Skip to main content

Advertisement

SpringerLink
Log in

Hyponatremia in patients with liver diseases: not just a cirrhosis-induced hemodynamic compromise

  • Review Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Hyponatremia (Na+ <135 mmol/l) is the most common electrolyte disorder. Cirrhosis represents a rather frequent cause of hyponatremia mainly due to systemic and splanchnic vasodilation resulting in decreased effective arterial blood volume, which leads to excessive non-osmotic secretion of antidiuretic hormone. However, hyponatremia of multifactorial origin may be seen in patients with liver diseases. The review focuses on the factors and pathogenetic mechanisms of decreased sodium levels other than the hemodynamic compromise of cirrhosis in patients with liver diseases. The mechanisms and causal or contributing role of pseudohyponatremia, hyperglycemia, infections, drugs and toxins as well as of endocrine disorders, renal failure and cardiac disease in patients with liver disease are meticulously discussed. Hyponatremia of multifactorial origin is frequently observed in patients with liver diseases, and special efforts should be made to delineate the underlying causative and precipitating factors as well as the risk factors of the osmotic demyelination syndrome in order to properly manage this serious electrolyte disorder and avoid treatment pitfalls.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med 2006;119:S30–S35

  2. 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;126:256–263

  3. Filippatos TD, Milionis HJ, Elisaf MS. Alterations in electrolyte equilibrium in patients with acute leukemia. Eur J Haematol 2005;75:449–460

  4. Liamis G, Mitrogianni Z, Liberopoulos EN, Tsimihodimos V, Elisaf M. Electrolyte disturbances in patients with hyponatremia. Intern Med 2007;46:685–690

  5. Angeli P, Wong F, Watson H, Gines P. Hyponatremia in cirrhosis: Results of a patient population survey. Hepatology 2006;44:1535–1542

  6. Filippatos TD, Liamis G, Christopoulou F, Elisaf MS. Ten common pitfalls in the evaluation of patients with hyponatremia. Eur J Intern Med 2016;29:22–25

  7. John S, Thuluvath PJ. Hyponatremia in cirrhosis: pathophysiology and management. World J Gastroenterol. 2015;21:3197–3205

  8. Liamis G, Filippatos TD, Elisaf MS. Correction of hypovolemia with crystalloid fluids: individualizing infusion therapy. Postgrad Med 2015;127:405–412

  9. Berl T. Impact of solute intake on urine flow and water excretion. J Am Soc Nephrol 2008;19:1076–1078

  10. Liamis G, Liberopoulos E, Barkas F, Elisaf M. Spurious electrolyte disorders: a diagnostic challenge for clinicians. Am J Nephrol 2013;38:50–57

  11. Filippatos TD, Elisaf MS. Recommendations for severe hypertriglyceridemia treatment, are there new strategies? Curr Vasc Pharmacol 2014;12:598–616

  12. Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis 2008;52:144–153

  13. Steinberger BA, Ford SM, Coleman TA. Intravenous immunoglobulin therapy results in post-infusional hyperproteinemia, increased serum viscosity, and pseudohyponatremia. Am J Hematol 2003;73:97–100

  14. Hussain I, Ahmad Z, Garg A. Extreme hypercholesterolemia presenting with pseudohyponatremia—a case report and review of the literature. J Clin Lipidol 2015;9:260–264

  15. Vo H, Gosmanov AR, Garcia-Rosell M, Wall BM. Pseudohyponatremia in acute liver disease. Am J Med Sci 2013;345:62–64

  16. Garibaldi BT, Cameron SJ, Choi M. Pseudohyponatremia in a patient with HIV and hepatitis C coinfection. J Gen Intern Med 2008;23:202–205

  17. Farooqi MS, Hashim IA. A woman with primary biliary cirrhosis and hyponatremia. Clin Chem 2015;61:1028–1031

  18. Dimeski G, Morgan TJ, Presneill JJ, Venkatesh B. Disagreement between ion selective electrode direct and indirect sodium measurements: estimation of the problem in a tertiary referral hospital. J Crit Care 2012;27:326.e329–e316

  19. Garcia-Compean D, Gonzalez-Gonzalez JA, Lavalle-Gonzalez FJ, Gonzalez-Moreno EI, Villarreal-Perez JZ, Maldonado-Garza HJ. Current concepts in diabetes mellitus and chronic liver disease: clinical outcomes, hepatitis C virus association, and therapy. Dig Dis Sci 2016;61:371–80

  20. Porepa L, Ray JG, Sanchez-Romeu P, Booth GL. Newly diagnosed diabetes mellitus as a risk factor for serious liver disease. CMAJ 2010;182:E526–E531

  21. Hiraizumi Y, Nishimura I, Ishii H, Tanaka N, Takeshita T, Sakuma Y, Kato M. Rat GnRH neurons exhibit large conductance voltage- and Ca2+-Activated K+ (BK) currents and express BK channel mRNAs. J Physiol Sci 2008;58:21–29

  22. Petit JM, Hamza S, Rollot F, Sigonney V, Crevisy E, Duvillard L, Raab JJ, Bronowicki JP, Bernard-Chabert B, Di Martino V, Doffoel M, Barraud H, Richou C, Jouve JL, Hillon P. Impact of liver disease severity and etiology on the occurrence of diabetes mellitus in patients with liver cirrhosis. Acta Diabetol 2014;51:455–460

  23. Garcia-Compean D, Jaquez-Quintana JO, Maldonado-Garza H. Hepatogenous diabetes. Current views of an ancient problem. Ann Hepatol 2009;8:13–20

  24. Dehghani SM, Nikeghbalian S, Eshraghian A, Haghighat M, Imanieh MH, Bahador A, Kazemi K, Malek-Hosseini SA. New-onset diabetes mellitus presenting with diabetic ketoacidosis after pediatric liver transplantation. Pediatr Transplant 2009;13:536–539

  25. Zornitzki T, Malnick S, Lysyy L, Knobler H. Interferon therapy in hepatitis C leading to chronic type 1 diabetes. World J Gastroenterol 2015;21:233–239

  26. Abdel-Hamid N, Jubori TA, Farhan A, Mahrous M, Gouri A, Awad E, Breuss J. Underlying pathways for interferon risk to type II diabetes mellitus. Curr Diabetes Rev 2013;9:472–477

  27. Gearhart MM, Parbhoo SK. Hyperglycemia in the critically ill patient. AACN Clin Issues 2006;17:50–55

  28. Hillier TA, Abbott RD, Barrett EJ. Hyponatremia: evaluating the correction factor for hyperglycemia. Am J Med 1999;106:399–403

  29. Chiasson JL, Aris-Jilwan N, Belanger R, Bertrand S, Beauregard H, Ekoe JM, Fournier H, Havrankova J. Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state. CMAJ 2003;168:859–866

  30. Liamis G, Liberopoulos E, Barkas F, Elisaf M. Diabetes mellitus and electrolyte disorders. World J Clin Cases 2014;2:488–496

  31. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med 2006;354:731–739

  32. Liamis GL, Milionis HJ, Rizos EC, Siamopoulos KC, Elisaf MS. Mechanisms of hyponatraemia in alcohol patients. Alcohol Alcohol 2000;35:612–616

  33. Yim SY, Seo YS, Jung CH, Kim TH, Kim ES, Keum B, Kim JH, An H, Yim HJ, Yeon JE, Jeen YT, Lee HS, Chun HJ, Byun KS, Um SH, Kim CD, Ryu HS. Risk factors for developing hyponatremia during terlipressin treatment: a retrospective analyses in variceal bleeding. J Clin Gastroenterol 2015;49:607–612

  34. Uriz J, Gines P, Cardenas A, Sort P, Jimenez W, Salmeron JM, Bataller R, Mas A, Navasa M, Arroyo V, Rodes J. Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome. J Hepatol 2000;33:43–48

  35. Prakoso E, Jones C, Koorey DJ, Strasser SI, Bowen D, McCaughan GW, Shackel NA. Terlipressin therapy for moderate-to-severe hyponatraemia in patients with liver failure. Intern Med J 2013;43:240–246

  36. Krag A. Terlipressin and hyponatraemia: the cause or the treatment? Intern Med J 2013;43:606–607

  37. Handler J. Well tolerated spironolactone-related hyponatremia. J Clin Hypertens (Greenwich) 2008;10:317–321

  38. Tanaka M, Kamoi K, Takahashi T. Interferon-alpha is a predisposing risk factor for carbamazepine-induced hyponatremia: a case of syndrome of inappropriate antidiuresis caused by interferon-alpha therapy. Int J Gen Med 2008;1:21–25

  39. Ridruejo E, Christensen AF, Mando OG. Central hypothyroidism and hypophysitis during treatment of chronic hepatitis C with pegylated interferon alpha and ribavirin. Eur J Gastroenterol Hepatol 2006;18:693–694

  40. Liamis G, Milionis HJ, Elisaf M. Endocrine disorders: causes of hyponatremia not to neglect. Ann Med 2011;43:179–187

  41. Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, Hsu CH, Hu TH, Heo J, Xu J, Lu L, Chao Y, Boucher E, Han KH, Paik SW, Robles-Avina J, Kudo M, Yan L, Sobhonslidsuk A, Komov D, Decaens T, Tak WY, Jeng LB, Liu D, Ezzeddine R, Walters I, Cheng AL. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol 2013;31:3517–3524

  42. Abou-Alfa GK, Capanu M, O’Reilly EM, Ma J, Chou JF, Gansukh B, Shia J, Kalin M, Katz S, Abad L, Reidy-Lagunes DL, Kelsen DP, Chen HX, Saltz LB. A phase II study of cixutumumab (IMC-A12, NSC742460) in advanced hepatocellular carcinoma. J Hepatol 2014;60:319–324

  43. Hedrick KT, Just SM, Kahn DR. Probable boceprevir-induced hyponatremia in a patient with chronic hepatitis C. Am J Health Syst Pharm 2015;72:449–452

  44. Liamis G, Milionis HJ, Elisaf M. Hyponatremia in patients with infectious diseases. J Infect 2011;63:327–335

  45. Brandolini M, Corbella M, De Silvestri A, Tinelli C, Albonico G, Albertini R, Ludovisi S, Bruno R, Marone P, Minoli L, Seminari E. Epidemiological characteristics of bloodstream infections in patients with different degrees of liver disease Infection. 2015;43:561–567

  46. Kim AC, Epstein ME, Gautam-Goyal P, Doan TL. Infections in alcoholic liver disease. Clin Liver Dis 2012;16:783–803

  47. Wang QM, Ji Q, Duan ZJ, Zhang M, Chang QY. A study on the position and etiology of infection in cirrhotic patients: a potential precipitating factor contributing to hepatic encephalopathy. Exp Ther Med 2013;6:584–590

  48. Radha Krishna Y, Saraswat VA, Das K, Himanshu G, Yachha SK, Aggarwal R, Choudhuri G. Clinical features and predictors of outcome in acute hepatitis A and hepatitis E virus hepatitis on cirrhosis. Liver Int 2009;29:392–398

  49. Terg R, Gadano A, Cartier M, Casciato P, Lucero R, Munoz A, Romero G, Levi D, Terg G, Miguez C, Abecasis R. Serum creatinine and bilirubin predict renal failure and mortality in patients with spontaneous bacterial peritonitis: a retrospective study. Liver Int 2009;29:415–419

  50. Murthy KA, Khan IM, Kiran PK, Hakeem H. A study of viral hepatitis e infection in a tertiary care hospital in Mysore, South India. Open Forum Infect Dis 2014;1:ofu036

  51. Gazi IF, Apostolou FA, Liberopoulos EN, Filippatos TD, Tellis CC, Elisaf MS, Tselepis AD. Leptospirosis is associated with markedly increased triglycerides and small dense low-density lipoprotein and decreased high-density lipoprotein. Lipids 2011;46:953–960

  52. Daher EF, Silva GB, Jr., Karbage NN, Carvalho PC, Jr., Kataoka RS, Silva EC, Magalhaes MM, Mota RM, Araujo SM, Gutierrez-Adrianzen OA, Liborio AB. Predictors of oliguric acute kidney injury in leptospirosis. A retrospective study on 196 consecutive patients. Nephron Clin Pract 2009;112:c25–c30

  53. Maheshwari A, Thuluvath PJ. Endocrine diseases and the liver. Clin Liver Dis 2011;15:55–67

  54. Kanda K, Kayahara T, Seno H, Yamashita Y, Chiba T. Conversion from latent to symptomatic Sheehan’s syndrome by pegylated interferon therapy for chronic hepatitis C. Intern Med 2008;47:939–941

  55. Karagiannis AK, Nakouti T, Pipili C, Cholongitas E. Adrenal insufficiency in patients with decompensated cirrhosis. World J Hepatol 2015;7:1112–1124

  56. Ludwig U, Holzner D, Denzer C, Greinert A, Haenle MM, Oeztuerk S, Koenig W, Boehm BO, Mason RA, Kratzer W, Graeter T. Subclinical and clinical hypothyroidism and non-alcoholic fatty liver disease: a cross-sectional study of a random population sample aged 18 to 65 years. BMC Endocr Disord 2015;15:41

  57. Hegedus L, Rasmussen N, Ravn V, Kastrup J, Krogsgaard K, Aldershvile J. Independent effects of liver disease and chronic alcoholism on thyroid function and size: the possibility of a toxic effect of alcohol on the thyroid gland. Metabolism 1988;37:229–233

  58. Combs S, Berl T. Dysnatremias in patients with kidney disease. Am J Kidney Dis 2014;63:294–303

  59. Bozanich NK, Kwo PY. Renal insufficiency in the patient with chronic liver disease. Clin Liver Dis 2015;19:45–56

  60. Mairiang P, Bhudhisawasdi V, Borirakchanyavat V, Sitprija V. Acute renal failure in obstructive jaundice in cholangiocarcinoma. Arch Intern Med 1990;150:2357–2360

  61. Basu G, Chrispal A, Boorugu H, Gopinath KG, Chandy S, Prakash JA, Thomas K, Abraham AM, John GT. Acute kidney injury in tropical acute febrile illness in a tertiary care centre-RIFLE criteria validation. Nephrol Dial Transplant 2011;26:524–531

  62. Yalavarthy R, Edelstein CL, Teitelbaum I. Acute renal failure and chronic kidney disease following liver transplantation. Hemodial Int 2007;11 Suppl 3:S7–S12

  63. Qureshi MO, Shafqat F, Dar FS, Salih M, Khokhar N. Renal failure in patients with end stage liver disease and its impact on clinical outcome. J Coll Physicians Surg Pak 2014;24:628–631

  64. Barbano B, Sardo L, Gigante A, Gasperini ML, Liberatori M, Giraldi GD, Lacanna A, Amoroso A, Cianci R. Pathophysiology, diagnosis and clinical management of hepatorenal syndrome: from classic to new drugs. Curr Vasc Pharmacol 2014;12:125–135

  65. Pereira G, Guevara M, Fagundes C, Sola E, Rodriguez E, Fernandez J, Pavesi M, Arroyo V, Gines P. Renal failure and hyponatremia in patients with cirrhosis and skin and soft tissue infection. A retrospective study. J Hepatol 2012;56:1040–1046

  66. Filippatos TD, Elisaf MS. Hyponatremia in patients with heart failure. World J Cardiol 2013;5:317–328

  67. Liamis G, Filippatos T, Elisaf M. Thiazide–associated hyponatremia in the elderly: what the clinician needs to know. J Geriatr Cardiol 2016;13:175–82

  68. Ford RM, Book W, Spivey JR. Liver disease related to the heart. Transplant Rev (Orlando) 2015;29:33–37

  69. Auletta M, Oliviero U, Iasiuolo L, Scherillo G, Antoniello S. Pulmonary hypertension associated with liver cirrhosis: an echocardiographic study. Angiology 2000;51:1013–1020

  70. Ocel JJ, Edwards WD, Tazelaar HD, Petrovic LM, Edwards BS, Kamath PS. Heart and liver disease in 32 patients undergoing biopsy of both organs, with implications for heart or liver transplantation. Mayo Clin Proc 2004;79:492–501

  71. Guimaraes EV, Schettino GC, Camargos PA, Penna FJ. Prevalence of hyponatremia at diagnosis and factors associated with the longitudinal variation in serum sodium levels in infants with cystic fibrosis. J Pediatr 2012;161:285–289

  72. Eltawansy S, Gomez J, Liss K, Nivera N, Babyatsky M. Syndrome of inappropriate anti-diuretic hormone secondary to non-cirrhotic primary hepatocellular carcinoma. Am J Case Rep 2015;16:31–36

  73. Cardenas A, Sola E, Rodriguez E, Barreto R, Graupera I, Pavesi M, Saliba F, Welzel TM, Martinez-Gonzalez J, Gustot T, Bernardi M, Arroyo V, Gines P. Hyponatremia influences the outcome of patients with acute-on-chronic liver failure: an analysis of the CANONIC study. Crit Care 2014;18:700

  74. Moini M, Hoseini-Asl MK, Taghavi SA, Sagheb MM, Nikeghbalian S, Salahi H, Bahador A, Motazedian M, Jafari P, Malek-Hosseini SA. Hyponatremia a valuable predictor of early mortality in patients with cirrhosis listed for liver transplantation. Clin Transplant 2011;25:638–645

  75. Serste T, Gustot T, Rautou PE, Francoz C, Njimi H, Durand F, Valla D, Lebrec D, Moreau R. Severe hyponatremia is a better predictor of mortality than MELDNa in patients with cirrhosis and refractory ascites. J Hepatol 2012;57:274–280

  76. Kim WR, Biggins SW, Kremers WK, Wiesner RH, Kamath PS, Benson JT, Edwards E, Therneau TM. Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med 2008;359:1018–1026

  77. Roman E, Cordoba J, Torrens M, Guarner C, Soriano G. Falls and cognitive dysfunction impair health-related quality of life in patients with cirrhosis. Eur J Gastroenterol Hepatol 2013;25:77–84

  78. Londono MC, Guevara M, Rimola A, Navasa M, Taura P, Mas A, Garcia-Valdecasas JC, Arroyo V, Gines P. Hyponatremia impairs early posttransplantation outcome in patients with cirrhosis undergoing liver transplantation. Gastroenterology 2006;130:1135–1143

  79. Wong VW, Chim AM, Wong GL, Sung JJ, Chan HL. Performance of the new MELD-Na score in predicting 3-month and 1-year mortality in Chinese patients with chronic hepatitis B. Liver Transpl 2007;13:1228–1235

  80. Biggins SW, Kim WR, Terrault NA, Saab S, Balan V, Schiano T, Benson J, Therneau T, Kremers W, Wiesner R, Kamath P, Klintmalm G. Evidence-based incorporation of serum sodium concentration into MELD. Gastroenterology 2006;130:1652–1660

  81. Biggins SW, Rodriguez HJ, Bacchetti P, Bass NM, Roberts JP, Terrault NA. Serum sodium predicts mortality in patients listed for liver transplantation. Hepatology 2005;41:32–39

  82. Londono MC, Cardenas A, Guevara M, Quinto L, de Las Heras D, Navasa M, Rimola A, Garcia-Valdecasas JC, Arroyo V, Gines P. MELD score and serum sodium in the prediction of survival of patients with cirrhosis awaiting liver transplantation. Gut 2007;56:1283–1290

  83. Amieva-Balmori M, Mejia-Loza SM, Ramos-Gonzalez R, Zamarripa-Dorsey F, Garcia-Ruiz E, Perez YLN, Juarez-Valdes EI, Lopez-Luria A, Remes-Troche JM. Model for end-stage liver disease-Na score or Maddrey discrimination function index, which score is best? World J Hepatol 2015;7:2119–2126

  84. Cheng XP, Zhao J, Chen Y, Meng FK, Xu B, Yu HW, Meng QH, Liu YM, Zhang SB, Meng S, Zhang JY, Zhang JY, Duan ZP, Zheng SJ. Comparison of the ability of the PDD-ICG clearance test, CTP, MELD, and MELD-Na to predict short-term and medium-term mortality in patients with decompensated hepatitis B cirrhosis. Eur J Gastroenterol Hepatol 2016;28:444–448

  85. Lv XH, Liu HB, Wang Y, Wang BY, Song M, Sun MJ. Validation of model for end-stage liver disease score to serum sodium ratio index as a prognostic predictor in patients with cirrhosis. J Gastroenterol Hepatol 2009;24:1547–1553

  86. Shen Y, Liu YM, Wang B, Zhu YG, Wang YY, Wang XL, Ji JL, Shao JG, Qin Y, Qin G. External validation and comparison of six prognostic models in a prospective cohort of HBV-ACLF in China. Ann Hepatol 2016;15:236–245

  87. Huo TI, Wang YW, Yang YY, Lin HC, Lee PC, Hou MC, Lee FY, Lee SD. Model for end-stage liver disease score to serum sodium ratio index as a prognostic predictor and its correlation with portal pressure in patients with liver cirrhosis. Liver Int 2007;27:498–506

  88. Liamis G, Filippatos TD, Elisaf MS. Treatment of hyponatremia: the role of lixivaptan. Expert Rev Clin Pharmacol 2014;7:431–441

  89. Lauriat SM, Berl T. The hyponatremic patient: practical focus on therapy. J Am Soc Nephrol 1997;8:1599–1607

  90. Singh TD, Fugate JE, Rabinstein AA. Central pontine and extrapontine myelinolysis: a systematic review. Eur J Neurol 2014;21:1443–1450

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, School of Medicine, University of Ioannina, 451 10, Ioannina, Greece

    G. Liamis, T. D. Filippatos, A. Liontos & M. S. Elisaf

Authors
  1. G. Liamis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. D. Filippatos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Liontos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. S. Elisaf
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T. D. Filippatos.

Ethics declarations

Conflict of interest

The present review was written independently; no company or institution supported it financially. The authors have no conflict of interest relevant to this manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liamis, G., Filippatos, T.D., Liontos, A. et al. Hyponatremia in patients with liver diseases: not just a cirrhosis-induced hemodynamic compromise. Hepatol Int 10, 762–772 (2016). https://doi.org/10.1007/s12072-016-9746-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-016-9746-1

Keywords

Search

Navigation