Biochemical Markers of Endothelial Activation in Primary Hyperparathyroidism

Abstract

Patients with primary hyperparathyroidism (PHPT) have impaired vasodilation both dependent and independent of endothelium. The aims of our study were to measure three different biochemical markers of endothelial activation, i. e., plasma thrombomodulin, soluble(s) E-selectin, and von Willebrand factor, in PHPT patients before and one year after successful parathyroidectomy, and to distinguish the potential effect of hypercalcemia and/or high parathyroid hormone from that of major cardiovascular risk factors (diabetes mellitus, hyperlipidemia, hypertension, obesity, smoking habit) on endothelial function. Twenty consecutive patients with PHPT subdivided into two groups according to the absence (n = 8) or presence (n = 12) of one or more risk factors, and fifteen healthy normocalcemic subjects were studied. Baseline thrombomodulin levels were similar in the groups with and without risk factors, and in controls. In contrast, sE-selectin and von Willebrand factor were higher in PHPT patients with risk factors than in those without risk factors (p < 0.05 and p < 0.01, respectively) and controls (p < 0.01). Neither thrombomodulin nor sE-selectin changed after parathyroidectomy in either PHPT group. Plasma von Willebrand factor decreased (p < 0.01) in patients without risk factors, while persisting at high levels in patients with risk factors. In conclusion, in spite of a limitation due to the small number of patients, our study suggests that classic cardiovascular risk factors seem to be the main determinants for the high plasma levels of sE-selectin and vWF in PHPT. Together with unaltered thrombomodulin and sE-selectin levels, a plasma vWF decrease after parathyroidectomy might reflect a specific mechanism of its endothelial calcium- and/or PTH-stimulated secretion in some PHPT patients without risk factors. Whether a vWF reduction after parathyroidectomy may be used as a biochemical index for improved endothelial function in PHPT patients without risk factors has yet to be demonstrated in larger studies.

Key words

Primary hyperparathyroidism · endothelium · von Willebrand factor

References

• 1 Hedback G, Oden A. The increased risk of death of primary hyperparathyroidism-an update.  Eur J Clin Invest. 1998;  28 271-276
• 2 Silverberg S J, Shane E, Jacobs T P, Siris E, Bilezikian J P. The natural history of treated and untreated asymptomatic primary hyperparathyroidism.  N Engl J Med. 1999;  341 1249-1255
• 3 Fallo F, Camporese G, Capitelli E, Andreozzi G M, Mantero F, Lumachi F. Ultrasound evaluation of carotid artery in primary hyperparathyroidism.  J Clin Endocrinol Metab. 2003;  88 2096-2099
• 4 Lumachi E, Ermani M, Luisetto G, Nardi A, Basso S MM, Camozzi V, Favia G. Relationship between serum parathyroid hormone, serum calcium and arterial blood pressure in patients with primary hyperparathyroidism: results of a multivariate analysis.  Eur J Endocrinol. 2002;  146 643-647
• 5 Garcia de la Torre N, Wass J AH, Turner H E. Parathyroid adenomas and cardiovascular risk.  Endocr-Relat Cancer. 2003;  10 309-322
• 6 Nillson I L, Aberg J A, Rastad J, Lind L. Endothelial vasodilatory dysfunction in primary hyperparathyroidism is reversed after parathyroidectomy.  Surgery. 1999;  126 1049-1055
• 7 Kosch M, Hausberg M, Vormbrock K, Kisters K, Rahn K H, Barenbrock M K. Studies on flow-mediated vasodilation and intima-media thickness of the brachial artery in patients with primary hyperparathyroidism.  Am J Hypertens. 2000;  13 759-764
• 8 Nillson I L, Rastad J, Johansson K, Lind L. Endothelial vasodilatory function and blood pressure response to local and systemic hypercalcemia.  Surgery. 2001;  130 986-990
• 9 Neunteufl T, Katzenschlager R, Abela C, Kostner K, Niederle B, Weidinger F, Stefenelli T. Impairment of endothelium-independent vasodilation in patients with hypercalcemia.  Cardiovasc Res. 1998;  40 396-401
• 10 Neunteufl T, Heher S, Prager G, Katzenschlager R, Abela C, Niederle B, Stefenelli T. Effects of successful parathyroidectomy on altered arterial reactivity in patients with hypercalcaemia: results of a 3-year follow-up study.  Clin Endocrinol. 2000;  53 229-233
• 11 Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990 s.  Nature. 1990;  362 801-809
• 12 Bombeli T, Muller M, Haeberli A. Anticoagulant property of the vascular endothelium.  Thromb Haemost. 1997;  77 408-423
• 13 Ross R. Atherosclerosis: an inflammatory disease.  N Engl J Med. 1999;  340 115-126
• 14 Anderson T J. Assessment and treatment of endothelial dysfunction in humans.  J Am Coll Cardiol. 1999;  34 631-638
• 15 Krieglstein C F, Granger D N. Adhesion molecules and their role in vascular disease.  Am J Hypertens. 2001;  14 S44-S54
• 16 Zacharieva S, Atanassova I, Nachev E, Orbetzova M, Kirilov G, Kalinova K, Shigarminova R. Markers of vascular function in hypertension due to Cushing’s syndrome.  Horm Metab Res. 2005;  37 36-39
• 17 Schram M T, Stehouwer C DA. Endothelial dysfunction, cellular adhesion molecules and the metabolic syndrome.  Horm Metab Res. 2005;  37, (Suppl 1) 49-55
• 18 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.  Diabetes Care. 1998;  21 (Suppl 1) S5-S19
• 19 National Institutes of Health, National Heart, Lung and Blood Institute . Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report.  Obes Res. 1998;  6 (Suppl 2) S51-S210
• 20 Cella G, Bellotto F, Tona F, Sbarai A, Mazzaro G, Motta G, Fareed J. Plasma markers of endothelial dysfunction in pulmonary hypertension.  Chest. 2001;  120 1226-1230
• 21 Casonato A, Sartori M T, Pontara E, Zucchetto S, Girolami A. Impaired release of tissue plasminogen activator (t-PA) following DDAVP infusion in von Willebrand factor content.  Blood Coagul Fibrinolysis. 1992;  3 149-153
• 22 Hwang S J, Ballantyne C M, Sharrett A R, Smith L C, Davis C L, Gotto A M jr, Boerwinckle E. Circulating adhesion molecules VCAM-1, ICAM-1 and E-selectin in carotid atherosclerosis and incident coronary heart disease patients: the Atherosclerosis Risk in Community Study (ARIC).  Circulation. 1997;  96 4219-4225
• 23 Ferri C, Desideri G, Balconcini R, Bellini C, Pasin M, Cantucci A, De Mattia G. Early-up regulation of endothelial adhesion molecule in obese hypertensive men.  Hypertension. 1999;  34 568-573
• 24 Abdu T A, Elhadd T, Pfeifer M, Clayton R N. Endothelial dysfunction in endocrine disease.  Trends Endocrinol Metab. 2001;  12 257-265
• 25 Lufkin E G, Fass D N, O’Fallon W M, Bowie E JW. Increased von Willebrand factor in diabetes mellitus.  Metabolism. 1979;  28 63-66
• 26 Badimon L, Badimon J J, Chesebro J H, Fuster V. von Willebrand factor and cardiovascular disease.  Thromb Haemost. 1993;  70 111-118
• 27 Smith F B, Lowe G DO, Fowkes F GR, Rumley A, Rumley A G, Donnan P T, Housley E. Smoking, haemostatic factors and lipid peroxides in a population case control study of peripheral arterial disease.  Atherosclerosis. 1993;  102 155-162
• 28 Lim H S, Lip G IH, Blann A D. Plasma von Willebrand factor and the development of the metabolic syndrome in patients with hypertension.  J Clin Endocrinol Metab. 2004;  89 5377-5381
• 29 Hernandez L R, Lundberg U, Arocha-Pinango C L. Experimental thrombosis I: relation with fibrinogen and other haemostatic parameters.  Thromb Res. 2000;  99 295-305
• 30 Takano S, Kimura S, Ohdama S, Aoki N. Plasma thrombomodudulin in health and disease.  Blood. 1990;  59 581-591
• 31 Ishii H, Uchiyama H, Kazama M. Soluble thrombomodulin antigen in conditioned medium is increased by damage of endothelial cells.  Thromb Haemost. 1991;  65 618-623
• 32 Inukai T, Fujiwara Y, Tayama K, Aso Y, Takemura Y. Clinical significance of measurement of urinary and serum thrombomodulin in patients with non-insulin-dependent diabetes mellitus.  Diabetes Res Clin Pract. 1996;  33 99-104
• 33 Mihara H, Murai A, Handa K, Saku K, Shirai K, Tanaka K, Arakawa K. Thrombomodulin levels in patients with coronary artery disease.  Artery. 1997;  22 293-308
• 34 Schumaker A, Seljeflot I, Sommervoll L, Christensen B, Otterstad J E, Arnesen H. Increased levels of endothelial markers in patients with coronary artery disease.  Thromb Res. 2002;  105 25-31
• 35 Martina V, Bruno G A, Brancaleoni V, Zumpano E, Tagliabue M, Fornengo R, Gasparri G, Pescarmona G P. Calcium blood level modulates nitric oxide action: effects of parathyroidectomy in patients with hyperparathyroidism.  J Endocrinol. 1998;  156 231-235
• 36 Massry S G, Iseki K, Campese V M. Serum calcium, parathyroid hormone, and blood pressure.  Am J Nephrol. 1986;  6 (Suppl 1) 19-28
• 37 Hatton D C, McCarron D A. Dietary calcium and blood pressure in experimental models of hypertension.  Hypertension. 1994;  23 513-530
• 38 Resnick L A. Calcitropic hormones in human and experimental hypertension.  Am J Hypertens. 1990;  3 S171-S178
• 39 Jiang B, Morimoto S, Yang J, Niinobau T, Fukuo K, Ogihara T. Expression of parathyroid hormone/parathyroid hormone-related peptide receptor in vascular endothelial cells.  J Cardiovas Pharmacol. 1998;  31 S142-S144
• 40 Knop M, Gerke V. Ca²⁺-regulated secretion of tissue-type plasminogen activator and von Willebrand factor in human endothelial cells.  Biochim Biophys Acta. 2002;  1600 162-167
• 41 Vita J A, Treasure C B, Nabel E G, McLenachan J M, Fish D, Yeung A C, Velkstein V I, Selwin A P, Ganz P. Coronary vasomotor response to acetylcoline relates to risk factors for coronary artery disease.  Circulation. 1990;  81 491-497
• 42 Nilius B, Droogmans G. Ion channels and their functional role in vascular endothelium.  Physiol Rev. 2001;  81 1415-1459