Phenotypes of Sporadic Primary Hyperparathyroidism: Evolution Defined by Technology. Lancet Diabetes Endocrinol. 2019, 7, 745–747. [Google Scholar] [CrossRef]
- Ponticelli, C.; Podestà, M.A.; Moroni, G. Hyperuricemia as a Trigger of Immune Response in Hypertension and Chronic Kidney Disease. Kidney Int. 2020, 98, 1149–1159. [Google Scholar] [CrossRef] [PubMed]
- Yanai, H.; Adachi, H.; Hakoshima, M.; Katsuyama, H. Molecular Biological and Clinical Understanding of the Pathophysiology and Treatments of Hyperuricemia and Its Association with Metabolic Syndrome, Cardiovascular Diseases and Chronic Kidney Disease. Int. J. Mol. Sci. 2021, 22, 9221. [Google Scholar] [CrossRef] [PubMed]
- Zheng, L.; Zhu, Y.; Ma, Y.; Zhang, H.; Zhao, H.; Zhang, Y.; Yang, Z.; Liu, Y. Relationship between Hyperuricemia and the Risk of Cardiovascular Events and Chronic Kidney Disease in Both the General Population and Hypertensive Patients: A Systematic Review and Meta-Analysis. Int. J. Cardiol. 2024, 399, 131779. [Google Scholar] [CrossRef]
- Maloberti, A.; Mengozzi, A.; Russo, E.; Cicero, A.F.G.; Angeli, F.; Agabiti Rosei, E.; Barbagallo, C.M.; Bernardino, B.; Bombelli, M.; Cappelli, F.; et al. The Results of the URRAH (Uric Acid Right for Heart Health) Project: A Focus on Hyperuricemia in Relation to Cardiovascular and Kidney Disease and Its Role in Metabolic Dysregulation. High Blood Press. Cardiovasc. Prev. 2023, 30, 411–425. [Google Scholar] [CrossRef]
- Newcombe, D.S. Endocrinopathies and Uric Acid Metabolism. Semin. Arthritis Rheum. 1972, 2, 281–300. [Google Scholar] [CrossRef] [PubMed]
- Scott, J.T.; Bywaters, E.G.L.; Dixon, A.S.J. Association of Hyperuricaemia and Gout with Hyperparathyroidism. Br. Med. J. 1964, 1, 1070–1073. [Google Scholar] [CrossRef]
- Ponvilawan, B.; Charoenngam, N.; Ungprasert, P. Primary Hyperparathyroidism Is Associated with a Higher Level of Serum Uric Acid: A Systematic Review and Meta-Analysis. Int. J. Rheum. Dis. 2020, 23, 174–180. [Google Scholar] [CrossRef]
- Costa, T.E.M.; Lauar, J.C.; Innecchi, M.L.R.; Coelho, V.A.; Moysés, R.M.A.; Elias, R.M. Hyperuricemia Is Associated with Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease. Int. Urol. Nephrol. 2022, 54, 2255–2261. [Google Scholar] [CrossRef]
- Hui, J.Y.; Choi, J.W.J.; Mount, D.B.; Zhu, Y.; Zhang, Y.; Choi, H.K. The Independent Association between Parathyroid Hormone Levels and Hyperuricemia: A National Population Study. Arthritis Res. Ther. 2012, 14, R56. [Google Scholar] [CrossRef]
- Sugimoto, R.; Watanabe, H.; Ikegami, K.; Enoki, Y.; Imafuku, T.; Sakaguchi, Y.; Murata, M.; Nishida, K.; Miyamura, S.; Ishima, Y.; et al. Down-Regulation of ABCG2, a Urate Exporter, by Parathyroid Hormone Enhances Urate Accumulation in Secondary Hyperparathyroidism. Kidney Int. 2017, 91, 658–670. [Google Scholar] [CrossRef] [PubMed]
- Almqvist, E.G.; Bondeson, A.G.; Bondeson, L.; Svensson, J. Increased Markers of Inflammation and Endothelial Dysfunction in Patients with Mild Primary Hyperparathyroidism. Scand. J. Clin. Lab. Investig. 2011, 71, 139–144. [Google Scholar] [CrossRef] [PubMed]
- Christensen, M.H.E.; Fenne, I.S.; Nordbø, Y.; Varhaug, J.E.; Nygård, K.O.; Lien, E.A.; Mellgren, G. Novel Inflammatory Biomarkers in Primary Hyperparathyroidism. Eur. J. Endocrinol. 2015, 173, 9–17. [Google Scholar] [CrossRef]
- Weinman, E.J.; Eknoyan, G.; Suki, W.N. The Influence of the Extracellular Fluid Volume on the Tubular Reabsorption of Uric Acid. J. Clin. Investig. 1975, 55, 283–291. [Google Scholar] [CrossRef]
- Carroll, R.; Matfin, G. Review: Endocrine and Metabolic Emergencies: Hypercalcaemia. Ther. Adv. Endocrinol. Metab. 2010, 1, 225–234. [Google Scholar] [CrossRef] [PubMed]
- Bilezikian, J.P.; Khan, A.A.; Silverberg, S.J.; Fuleihan, G.E.H.; Marcocci, C.; Minisola, S.; Perrier, N.; Sitges-Serra, A.; Thakker, R.V.; Guyatt, G.; et al. Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop. J. Bone Miner. Res. 2022, 37, 2293–2314. [Google Scholar] [CrossRef]
- Vescini, F.; Borretta, G.; Chiodini, I.; Boniardi, M.; Carotti, M.; Castellano, E.; Cipriani, C.; Eller-Vainicher, C.; Giannini, S.; Iacobone, M.; et al. Italian Guidelines for the Management of Sporadic Primary Hyperparathyroidism. Endocr. Metab. Immune Disord. Drug Targets 2023, 24, 991–1006. [Google Scholar] [CrossRef]
- Wilhelm, S.M.; Wang, T.S.; Ruan, D.T.; Lee, J.A.; Asa, S.L.; Duh, Q.Y.; Doherty, G.M.; Herrera, M.F.; Pasieka, J.L.; Perrier, N.D.; et al. The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism. JAMA Surg. 2016, 151, 959–968. [Google Scholar] [CrossRef]
- Jin, M. Uric Acid, Hyperuricemia and Vascular Diseases. Front. Biosci. 2012, 17, 656. [Google Scholar] [CrossRef]
- Maiuolo, J.; Oppedisano, F.; Gratteri, S.; Muscoli, C.; Mollace, V. Regulation of Uric Acid Metabolism and Excretion. Int. J. Cardiol. 2016, 213, 8–14. [Google Scholar] [CrossRef] [PubMed]
- Keenan, R.T. The Biology of Urate. Semin. Arthritis Rheum. 2020, 50, S2–S10. [Google Scholar] [CrossRef]
- Bobulescu, I.A.; Moe, O.W. Renal Transport of Uric Acid: Evolving Concepts and Uncertainties. Adv. Chronic Kidney Dis. 2012, 19, 358–371. [Google Scholar] [CrossRef]
- Hoque, K.M.; Dixon, E.E.; Lewis, R.M.; Allan, J.; Gamble, G.D.; Phipps-Green, A.J.; Halperin Kuhns, V.L.; Horne, A.M.; Stamp, L.K.; Merriman, T.R.; et al. The ABCG2 Q141K Hyperuricemia and Gout Associated Variant Illuminates the Physiology of Human Urate Excretion. Nat. Commun. 2020, 11, 2767. [Google Scholar] [CrossRef]
- Eckenstaler, R.; Benndorf, R.A. The Role of ABCG2 in the Pathogenesis of Primary Hyperuricemia and Gout—An Update. Int. J. Mol. Sci. 2021, 22, 6678. [Google Scholar] [CrossRef] [PubMed]
- Hosomi, A.; Nakanishi, T.; Fujita, T.; Tamai, I. Extra-Renal Elimination of Uric Acid via Intestinal Efflux Transporter BCRP/ABCG2. PLoS ONE 2012, 7, e30456. [Google Scholar] [CrossRef] [PubMed]
- Matsuo, H.; Tsunoda, T.; Ooyama, K.; Sakiyama, M.; Sogo, T.; Takada, T.; Nakashima, A.; Nakayama, A.; Kawaguchi, M.; Higashino, T.; et al. Hyperuricemia in Acute Gastroenteritis Is Caused by Decreased Urate Excretion via ABCG2. Sci. Rep. 2016, 6, 31003. [Google Scholar] [CrossRef]
- Fiori, E.; De Fazio, L.; Pidone, C.; Perone, F.; Tocci, G.; Battistoni, A.; Barbato, E.; Volpe, M.; Gallo, G. Asymptomatic Hyperuricemia: To Treat or Not a Threat? A Clinical and Evidence-Based Approach to the Management of Hyperuricemia in the Context of Cardiovascular Diseases. J. Hypertens. 2024, 42, 1665–1680. [Google Scholar] [CrossRef]
- FitzGerald, J.D.; Dalbeth, N.; Mikuls, T.; Brignardello-Petersen, R.; Guyatt, G.; Abeles, A.M.; Gelber, A.C.; Harrold, L.R.; Khanna, D.; King, C.; et al. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res. 2020, 72, 744–760. [Google Scholar] [CrossRef]
- Konta, T.; Ichikawa, K.; Kawasaki, R.; Fujimoto, S.; Iseki, K.; Moriyama, T.; Yamagata, K.; Tsuruya, K.; Narita, I.; Kondo, M.; et al. Association between Serum Uric Acid Levels and Mortality: A Nationwide Community-Based Cohort Study. Sci. Rep. 2020, 10, 6066. [Google Scholar] [CrossRef]
- Perlstein, T.S.; Gumieniak, O.; Hopkins, P.N.; Murphey, L.J.; Brown, N.J.; Williams, G.H.; Hollenberg, N.K.; Fisher, N.D.L. Uric Acid and the State of the Intrarenal Renin-Angiotensin System in Humans. Kidney Int. 2004, 66, 1465–1470. [Google Scholar] [CrossRef] [PubMed]
- Wei, X.; Zhang, M.; Huang, S.; Lan, X.; Zheng, J.; Luo, H.; He, Y.; Lei, W. Hyperuricemia: A Key Contributor to Endothelial Dysfunction in Cardiovascular Diseases. FASEB J. 2023, 37, e23012. [Google Scholar] [CrossRef]
- Bahadoran, Z.; Mirmiran, P.; Kashfi, K.; Ghasemi, A. Hyperuricemia-Induced Endothelial Insulin Resistance: The Nitric Oxide Connection. Pflugers Arch. 2022, 474, 83–98. [Google Scholar] [CrossRef] [PubMed]
- Zhu, Y.; Hu, Y.; Huang, T.; Zhang, Y.; Li, Z.; Luo, C.; Luo, Y.; Yuan, H.; Hisatome, I.; Yamamoto, T.; et al. High Uric Acid Directly Inhibits Insulin Signalling and Induces Insulin Resistance. Biochem. Biophys. Res. Commun. 2014, 447, 707–714. [Google Scholar] [CrossRef] [PubMed]
- Mandal, A.K.; Leask, M.P.; Estiverne, C.; Choi, H.K.; Merriman, T.R.; Mount, D.B. Genetic and Physiological Effects of Insulin on Human Urate Homeostasis. Front. Physiol. 2021, 12, 713710. [Google Scholar] [CrossRef]
- Fujii, W.; Yamazaki, O.; Hirohama, D.; Kaseda, K.; Kuribayashi-Okuma, E.; Tsuji, M.; Hosoyamada, M.; Kochi, Y.; Shibata, S. Gene-Environment Interaction Modifies the Association between Hyperinsulinemia and Serum Urate Levels through SLC22A12. J. Clin. Investig. 2025, 135, e186633. [Google Scholar] [CrossRef]
- Yu, W.; Cheng, J.-D. Uric Acid and Cardiovascular Disease: An Update From Molecular Mechanism to Clinical Perspective. Front. Pharmacol. 2020, 11, 582680. [Google Scholar] [CrossRef]
- Borghi, C.; Agnoletti, D.; Cicero, A.F.G.; Lurbe, E.; Virdis, A. Uric Acid and Hypertension: A Review of Evidence and Future Perspectives for the Management of Cardiovascular Risk. Hypertension 2022, 79, 1927–1936. [Google Scholar] [CrossRef]
- Del Pinto, R.; Viazzi, F.; Pontremoli, R.; Ferri, C.; Carubbi, F.; Russo, E. The URRAH Study. Panminerva Med. 2021, 63, 416–423. [Google Scholar] [CrossRef] [PubMed]
- D’Elia, L.; Masulli, M.; Cirillo, P.; Virdis, A.; Casiglia, E.; Tikhonoff, V.; Angeli, F.; Barbagallo, C.M.; Bombelli, M.; Cappelli, F.; et al. Serum Uric Acid/Serum Creatinine Ratio and Cardiovascular Mortality in Diabetic Individuals—The Uric Acid Right for Heart Health (URRAH) Project. Metabolites 2024, 14, 164. [Google Scholar] [CrossRef]
- Badve, S.V.; Pascoe, E.M.; Tiku, A.; Boudville, N.; Brown, F.G.; Cass, A.; Clarke, P.; Dalbeth, N.; Day, R.O.; de Zoysa, J.R.; et al. Effects of Allopurinol on the Progression of Chronic Kidney Disease. N. Engl. J. Med. 2020, 382, 2504–2513. [Google Scholar] [CrossRef]
- Bilezikian, J.P.; Khan, A.A.; Potts, J.T. Guidelines for the Management of Asymptomatic Primary Hyperparathyroidism: Summary Statement from the Third International Workshop. J. Clin. Endocrinol. Metab. 2009, 94, 335–339. [Google Scholar] [CrossRef]
- Cetani, F.; Pardi, E.; Marcocci, C. Parathyroid Carcinoma. Front. Horm. Res. 2018, 51, 63–76. [Google Scholar] [CrossRef]
- Lambers, T.T.; Bindels, R.J.M.; Hoenderop, J.G.J. Coordinated Control of Renal Ca2+ Handling. Kidney Int. 2006, 69, 650–654. [Google Scholar] [CrossRef] [PubMed]
- Van Abel, M.; Hoenderop, J.G.J.; Van Der Kemp, A.W.C.M.; Friedlaender, M.M.; Van Leeuwen, J.P.T.M.; Bindels, R.J.M. Coordinated Control of Renal Ca2+ Transport Proteins by Parathyroid Hormone. Kidney Int. 2005, 68, 1708–1721. [Google Scholar] [CrossRef] [PubMed]
- Alexander, R.T.; Dimke, H. Effects of Parathyroid Hormone on Renal Tubular Calcium and Phosphate Handling. Acta Physiol. 2023, 238, e13959. [Google Scholar] [CrossRef]
- Hoover, R.S.; Tomilin, V.; Hanson, L.; Pochynyuk, O.; Ko, B. PTH Modulation of NCC Activity Regulates TRPV5 Ca2+ Reabsorption. Am. J. Physiol. Renal Physiol. 2015, 310, F144–F151. [Google Scholar] [CrossRef]
- Lanzano, L.; Lei, T.; Okamura, K.; Giral, H.; Caldas, Y.; Masihzadeh, O.; Gratton, E.; Levi, M.; Blaine, J. Differential Modulation of the Molecular Dynamics of the Type IIa and IIc Sodium Phosphate Cotransporters by Parathyroid Hormone. Am. J. Physiol. Cell Physiol. 2011, 301, C850–C861. [Google Scholar] [CrossRef]
- Picard, N.; Capuano, P.; Stange, G.; Mihailova, M.; Kaissling, B.; Murer, H.; Biber, J.; Wagner, C.A. Acute Parathyroid Hormone Differentially Regulates Renal Brush Border Membrane Phosphate Cotransporters. Pflugers Arch. 2010, 460, 677–687. [Google Scholar] [CrossRef]
- Wagner, C.A.; Rubio-Aliaga, I.; Hernando, N. Renal Phosphate Handling and Inherited Disorders of Phosphate Reabsorption: An Update. Pediatr. Nephrol. 2019, 34, 549–559. [Google Scholar] [CrossRef]
- Fu, Q.; Jilka, R.L.; Manolagas, S.C.; O’Brien, C.A. Parathyroid Hormone Stimulates Receptor Activator of NFκB Ligand and Inhibits Osteoprotegerin Expression via Protein Kinase A Activation of CAMP-Response Element-Binding Protein. J. Biol. Chem. 2002, 277, 48868–48875. [Google Scholar] [CrossRef]
- Goltzman, D. Physiology of Parathyroid Hormone. Endocrinol. Metab. Clin. N. Am. 2018, 47, 743–758. [Google Scholar] [CrossRef]
- Khundmiri, S.J.; Murray, R.D.; Lederer, E. PTH and Vitamin D. Compr. Physiol. 2016, 6, 561–601. [Google Scholar]
- Hernando, N.; Wagner, C.A. Mechanisms and Regulation of Intestinal Phosphate Absorption. Compr. Physiol. 2018, 8, 1065–1090. [Google Scholar] [CrossRef]
- Insogna, K.L. Primary Hyperparathyroidism. N. Engl. J. Med. 2018, 379, 1050–1059. [Google Scholar] [CrossRef]
- Walker, M.D.; McMahon, D.J.; Inabnet, W.B.; Lazar, R.M.; Brown, I.; Vardy, S.; Cosman, F.; Silverberg, S.J. Neuropsychological Features in Primary Hyperparathyroidism: A Prospective Study. J. Clin. Endocrinol. Metab. 2009, 94, 1951–1958. [Google Scholar] [CrossRef]
- Oberger Marques, J.V.; Moreira, C.A. Primary Hyperparathyroidism. Best. Pract. Res. Clin. Rheumatol. 2020, 34, 101514. [Google Scholar] [CrossRef]
- Alexander, G.M.; Dieppe, P.A.; Doherty, M.; Scott, D.G.I. Pyrophosphate Arthropathy: A Study of Metabolic Associations and Laboratory Data. Ann. Rheum. Dis. 1982, 41, 377–381. [Google Scholar] [CrossRef]
- Rynes, R.I.; Merzig, E.G. Calcium Pyrophosphate Crystal Deposition Disease and Hyperparathyroidism: A Controlled, Prospective Study. J. Rheumatol. 1978, 5, 460–468. [Google Scholar]
- Kobayashi, S.; Sugenoya, A.; Takahashi, S.; Kasuga, Y.; Masuda, H.; Shimizu, T.; Komatsu, M.; Haba, Y.; Iida, F.; Shigematsu, S. Two Cases of Acute Pseudogout Attack Following Parathyroidectomy. Endocrinol. Jpn. 1991, 38, 309–314. [Google Scholar] [CrossRef]
- White, J.C.; Brandt, F.B.; Geelhoed, G.W. Actue Pseudogout Following Parathyroidectomy. Am. Surg. 1988, 54, 506–509. [Google Scholar] [PubMed]
- Bilezikian, J.P.; Connor, T.B.; Aptekar, R.; Freijanes, J.; Aurbach, G.D.; Pachas, W.N.; Wells, S.A.; Decker, J.L. Pseudogout after parathyroidectomy. Lancet 1973, 301, 445–446. [Google Scholar] [CrossRef] [PubMed]
- Mittal, M.; Patra, S.; Saxena, S.; Roy, A.; Yadav, T.; Vedant, D. Gout in Primary Hyperparathyroidism, Connecting Crystals to the Minerals. J. Endocr. Soc. 2022, 6, bvac018. [Google Scholar] [CrossRef] [PubMed]
- Broulik, P.D.; štěpán, J.J.; Pacovský, V. Primary Hyperparathyroidism and Hyperuricaemia Are Associated but Not Correlated with Indicators of Bone Turnover. Clinica Chimica Acta 1987, 170, 195–200. [Google Scholar] [CrossRef]
- Kong, S.-K.; Tsai, M.-C.; Yeh, C.-L.; Tsai, Y.-C.; Chien, M.-N.; Lee, C.-C.; Tsai, W.-H. Association between Primary Hyperparathyroidism and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis. Bone 2024, 185, 117130. [Google Scholar] [CrossRef]
- Tournis, S.; Makris, K.; Cavalier, E.; Trovas, G. Cardiovascular Risk in Patients with Primary Hyperparathyroidism. Curr. Pharm. Des. 2020, 26, 5628–5636. [Google Scholar] [CrossRef]
- Chin, K.-Y.; Ima-Nirwana, S.; Wan Ngah, W.Z. Significant Association between Parathyroid Hormone and Uric Acid Level in Men. Clin. Interv. Aging 2015, ume 10, 1377–1380. [Google Scholar] [CrossRef]
- Oprea, T.E.; Barbu, C.G.; Martin, S.C.; Sarbu, A.E.; Calapod, R.I.; Nistor, I.M.; Fica, S.V. Uric Acid in Primary Hyperparathyroidism: Assessment of Surgical versus Conservative Approach. Chirurgia 2023, 118, 146. [Google Scholar] [CrossRef] [PubMed]
- Neer, R.M.; Arnaud, C.D.; Zanchetta, J.R.; Prince, R.; Gaich, G.A.; Reginster, J.-Y.; Hodsman, A.B.; Eriksen, E.F.; Ish-Shalom, S.; Genant, H.K.; et al. Effect of Parathyroid Hormone (1-34) on Fractures and Bone Mineral Density in Postmenopausal Women with Osteoporosis. N. Engl. J. Med. 2001, 344, 1434–1441. [Google Scholar] [CrossRef]
- Miller, P.D.; Schwartz, E.N.; Chen, P.; Misurski, D.A.; Krege, J.H. Teriparatide in Postmenopausal Women with Osteoporosis and Mild or Moderate Renal Impairment. Osteoporos. Int. 2007, 18, 59–68. [Google Scholar] [CrossRef]
- U.S. Food and Drug Administration. TYMLOS (Abaloparatide) Injection, for Subcutaneous Use—Prescribing Information. 2025. Available online: https://www.Accessdata.Fda.Gov/Drugsatfda_docs/Label/2025/208743s017lbl.Pdf (accessed on 18 June 2025).
- Liu, Z.; Ding, X.; Wu, J.; He, H.; Wu, Z.; Xie, D.; Yang, Z.; Wang, Y.; Tian, J. Dose-Response Relationship between Higher Serum Calcium Level and Higher Prevalence of Hyperuricemia: A Cross-Sectional Study. Medicine 2019, 98, e15611. [Google Scholar] [CrossRef]
- Gu, F.; Luo, X.; Jin, X.; Cai, C.; Zhao, W. Association of Total Calcium With Serum Uric Acid Levels Among United States Adolescents Aged 12–19 Years: A Cross-Sectional Study. Front. Med. 2022, 9, 915371. [Google Scholar] [CrossRef]
- Christensson, T. Serum Urate in Subjects with Hypercalcaemic Hyperparathyroidism. Clinica Chimica Acta 1977, 80, 529–533. [Google Scholar] [CrossRef]
- Han, Y.; Han, K.; Zhang, Y.; Zeng, X. Serum 25-Hydroxyvitamin D Might Be Negatively Associated with Hyperuricemia in U.S. Adults: An Analysis of the National Health and Nutrition Examination Survey 2007–2014. J. Endocrinol. Investig. 2022, 45, 719–729. [Google Scholar] [CrossRef]
- Isnuwardana, R.; Bijukchhe, S.; Thadanipon, K.; Ingsathit, A.; Thakkinstian, A. Association Between Vitamin D and Uric Acid in Adults: A Systematic Review and Meta-Analysis. Horm. Metab. Res. 2020, 52, 732–741. [Google Scholar] [CrossRef]
- Ma, Z.; Xiong, T.; Li, Y.; Kong, B.; Lu, W.; Zhang, Z.; Chen, L.; Tang, Y.; Yao, P.; Xiong, J.; et al. The Inverted U-Shaped Association between Serum Vitamin D and Serum Uric Acid Status in Children and Adolescents: A Large Cross-Sectional and Longitudinal Analysis. Nutrients 2024, 16, 1492. [Google Scholar] [CrossRef]
- Chen, W.; Roncal-Jimenez, C.; Lanaspa, M.; Gerard, S.; Chonchol, M.; Johnson, R.J.; Jalal, D. Uric Acid Suppresses 1 Alpha Hydroxylase in Vitro and in Vivo. Metabolism 2014, 63, 150–160. [Google Scholar] [CrossRef]
- Ponvilawan, B.; Charoenngam, N. Vitamin D and Uric Acid: Is Parathyroid Hormone the Missing Link? J. Clin. Transl. Endocrinol. 2021, 25, 100263. [Google Scholar] [CrossRef]
- Ejaz, A.A.; Nakagawa, T.; Kanbay, M.; Kuwabara, M.; Kumar, A.; Garcia Arroyo, F.E.; Roncal-Jimenez, C.; Sasai, F.; Kang, D.-H.; Jensen, T.; et al. Hyperuricemia in Kidney Disease: A Major Risk Factor for Cardiovascular Events, Vascular Calcification, and Renal Damage. Semin. Nephrol. 2020, 40, 574–585. [Google Scholar] [CrossRef]
- Portillo, M.R.; Rodríguez-Ortiz, M.E. Secondary Hyperparthyroidism: Pathogenesis, Diagnosis, Preventive and Therapeutic Strategies. Rev. Endocr. Metab. Disord. 2017, 18, 79–95. [Google Scholar] [CrossRef]
- Zaidi, A.; Michaelis, M.L. Effects of Reactive Oxygen Species on Brain Synaptic Plasma Membrane Ca2+-ATPase. Free Radic. Biol. Med. 1999, 27, 810–821. [Google Scholar] [CrossRef]
- Hoenderop, J.G.J.; Nilius, B.; Bindels, R.J.M. Calcium Absorption Across Epithelia. Physiol. Rev. 2005, 85, 373–422. [Google Scholar] [CrossRef]
- Huschenbett, J.; Zaidi, A.; Michaelis, M.L. Sensitivity of the Synaptic Membrane Na+/Ca2+ Exchanger and the Expressed NCX1 Isoform to Reactive Oxygen Species. Biochim. Et. Biophys. Acta (BBA)-Biomembr. 1998, 1374, 34–46. [Google Scholar] [CrossRef]
- Gonzalez-Vicente, A.; Hong, N.; Garvin, J.L. Effects of Reactive Oxygen Species on Renal Tubular Transport. Am. J. Physiol.-Ren. Physiol. 2019, 317, F444–F455. [Google Scholar] [CrossRef]
- Li, D.; Wang, L.; Ou, J.; Wang, C.; Zhou, J.; Lu, L.; Wu, Y.; Gao, J. Reactive Oxygen Species Induced by Uric Acid Promote NRK-52E Cell Apoptosis through the NEK7-NLRP3 Signaling Pathway. Mol. Med. Rep. 2021, 24, 729. [Google Scholar] [CrossRef]
- Milanesi, S.; Verzola, D.; Cappadona, F.; Bonino, B.; Murugavel, A.; Pontremoli, R.; Garibotto, G.; Viazzi, F. Uric Acid and Angiotensin II Additively Promote Inflammation and Oxidative Stress in Human Proximal Tubule Cells by Activation of Toll-like Receptor 4. J. Cell Physiol. 2019, 234, 10868–10876. [Google Scholar] [CrossRef]
- Verzola, D.; Ratto, E.; Villaggio, B.; Parodi, E.L.; Pontremoli, R.; Garibotto, G.; Viazzi, F. Uric Acid Promotes Apoptosis in Human Proximal Tubule Cells by Oxidative Stress and the Activation of NADPH Oxidase NOX 4. PLoS ONE 2014, 9, e115210. [Google Scholar] [CrossRef]
- Martinon, F.; Pétrilli, V.; Mayor, A.; Tardivel, A.; Tschopp, J. Gout-Associated Uric Acid Crystals Activate the NALP3 Inflammasome. Nature 2006, 440, 237–241. [Google Scholar] [CrossRef] [PubMed]
- Tatsiy, O.; Mayer, T.Z.; de Carvalho Oliveira, V.; Sylvain-Prévost, S.; Isabel, M.; Dubois, C.M.; McDonald, P.P. Cytokine Production and NET Formation by Monosodium Urate-Activated Human Neutrophils Involves Early and Late Events, and Requires Upstream TAK1 and Syk. Front. Immunol. 2020, 10, 2996. [Google Scholar] [CrossRef] [PubMed]
- Mulay, S.R.; Anders, H.-J. Crystallopathies. N. Engl. J. Med. 2016, 374, 2465–2476. [Google Scholar] [CrossRef]
- Crișan, T.O.; Cleophas, M.C.P.; Oosting, M.; Lemmers, H.; Toenhake-Dijkstra, H.; Netea, M.G.; Jansen, T.L.; Joosten, L.A.B. Soluble Uric Acid Primes TLR-Induced Proinflammatory Cytokine Production by Human Primary Cells via Inhibition of IL-1Ra. Ann. Rheum. Dis. 2016, 75, 755–762. [Google Scholar] [CrossRef]
- Crişan, T.O.; Cleophas, M.C.P.; Novakovic, B.; Erler, K.; van de Veerdonk, F.L.; Stunnenberg, H.G.; Netea, M.G.; Dinarello, C.A.; Joosten, L.A.B. Uric Acid Priming in Human Monocytes Is Driven by the AKT–PRAS40 Autophagy Pathway. Proc. Natl. Acad. Sci. USA 2017, 114, 5485–5490. [Google Scholar] [CrossRef]
- Spiga, R.; Marini, M.A.; Mancuso, E.; Di Fatta, C.; Fuoco, A.; Perticone, F.; Andreozzi, F.; Mannino, G.C.; Sesti, G. Uric Acid Is Associated With Inflammatory Biomarkers and Induces Inflammation Via Activating the NF-ΚB Signaling Pathway in HepG2 Cells. Arterioscler. Thromb. Vasc. Biol. 2017, 37, 1241–1249. [Google Scholar] [CrossRef]
- Chung, Y.-H.; Choi, B.; Song, D.-H.; Song, Y.; Kang, S.-W.; Yoon, S.-Y.; Kim, S.W.; Lee, H.K.; Chang, E.-J. Interleukin-1β Promotes the LC3-Mediated Secretory Function of Osteoclast Precursors by Stimulating the Ca2+-Dependent Activation of ERK. Int. J. Biochem. Cell Biol. 2014, 54, 198–207. [Google Scholar] [CrossRef]
- Guise, T.A.; Garrett, I.R.; Bonewald, L.F.; Mundy, G.R. Interleukin-1 Receptor Antagonist Inhibits the Hypercalcemia Mediated by Interleukin-1. J. Bone Miner. Res. 1993, 8, 583–587. [Google Scholar] [CrossRef]
- Bornefalk, E.; Ljunghall, S.; Lindh, E.; Bengtson, O.; Johansson, A.G.; Ljunggren, Ö. Regulation of Interleukin-6 Secretion from Mononuclear Blood Cells by Extracellular Calcium. J. Bone Miner. Res. 1997, 12, 228–233. [Google Scholar] [CrossRef]
- Adebanjo, O.A.; Moonga, B.S.; Yamate, T.; Sun, L.; Minkin, C.; Abe, E.; Zaidi, M. Mode of Action of Interleukin-6 on Mature Osteoclasts. Novel Interactions with Extracellular Ca2+ Sensing in the Regulation of Osteoclastic Bone Resorption. J. Cell Biol. 1998, 142, 1347–1356. [Google Scholar] [CrossRef]
- Bendre, M.S.; Montague, D.C.; Peery, T.; Akel, N.S.; Gaddy, D.; Suva, L.J. Interleukin-8 Stimulation of Osteoclastogenesis and Bone Resorption Is a Mechanism for the Increased Osteolysis of Metastatic Bone Disease. Bone 2003, 33, 28–37. [Google Scholar] [CrossRef]
- Osta, B.; Benedetti, G.; Miossec, P. Classical and Paradoxical Effects of TNF-α on Bone Homeostasis. Front. Immunol. 2014, 5, 48. [Google Scholar] [CrossRef] [PubMed]
- Hendy, G.N.; Canaff, L. Calcium-Sensing Receptor, Proinflammatory Cytokines and Calcium Homeostasis. Semin. Cell Dev. Biol. 2016, 49, 37–43. [Google Scholar] [CrossRef] [PubMed]
- Canaff, L.; Hendy, G.N. Calcium-Sensing Receptor Gene Transcription Is Up-Regulated by the Proinflammatory Cytokine, Interleukin-1β. J. Biol. Chem. 2005, 280, 14177–14188. [Google Scholar] [CrossRef] [PubMed]
- Paccou, J.; Boudot, C.; Mary, A.; Kamel, S.; Drüeke, T.B.; Fardellone, P.; Massy, Z.; Brazier, M.; Mentaverri, R. Determination and Modulation of Total and Surface Calcium-Sensing Receptor Expression in Monocytes In Vivo and In Vitro. PLoS ONE 2013, 8, e74800. [Google Scholar] [CrossRef]
- Li, T.; Sun, M.; Yin, X.; Wu, C.; Wu, Q.; Feng, S.; Li, H.; Luan, Y.; Wen, J.; Yan, L.; et al. Expression of the Calcium Sensing Receptor in Human Peripheral Blood T Lymphocyte and Its Contribution to Cytokine Secretion through MAPKs or NF-ΚB Pathways. Mol. Immunol. 2013, 53, 414–420. [Google Scholar] [CrossRef]
- Rossol, M.; Pierer, M.; Raulien, N.; Quandt, D.; Meusch, U.; Rothe, K.; Schubert, K.; Schöneberg, T.; Schaefer, M.; Krügel, U.; et al. Extracellular Ca2+ Is a Danger Signal Activating the NLRP3 Inflammasome through G Protein-Coupled Calcium Sensing Receptors. Nat. Commun. 2012, 3, 1329. [Google Scholar] [CrossRef]
- Werner, L.E.; Wagner, U. Calcium-Sensing Receptor-Mediated NLRP3 Inflammasome Activation in Rheumatoid Arthritis and Autoinflammation. Front. Physiol. 2023, 13, 1078569. [Google Scholar] [CrossRef]
- Ahn, S.H.; Lee, S.H.; Kim, B.-J.; Lim, K.-H.; Bae, S.J.; Kim, E.H.; Kim, H.-K.; Choe, J.W.; Koh, J.-M.; Kim, G.S. Higher Serum Uric Acid Is Associated with Higher Bone Mass, Lower Bone Turnover, and Lower Prevalence of Vertebral Fracture in Healthy Postmenopausal Women. Osteoporos. Int. 2013, 24, 2961–2970. [Google Scholar] [CrossRef]
- Yan, D.; Wang, J.; Hou, X.; Bao, Y.; Zhang, Z.; Hu, C.; Jia, W. Association of Serum Uric Acid Levels with Osteoporosis and Bone Turnover Markers in a Chinese Population. Acta Pharmacol. Sin. 2018, 39, 626–632. [Google Scholar] [CrossRef] [PubMed]
- Sautin, Y.Y.; Johnson, R.J. Uric Acid: The Oxidant-Antioxidant Paradox. Nucleosides Nucleotides Nucleic Acids 2008, 27, 608–619. [Google Scholar] [CrossRef] [PubMed]
- Stein, E.M.; Silva, B.C.; Boutroy, S.; Zhou, B.; Wang, J.; Udesky, J.; Zhang, C.; McMahon, D.J.; Romano, M.; Dworakowski, E.; et al. Primary Hyperparathyroidism Is Associated with Abnormal Cortical and Trabecular Microstructure and Reduced Bone Stiffness in Postmenopausal Women. J. Bone Miner. Res. 2013, 28, 1029–1040. [Google Scholar] [CrossRef]
- Makras, P.; Anastasilakis, A.D. Bone Disease in Primary Hyperparathyroidism. Metabolism 2018, 80, 57–65. [Google Scholar] [CrossRef] [PubMed]
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Malagrinò, M.; Zavatta, G. Uric Acid in Primary Hyperparathyroidism: Marker, Consequence, or Bystander? Metabolites 2025, 15, 444. https://doi.org/10.3390/metabo15070444
Malagrinò M, Zavatta G. Uric Acid in Primary Hyperparathyroidism: Marker, Consequence, or Bystander? Metabolites. 2025; 15(7):444. https://doi.org/10.3390/metabo15070444
Chicago/Turabian StyleMalagrinò, Matteo, and Guido Zavatta. 2025. "Uric Acid in Primary Hyperparathyroidism: Marker, Consequence, or Bystander?" Metabolites 15, no. 7: 444. https://doi.org/10.3390/metabo15070444
APA StyleMalagrinò, M., & Zavatta, G. (2025). Uric Acid in Primary Hyperparathyroidism: Marker, Consequence, or Bystander? Metabolites, 15(7), 444. https://doi.org/10.3390/metabo15070444