Paraneoplastik Uygunsuz Antidıüretik Hormon Salınımı Sendromu (SIADH)
Özet
Uygunsuz Antidiüretik Hormon Salınımı Sendromu (SIADH), özellikle onkoloji hastalarında hastanede yatış gerektiren hiponatreminin en önemli nedenlerinden biridir. Temelinde yatan patofizyoloji, ektopik veya aşırı ADH üretimi sonucu böbreklerde suyun geri emiliminin artması ve buna bağlı gelişen hipotonik övolemik hiponatremidir. Özellikle küçük hücreli akciğer kanseri (SCLC) gibi malignitelerle güçlü ilişkisi olan bu paraneoplastik sendrom, hastaların yaşam kalitesini düşürür, kemik kırıkları riskini artırır ve mortaliteyi olumsuz etkiler. Tanısı Bartter ve Schwartz kriterlerine göre diğer hiponatremi nedenlerinin dışlanması esasına dayanır. Tedavi yönetiminde geleneksel sıvı kısıtlaması, ciddi olgularda hipertonik salin infüzyonunun yanı sıra, son yıllarda övolemik hiponatremi tedavisinde etkinliği kanıtlanmış V2 reseptör antagonisti Tolvaptan gibi farmakolojik ajanlar öne çıkmaktadır. Sodyum seviyelerinin hızlı ve güvenli bir şekilde normalleştirilmesi, onkolojik tedavilerin başarısını optimize ederken hastanede kalış sürelerini ve sağlık maliyetlerini azaltmaktadır.
The Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) represents a primary etiology of hyponatremia in hospitalized cancer patients. Characterized pathophysiologically by excessive or ectopic antidiuretic hormone (ADH) release, it induces increased renal water reabsorption, culminating in hypotonic and euvolemic hyponatremia. This paraneoplastic condition exhibits a strong correlation with small cell lung cancer (SCLC), significantly diminishing patient performance status, elevating bone fracture risks, and serving as a negative prognostic indicator for overall survival. Diagnosis remains an exclusion-based process utilizing the Bartter and Schwartz criteria to differentiate it from other volume states. Management strategies encompass standard fluid restriction, hypertonic saline for symptomatic acute cases, and modern pharmacological interventions such as Tolvaptan, an oral V2 receptor antagonist proven highly effective in malignant environments. Timely and precise normalization of serum sodium levels plays a critical role in reducing hospital length of stay and healthcare expenditures while enabling uninterrupted oncological treatments.
Referanslar
Schwartz WB, Bennett W, Curelop S, Bartter FC. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med. 1957;23(4):529–542. doi:10.1016/0002-9343(57)90224-3
Feldman BJ, Rosenthal SM, Vargas GA, et al. Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med. 2005;352(18):1884–1890. doi:10.1056/NEJMoa042743
Esposito P, Piotti G, Bianzina S, Malul Y, Dal Canton A. The syndrome of inappropriate antidiuresis: pathophysiology, clinical management and new therapeutic options. Nephron Clin Pract. 2011;119(1):62–73. doi:10.1159/000324653
Ball SG. Vasopressin and disorders of water balance: the physiology and pathophysiology of vasopressin. Ann Clin Biochem. 2007;44(5):417–431. doi:10.1258/000456307781646030
Tian Y, Sandberg K, Murase T, Baker EA, Speth RC, Verbalis JG. Vasopressin V2 receptor binding is down-regulated during renal escape from vasopressin-induced antidiuresis. Endocrinology. 2000;141(1):307–314. doi:10.1210/endo.141.1.7256
Verbalis JG. Whole-body volume regulation and escape from antidiuresis. Am J Med. 2006;119(7):21–29. doi:10.1016/j.amjmed.2006.05.004
Berardi R, Rinaldi S, Caramanti M, et al. Hyponatremia in cancer patients: time for a new approach. Crit Rev Oncol Hematol. 2016;102:15–25. doi:10.1016/j.critrevonc.2016.03.010
Hannon MJ, Thompson CJ. The syndrome of inappropriate antidiuretic hormone: prevalence, causes and consequences. Eur J Endocrinol. 2010;162(1):5–12. doi:10.1530/EJE-09-1063
Kanaji N, Watanabe N, Kita N, et al. Paraneoplastic syndromes associated with lung cancer. World J Clin Oncol. 2014;5(3):197–223. doi:10.5306/wjco.v5.i3.197
Cuesta M, Garrahy A, Thompson CJ. SIAD: practical recommendations for diagnosis and management. J Endocrinol Invest. 2016;39(9):991–1001. doi:10.1007/s40618-016-0463-3
Gray ST, Holbrook EH, Najm MH, Sadow PM, Curry WT, Lin DT. Syndrome of inappropriate antidiuretic hormone secretion in patients with olfactory neuroblastoma. Otolaryngol Head Neck Surg. 2012;147(1):147–151. doi:10.1177/0194599812438842
Sørensen JB, Andersen MK, Hansen HH. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in malignant disease. J Intern Med. 1995;238(2):97–110. doi:10.1111/j.1365-2796.1995.tb00907.x
Robertson GL. Vincristine neurotoxicity and abnormal secretion of antidiuretic hormone. Arch Gen Intern Med. 1973;132(5):717–720. doi:10.1001/archinte.1973.03650110061013
Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis. 2008;52(1):144–153. doi:10.1053/j.ajkd.2008.03.004
Berardi R, Santoni M, Rinaldi S, et al. Risk of hyponatraemia in cancer patients treated with targeted therapies: a systematic review and meta-analysis of clinical trials. PLoS One Epub. 2016;11(5).
Khaja M, Torchon F, Millerman K. A rare case of sorafenib-induced severe hyponatremia [case report]. SAGE Open Med Case Rep. 2019;7:2050313X19846048.
Jhaveri KD, Wanchoo R, Sakhiya V, Ross DW, Fishbane S. Adverse renal effects of novel molecular oncologic targeted therapies: a narrative review. Kidney Int Rep. 2016;2(1):108–123. doi:10.1016/j.ekir.2016.09.055
Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrol Dial Transplant. 2014;29(2):1–39.
Verbalis JG. Managing hyponatremia in patients with syndrome of inappropriate antidiuretic hormone secretion. J Hosp Med. 2010;5(3):18–26. doi:10.1002/jhm.783
Renneboog B, Sattar L, Decaux G. Attention and postural balance are much more affected in older than in younger adults with mild or moderate chronic hyponatremia. Eur J Intern Med. 2017;41:25–26. doi:10.1016/j.ejim.2017.02.008
Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006;119(1):71–78. doi:10.1016/j.amjmed.2005.09.026
Gankam KF, Andres C, Sattar L, et al. Mild hyponatremia and risk of fracture in the ambulatory elderly. Q J Med. 2008;101(7):583–588. doi:10.1093/qjmed/hcn061
Barsony J, Sugimura Y, Verbalis JG. Osteoclast response to low extracellular sodium and the mechanism of hyponatremia-induced bone loss. J Biol Chem. 2011;286(12):10864–10875. doi:10.1074/jbc.M110.155002
Berardi R, Morgese F, Rinaldi S, Torniai M. Electrolyte disorders in cancer patients: clinical implication and management. In: Blair MT, editor. New Developments in Oncology Research. Nova Science Publisher; 2019.
Liamis G, Rodenburg EM, Hofman A, Zietse R, Stricker BH, Hoorn EJ. Electrolyte disorders in community subjects: prevalence and risk factors. Am J Med. 2013;126(3):256–263. doi:10.1016/j.amjmed.2012.06.037
Wald R, Jaber BL, Price LL, Upadhyay A, Madias NE. Impact of hospital-associated hyponatremia on selected outcomes. Arch Intern Med. 2010;170(3):294–302. doi:10.1001/archinternmed.2009.513
Berardi R, Antonuzzo A, Blasi L, et al. Practical issues for the management of hyponatremia in oncology. Endocrine. 2018;61(1):158–164. doi:10.1007/s12020-018-1547-y
Oster JR, Singer I. Hyponatremia, hyposmolality, and hypotonicity: tables and fables. Arch Intern Med. 1999;159(4):333–336. doi:10.1001/archinte.159.4.333
Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013;126(10):1–42. doi:10.1016/j.amjmed.2013.07.006
Castillo JJ, Vincent M, Justice E. Diagnosis and management of hyponatremia in cancer patients. Oncologist. 2012;17(6):756–765. doi:10.1634/theoncologist.2011-0400
Thaler SM, Teitelbaum I, Berl T. “Beer potomania” in non-beer drinkers: effect of low dietary solute intake. Am J Kidney Dis. 1998;31(6):1028–1031. doi:10.1053/ajkd.1998.v31.pm9631849
Grohè C, Berardi R, Burst V. Hyponatraemia-SIADH in lung cancer diagnostic and treatment algorithms. Crit Rev Oncol Hematol. 2015;96(1):1–8. doi:10.1016/j.critrevonc.2015.04.005
Tenny S, Thorell W. Cerebral Salt Wasting Syndrome. Treasure Island (FL): StatPearls Publishing; 2019.
Tudor RM, Thompson CJ. Posterior pituitary dysfunction following traumatic brain injury: review. Pituitary. 2019;22(3):296–304. doi:10.1007/s11102-018-0917-z
De Troyer A, Demanet JC. Correction of antidiuresis by demeclocycline. N Engl J Med. 1975;293(18):915–918. doi:10.1056/NEJM197510302931809
Cherrill DA, Stote RM, Birge JR, Singer I. Demeclocycline treatment in the syndrome of inappropriate antidiuretic hormone secretion. Ann Intern Med. 1975;83(5):654–656. doi:10.7326/0003-4819-83-5-654
Perks WH, Mohr P, Liversedge LA. Demeclocycline in inappropriate A.D.H. syndrome. Lancet. 1976;2(8000):1414. doi:10.1016/S0140-6736(76)91958-9
Onitilo AA, Kio E, Doi SA. Tumor-related hyponatremia. Clin Med Res. 2007;5(4):228–237. doi:10.3121/cmr.2007.762
Smith D, Moore K, Tormey W, Baylis PH, Thompson CJ. Downward resetting of the osmotic threshold for thirst in patients with SIADH. Am J Physiol Endocrinol Metab. 2004;287(5):E1019–E1023. doi:10.1152/ajpendo.00033.2004
Furst H, Hallows KR, Post J, et al. The urine/plasma electrolyte ratio: a predictive guide to water restriction. Am J Med Sci. 2000;319(4):240–244. doi:10.1097/00000441-200004000-00007
Runkle I, Villabona C, Navarro A, et al. Treatment of hyponatremia induced by the syndrome of Inappropriate antidiuretic hormone secretion: a multidisciplinary spanish algorithm. Nefrologia. 2014;34(4):439–450. doi:10.3265/Nefrologia.pre2014.Apr.12220
Santini D, Berardi R, Caramanti M, Peri A, Armento G, Barni S on behalf of the Italian Association of Medical Oncology (AIOM). Electrolytes disorder: recommendations for diagnosis and treatment in cancer patients. Position paper.
Verbalis JG, Adler S, Schrier RW, Berl T, Zhao Q, Czerwiec FS. SALT Investigators. Efficacy and safety of oral tolvaptan therapy in patients with the syndrome of inappropriate antidiuretic hormone secretion. Eur J Endocrinol. 2011;164(5):725–732. doi:10.1530/EJE-10-1078
Salahudeen AK, Ali N, George M, Lahoti A, Palla S. Tolvaptan in hospitalized cancer patients with hyponatremia: a double-blind, randomized, placebo-controlled clinical trial on efficacy and safety. Cancer. 2014;120(5):744–751. doi:10.1002/cncr.28468
Shoaf SE, Bricmont P, Mallikaarjun S. Effects of CYP3A4 inhibition and induction on the pharmacokinetics and pharmacodynamics of tolvaptan, a non-peptide AVP antagonist in healthy subjects. Br J Clin Pharmacol. 2012;73(4):579–587. doi:10.1111/j.1365-2125.2011.04114.x
Petereit C, Zaba O, Teber I, Lüders H, Grohé C. A rapid and efficient way to manage hyponatremia in patients with SIADH and small cell lung cancer: treatment with tolvaptan. BMC Pulm Med. 2013;13(1):55. doi:10.1186/1471-2466-13-55
Berardi R, Mastroianni C, Lo Russo G, et al. Syndrome of inappropriate anti-diuretic hormone secretion in cancer patients: results of the first multicenter Italian study. Ther Adv Med Oncol. 2019;11:1758835919877725.
Berardi R, Lo Russo G, Tiseo M, et al. ASSERT: A Prospective, Observational Study Measuring Sodium Improvement and Outcomes in Patients Treated for Moderate to Severe Hyponatremia Secondary to SIADH. Poster Presented At: European Society for Medical Oncology (ESMO) Congress. Barcelona: Spain; 2019 September 27.
Selmer C, Madsen JC, Torp-Pedersen C, Gislason GH, Faber J. Hyponatremia, all-cause mortality, and risk of cancer diagnoses in the primary care setting: a large population study. Eur J Intern Med. 2016;36:36–43. doi:10.1016/j.ejim.2016.07.028
Mohan S, Gu S, Parikh A, Radhakrishnan J. Prevalence of hyponatremia and association with mortality: results from NHANES. Am J Med. 2013;126(12):1127–1137. doi:10.1016/j.amjmed.2013.07.021
Kang SH, Kim HW, Lee SY, et al. Is the sodium level per se related to mortality in hospitalized patients with severe hyponatremia? Clin Nephrol. 2012;77(3):182–187. doi:10.5414/CN107177
Kinsella S, Moran S, Sullivan MO, Molloy MG, Eustace JA. Hyponatremia independent of osteoporosis is associated with fracture occurrence. Clin J Am Soc Nephrol. 2010;5(2):275–280. doi:10.2215/CJN.06120809
Hoorn EJ, Rivadeneira F, Van Meurs JB, et al. Mild hyponatremia as a risk factor for fractures: the rotterdam study. J Bone Miner Res. 2011;26(8):1822–1828. doi:10.1002/jbmr.380
Verbalis JG, Barsony J, Sugimura Y, et al. Hyponatremia-induced osteoporosis. J Bone Miner Res. 2010;25(3):554–563. doi:10.1359/jbmr.090827
Ayus JC, Negri AL, Kalantar-Zadeh K, Moritz ML. Is chronic hyponatremia a novel risk factor for hip fracture in the elderly? Nephrol Dial Transplant. 2012;27(10):3725–3731. doi:10.1093/ndt/gfs412
Berghmans T, Paesmans M, Body JJ. A prospective study on hyponatraemia in medical cancer patients: epidemiology, aetiology and differential diagnosis. Support Care Cancer. 2000;8(3):192–197. doi:10.1007/s005200050284
Petereit C, Zaba O, Teber I, Grohé C. Is hyponatraemia a prognostic marker of survival for lung cancer? Pneumologie. 2011;65(9):565–571. doi:10.1055/s-0030-1256668
Hansen O, Sørensen P, Hansen KH. The occurrence of hyponatremia in SCLC and the influence on prognosis: a retrospective study of 453 patients treated in a single institution in a 10-year period. Lung Cancer. 2010;68(1):111–114. doi:10.1016/j.lungcan.2009.05.015
Corona G, Giuliani C, Parenti G, et al. Moderate hyponatremia is associated with increased risk of mortality: evidence from a meta-analysis. PLoS One. 2013;8(12):e80451. doi:10.1371/journal.pone.0080451
Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Survival determinants in extensive-stage non-small-cell lung cancer: the southwest oncology group experience. J Clin Oncol. 1991;9(9):1618–1626. doi:10.1200/JCO.1991.9.9.1618
Sengelov L, Kamby C, Geertsen P, Andersen LJ, Von der Maase H. Predictive factors of response to cisplatin-based chemotherapy and the relation of response to survival in patients with metastatic urothelial cancer. Cancer Chemother Pharmacol. 2000;46(5):357–364. doi:10.1007/s002800000176
Tai P, Yu E, Jones K, Sadikov E, Mahmood S, Tonita J. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) in patients with limited stage small cell lung cancer. Lung Cancer. 2006;53(2):211–215. doi:10.1016/j.lungcan.2006.05.009
Sengupta A, Banerjee SN, Biswas NM, et al. The incidence of hyponatraemia and its effect on the ECOG performance status among lung cancer patients. J Clin Diagn Res. 2013;7(8):1678–1682. doi:10.7860/JCDR/2013/5900.3225
Hermes A, Waschki B, Reck M. Hyponatremia as prognostic factor in small cell lung cancer, a retrospective single institution analysis. Respir Med. 2012;106(6):900–904. doi:10.1016/j.rmed.2012.02.010
Castillo JJ, Glezerman IG, Boklage SH, et al. The occurrence of hyponatremia and its importance as a prognostic factor in a cross-section of cancer patients. BMC Cancer. 2016;16(1):564. doi:10.1186/s12885-016-2610-9
Svaton M, Fiala O, Pesek M, et al. Predictive and prognostic significance of sodium levels in patients with NSCLC treated by erlotinib. Anticancer Res. 2014;34(12):7461–7465.
Berardi R, Santoni M, Newsom-Davis T, et al. Hyponatremia normalization as an independent prognostic factor in patients with advanced non-small cell lung cancer treated with first-line therapy. Oncotarget. 2017;8(14):23871–23879. doi:10.18632/oncotarget.13372
Kim HS, Yi SY, Jun HJ, et al. Clinical outcome of gastric cancer patients with bone marrow metastases. Oncology. 2007;73(3–4):192–197. doi:10.1159/000127386
Choi JS, Bae EH, Ma SK, Kweon SS, Kim SW. Prognostic impact of hyponatraemia in patients with colorectal cancer. Colorectal Dis. 2015;17(5):409–416. doi:10.1111/codi.12878
Berardi R, Caramanti M, Fiordoliva I, et al. Hyponatraemia is a predictor of clinical outcome for malignant pleural mesothelioma. Support Care Cancer. 2015;23(3):621–626. doi:10.1007/s00520-014-2398-6
Jeppesen AN, Jensen HK, Donskov F, Marcussen N, von der Maase H. Hyponatremia as a prognostic and predictive factor in metastatic renal cell carcinoma. Br J Cancer. 2010;102(5):867–872. doi:10.1038/sj.bjc.6605563
Vasudev NS, Brown JE, Brown SR, et al. Prognostic factors in renal cell carcinoma: association of preoperative sodium concentration with survival. Clin Cancer Res. 2008;14(6):1775–1781. doi:10.1158/1078-0432.CCR-07-1721
Tiseo M, Buti S, Boni, Mattioni R, Ardizzoni A. Prognostic role of hyponatremia in 564 small cell lung cancer patients treated with topotecan. Lung Cancer. 2014;86(1):91–95. doi:10.1016/j.lungcan.2014.07.022
Schutz FA, Xie W, Donskov F, et al. The impact of low serum sodium on treatment outcome of targeted therapy in metastatic renal cell carcinoma: results from the international metastatic renal cell cancer database consortium. Eur Urol. 2014;65(4):723–730. doi:10.1016/j.eururo.2013.10.013
Rinaldi S, Santoni M, Leoni G, et al. The prognostic and predictive role of hyponatremia in patients with advanced non-small cell lung cancer (NSCLC) with bone metastases. Support Care Cancer. 2019;27(4):1255–1261. doi:10.1007/s00520-018-4489-2
Peri A, Giuliani C. Management of euvolemic hyponatremia attributed to SIADH in the hospital setting. Minerva Endocrinol. 2014;39(1):33–41.
Berardi R, Caramanti M, Castagnani M, et al. Hyponatremia is a predictor of hospital length and cost of stay and outcome in cancer patients. Supp Care Cancer. 2015;23(10):3095–3101. doi:10.1007/s00520-015-2683-z
Nelson M, Palmer JL, Fu J, Williams JL, Yadav R, Guo Y. Hyponatraemia in cancer patients on an inpatient rehabilitation unit. Eur J Cancer Care. 2014;23(3):363–369. doi:10.1111/ecc.12140
Berardi R, Mastroianni C, Lo Russo G, et al. Syndrome of inappropriate anti-diuretic hormone secretion in cancer patients: results of the first multicenter Italian study. Ther Adv Med Oncol. 2019;11:1758835919877725. doi:10.1177/1758835919877725
