Management of Hyponatremia in End-Stage Liver Disease

  • Vanessa G. Henke
  • Michael P. Bokoch
  • Linda L. LiuEmail author


The proper diagnosis of hyponatremia is a vital component of the perioperative care of liver transplant patients, as hyponatremia is common among patients with end-stage liver disease. The general recommendation for the treatment of chronic hyponatremia is to limit the speed of correction. Unfortunately, the peri-transplantation period is often punctuated by large fluctuations in serum sodium concentration, which increases the risk of neurologic complications and osmotic demyelination syndrome. Consequently, the therapeutic goals and management strategies for hyponatremia vary greatly between the pre-transplantation, intraoperative, and post-transplantation periods. In this chapter, the definition, prognosis, pathophysiology, and treatment of hyponatremia in patients with cirrhosis are reviewed.


Hyponatremia End-stage liver disease Diagnosis of hyponatremia Treatment of hyponatremia Intraoperative management Osmotic demyelination syndrome 


  1. 1.
    Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med. 2006;119:S30–5. CrossRefPubMedGoogle Scholar
  2. 2.
    Leung AA, McAlister FA, Rogers SO Jr, Pazo V, Wright A, Bates DW. Preoperative hyponatremia and perioperative complications. Arch Intern Med. 2012;172:1474–81. Scholar
  3. 3.
    Angeli P, Wong F, Watson H, Gines P, Investigators C. Hyponatremia in cirrhosis: results of a patient population survey. Hepatology. 2006;44:1535–42. Scholar
  4. 4.
    Guevara M, Baccaro ME, Torre A, Gomez-Anson B, Rios J, Torres F, et al. Hyponatremia is a risk factor of hepatic encephalopathy in patients with cirrhosis: a prospective study with time-dependent analysis. Am J Gastroenterol. 2009;104:1382–9. Scholar
  5. 5.
    Gines P, Guevara M. Hyponatremia in cirrhosis: pathogenesis, clinical significance, and management. Hepatology. 2008;48:1002–10. Scholar
  6. 6.
    Amodio P, Del Piccolo F, Petteno E, Mapelli D, Angeli P, Iemmolo R, et al. Prevalence and prognostic value of quantified electroencephalogram (EEG) alterations in cirrhotic patients. J Hepatol. 2001;35:37–45.CrossRefGoogle Scholar
  7. 7.
    Sola E, Watson H, Graupera I, Turon F, Barreto R, Rodriguez E, et al. Factors related to quality of life in patients with cirrhosis and ascites: relevance of serum sodium concentration and leg edema. J Hepatol. 2012;57:1199–206. Scholar
  8. 8.
    Saab S, Ibrahim AB, Shpaner A, Younossi ZM, Lee C, Durazo F, et al. MELD fails to measure quality of life in liver transplant candidates. Liver Transpl. 2005;11:218–23. Scholar
  9. 9.
    Sterns RH, Silver SM. Brain volume regulation in response to hypo-osmolality and its correction. Am J Med. 2006;119:S12–6. CrossRefPubMedGoogle Scholar
  10. 10.
    Cordoba J, Gottstein J, Blei AT. Chronic hyponatremia exacerbates ammonia-induced brain edema in rats after portacaval anastomosis. J Hepatol. 1998;29:589–94.CrossRefGoogle Scholar
  11. 11.
    Heuman DM, Abou-Assi SG, Habib A, Williams LM, Stravitz RT, Sanyal AJ, et al. Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death. Hepatology. 2004;40:802–10. Scholar
  12. 12.
    Biggins SW, Rodriguez HJ, Bacchetti P, Bass NM, Roberts JP, Terrault NA. Serum sodium predicts mortality in patients listed for liver transplantation. Hepatology. 2005;41:32–9. Scholar
  13. 13.
    Ruf AE, Kremers WK, Chavez LL, Descalzi VI, Podesta LG, Villamil FG. Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone. Liver Transpl. 2005;11:336–43. Scholar
  14. 14.
    Kim WR, Biggins SW, Kremers WK, Wiesner RH, Kamath PS, Benson JT, et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med. 2008;359:1018–26. Scholar
  15. 15.
    Londono MC, Cardenas A, Guevara M, Quinto L, de Las Heras D, Navasa M, et al. MELD score and serum sodium in the prediction of survival of patients with cirrhosis awaiting liver transplantation. Gut. 2007;56:1283–90. Scholar
  16. 16.
    Cardenas A, Sola E, Rodriguez E, Barreto R, Graupera I, Pavesi M, et al. Hyponatremia influences the outcome of patients with acute-on-chronic liver failure: an analysis of the CANONIC study. Crit Care. 2014;18:700. Scholar
  17. 17.
    Machicao VI. Model for end-stage liver disease-sodium score: the evolution in the prioritization of liver transplantation. Clin Liver Dis. 2017;21:275–87. Scholar
  18. 18.
    Fisher RA, Heuman DM, Harper AM, Behnke MK, Smith AD, Russo MW, et al. Region 11 MELD Na exception prospective study. Ann Hepatol. 2012;11:62–7.PubMedGoogle Scholar
  19. 19.
    Sharma P, Schaubel DE, Goodrich NP, Merion RM. Serum sodium and survival benefit of liver transplantation. Liver Transpl. 2015;21:308–13. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Leise MD, Yun BC, Larson JJ, Benson JT, Yang JD, Therneau TM, et al. Effect of the pretransplant serum sodium concentration on outcomes following liver transplantation. Liver Transpl. 2014;20:687–97. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Wang P, Huang G, Tam N, Wu C, Fu S, Hughes BP, et al. Influence of preoperative sodium concentration on outcome of patients with hepatitis B virus cirrhosis after liver transplantation. Eur J Gastroenterol Hepatol. 2016;28:1210–5. Scholar
  22. 22.
    Londono MC, Guevara M, Rimola A, Navasa M, Taura P, Mas A, et al. Hyponatremia impairs early posttransplantation outcome in patients with cirrhosis undergoing liver transplantation. Gastroenterology. 2006;130:1135–43. Scholar
  23. 23.
    Dawwas MF, Lewsey JD, Neuberger JM, Gimson AE. The impact of serum sodium concentration on mortality after liver transplantation: a cohort multicenter study. Liver Transpl. 2007;13:1115–24. Scholar
  24. 24.
    Urso C, Brucculeri S, Caimi G. Employment of vasopressin receptor antagonists in management of hyponatraemia and volume overload in some clinical conditions. J Clin Pharm Ther. 2015;40:376–85. Scholar
  25. 25.
    Asbert M, Gines A, Gines P, Jimenez W, Claria J, Salo J, et al. Circulating levels of endothelin in cirrhosis. Gastroenterology. 1993;104:1485–91.CrossRefGoogle Scholar
  26. 26.
    Bernardi M, Ricci CS, Santi L. Hyponatremia in patients with cirrhosis of the liver. J Clin Med. 2014;4:85–101. Scholar
  27. 27.
    Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014;170:G1–47. Scholar
  28. 28.
    Sterns RH, Hix JK, Silver SM. Management of hyponatremia in the ICU. Chest. 2013;144:672–9. Scholar
  29. 29.
    Sterns RH, Nigwekar SU, Hix JK. The treatment of hyponatremia. Semin Nephrol. 2009;29:282–99. Scholar
  30. 30.
    Sterns RH, Hix JK, Silver S. Treating profound hyponatremia: a strategy for controlled correction. Am J Kidney Dis. 2010;56:774–9. Scholar
  31. 31.
    Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120:S1–21. CrossRefPubMedGoogle Scholar
  32. 32.
    Hoorn EJ, Zietse R. Diagnosis and treatment of hyponatremia: compilation of the guidelines. J Am Soc Nephrol. 2017;28:1340–9. Scholar
  33. 33.
    Norenberg MD. Central pontine myelinolysis: historical and mechanistic considerations. Metab Brain Dis. 2010;25:97–106. Scholar
  34. 34.
    Gankam Kengne F, Nicaise C, Soupart A, Boom A, Schiettecatte J, Pochet R, et al. Astrocytes are an early target in osmotic demyelination syndrome. J Am Soc Nephrol. 2011;22:1834–45. Scholar
  35. 35.
    Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013;126:S1–42. CrossRefPubMedGoogle Scholar
  36. 36.
    Yun BC, Kim WR, Benson JT, Biggins SW, Therneau TM, Kremers WK, et al. Impact of pretransplant hyponatremia on outcome following liver transplantation. Hepatology. 2009;49:1610–5. Scholar
  37. 37.
    Crivellin C, Cagnin A, Manara R, Boccagni P, Cillo U, Feltracco P, et al. Risk factors for central pontine and extrapontine myelinolysis after liver transplantation: a single-center study. Transplantation. 2015;99:1257–64. Scholar
  38. 38.
    Louis G, Megarbane B, Lavoue S, Lassalle V, Argaud L, Poussel JF, et al. Long-term outcome of patients hospitalized in intensive care units with central or extrapontine myelinolysis. Crit Care Med. 2012;40:970–2. Scholar
  39. 39.
    Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002;35:716–21. Scholar
  40. 40.
    Lee J, Kim DK, Lee JW, Oh KH, Oh YK, Na KY, et al. Rapid correction rate of hyponatremia as an independent risk factor for neurological complication following liver transplantation. Tohoku J Exp Med. 2013;229:97–105.CrossRefGoogle Scholar
  41. 41.
    Hix JK, Silver S, Sterns RH. Diuretic-associated hyponatremia. Semin Nephrol. 2011;31:553–66. Scholar
  42. 42.
    Rose BD, Post TW. Clinical physiology of acid-base and electrolyte disorders. 5th ed. Medical Publishing Division: McGraw-Hill; 2001.Google Scholar
  43. 43.
    John S, Thuluvath PJ. Hyponatremia in cirrhosis: pathophysiology and management. World J Gastroenterol. 2015;21:3197–205. Scholar
  44. 44.
    European Association for the Study of the L. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010;53:397–417. Scholar
  45. 45.
    Runyon BA. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013;57:1651–3. Scholar
  46. 46.
    Rose BD. New approach to disturbances in the plasma sodium concentration. Am J Med. 1986;81:1033–40.CrossRefGoogle Scholar
  47. 47.
    Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355:2099–112. Scholar
  48. 48.
    Wong F, Watson H, Gerbes A, Vilstrup H, Badalamenti S, Bernardi M, et al. Satavaptan for the management of ascites in cirrhosis: efficacy and safety across the spectrum of ascites severity. Gut. 2012;61:108–16. Scholar
  49. 49.
    Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367:2407–18. Scholar
  50. 50.
    Dahl E, Gluud LL, Kimer N, Krag A. Meta-analysis: the safety and efficacy of vaptans (tolvaptan, satavaptan and lixivaptan) in cirrhosis with ascites or hyponatraemia. Aliment Pharmacol Ther. 2012;36:619–26. Scholar
  51. 51.
    Rozen-Zvi B, Yahav D, Gheorghiade M, Korzets A, Leibovici L, Gafter U. Vasopressin receptor antagonists for the treatment of hyponatremia: systematic review and meta-analysis. Am J Kidney Dis. 2010;56:325–37. Scholar
  52. 52.
    O'Leary JG, Davis GL. Conivaptan increases serum sodium in hyponatremic patients with end-stage liver disease. Liver Transpl. 2009;15:1325–9. Scholar
  53. 53.
    Abbasoglu O, Goldstein RM, Vodapally MS, Jennings LW, Levy MF, Husberg BS, et al. Liver transplantation in hyponatremic patients with emphasis on central pontine myelinolysis. Clin Transpl. 1998;12:263–9.Google Scholar
  54. 54.
    Miller PD, Linas SL, Schrier RW. Plasma demeclocycline levels and nephrotoxicity. Correlation in hyponatremic cirrhotic patients. JAMA. 1980;243:2513–5.CrossRefGoogle Scholar
  55. 55.
    Gadano A, Moreau R, Pessione F, Trombino C, Giuily N, Sinnassamy P, et al. Aquaretic effects of niravoline, a kappa-opioid agonist, in patients with cirrhosis. J Hepatol. 2000;32:38–42.CrossRefGoogle Scholar
  56. 56.
    Brandman D, Biggins SW, Hameed B, Roberts JP, Terrault NA. Pretransplant severe hepatic encephalopathy, peritransplant sodium and post-liver transplantation morbidity and mortality. Liver Int. 2012;32:158–64. Scholar
  57. 57.
    Lee EM, Kang JK, Yun SC, Kim KH, Kim SJ, Hwang KS, et al. Risk factors for central pontine and extrapontine myelinolysis following orthotopic liver transplantation. Eur Neurol. 2009;62:362–8. Scholar
  58. 58.
    Morard I, Gasche Y, Kneteman M, Toso C, Mentha A, Meeberg G, et al. Identifying risk factors for central pontine and extrapontine myelinolysis after liver transplantation: a case-control study. Neurocrit Care. 2014;20:287–95. Scholar
  59. 59.
    Wszolek ZK, McComb RD, Pfeiffer RF, Steg RE, Wood RP, Shaw BW Jr, et al. Pontine and extrapontine myelinolysis following liver transplantation. Relationship to serum sodium. Transplantation. 1989;48:1006–12.CrossRefGoogle Scholar
  60. 60.
    Hudcova J, Ruthazer R, Bonney I, Schumann R. Sodium homeostasis during liver transplantation and correlation with outcomes. Anesth Analg. 2014;119:1420–8. Scholar
  61. 61.
    McCormick PA, Mistry P, Kaye G, Burroughs AK, McIntyre N. Intravenous albumin infusion is an effective therapy for hyponatraemia in cirrhotic patients with ascites. Gut. 1990;31:204–7.CrossRefGoogle Scholar
  62. 62.
    Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med. 2000;342:1581–9. Scholar
  63. 63.
    Larner AJ, Vickers CR, Adu D, Buckels JA, Elias E, Neuberger J. Correction of severe hyponatraemia by continuous arteriovenous haemofiltration before liver transplantation. BMJ. 1988;297:1514–5.CrossRefGoogle Scholar
  64. 64.
    Murphy N, Auzinger G, Bernel W, Wendon J. The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatology. 2004;39:464–70. Scholar
  65. 65.
    Hackworth WA, Heuman DM, Sanyal AJ, Fisher RA, Sterling RK, Luketic VA, et al. Effect of hyponatraemia on outcomes following orthotopic liver transplantation. Liver Int. 2009;29:1071–7. Scholar
  66. 66.
    Langer T, Ferrari M, Zazzeron L, Gattinoni L, Caironi P. Effects of intravenous solutions on acid-base equilibrium: from crystalloids to colloids and blood components. Anaesthesiol Intensive Ther. 2014;46:350–60. Scholar
  67. 67.
    Ghaffaripour S, Jannatmakan F, Firoozifar M. Practical protocol for management of severe hyponatremia in patients undergoing liver transplant surgery. Prog Transplant. 2015;25:106. Scholar
  68. 68.
    Atchison SR, Rettke SR, Fromme GA, Janossy TA, Kunkel SE, Williamson KR, et al. Plasma glucose concentrations during liver transplantation. Mayo Clin Proc. 1989;64:241–5.CrossRefGoogle Scholar
  69. 69.
    MacMillan TE, Tang T, Cavalcanti RB. Desmopressin to prevent rapid sodium correction in severe hyponatremia: a systematic review. Am J Med. 2015;128:1362 e15–24. Scholar
  70. 70.
    Brinson EL, Yu JS, Liu LL, Bokoch MP. Desmopressin reverses overly rapid serum sodium correction in a hyponatremic patient undergoing living donor liver transplantation: a case report. A A Pract. 2018;11(3):82–4.CrossRefGoogle Scholar
  71. 71.
    Bonham CA, Dominguez EA, Fukui MB, Paterson DL, Pankey GA, Wagener MM, et al. Central nervous system lesions in liver transplant recipients: prospective assessment of indications for biopsy and implications for management. Transplantation. 1998;66:1596–604.CrossRefGoogle Scholar
  72. 72.
    Rafat C, Schortgen F, Gaudry S, Bertrand F, Miguel-Montanes R, Labbe V, et al. Use of desmopressin acetate in severe hyponatremia in the intensive care unit. Clin J Am Soc Nephrol. 2014;9:229–37. Scholar
  73. 73.
    Perianayagam A, Sterns RH, Silver SM, Grieff M, Mayo R, Hix J, et al. DDAVP is effective in preventing and reversing inadvertent overcorrection of hyponatremia. Clin J Am Soc Nephrol. 2008;3:331–6. Scholar
  74. 74.
    Soupart A, Ngassa M, Decaux G. Therapeutic relowering of the serum sodium in a patient after excessive correction of hyponatremia. Clin Nephrol. 1999;51:383–6.PubMedGoogle Scholar
  75. 75.
    Oya S, Tsutsumi K, Ueki K, Kirino T. Reinduction of hyponatremia to treat central pontine myelinolysis. Neurology. 2001;57:1931–2.CrossRefGoogle Scholar
  76. 76.
    Saner FH, Koeppen S, Meyer M, Kohnle M, Herget-Rosenthal S, Sotiropoulos GC, et al. Treatment of central pontine myelinolysis with plasmapheresis and immunoglobulins in liver transplant patient. Transpl Int. 2008;21:390–1. Scholar
  77. 77.
    Butterworth RF. Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure. J Clin Exp Hepatol. 2015;5:S96–S103. CrossRefPubMedGoogle Scholar
  78. 78.
    Wendon J, Cordoba J, Dhawan A, Larsen FS, Manns M, Nevens F, et al. EASL 2017 clinical practice guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66:1047–81. Scholar
  79. 79.
    Lai A, Zeller M, Millen T, Kavsak P, Lamontagne F, Cook D, et al. Chloride concentration of commonly available 5% human albumin solutions. In: Paper presented at the Society of Critical Care Medicine 46th Critical Care Congress, Honolulu, 2016.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  • Vanessa G. Henke
    • 1
  • Michael P. Bokoch
    • 1
  • Linda L. Liu
    • 1
    Email author
  1. 1.Department of Anesthesia and Perioperative CareUniversity of California, San Francisco, School of MedicineSan FranciscoUSA

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