Hyponatremia in patients with cirrhosis
- Richard H Sterns, MD
Richard H Sterns, MD
- Editor-in-Chief — Nephrology
- Section Editor — Fluid and Electrolytes
- Professor of Medicine
- University of Rochester School of Medicine and Dentistry
- Bruce A Runyon, MD
Bruce A Runyon, MD
- Section Editor — Cirrhosis and Its Complications
- Clinical Professor of Medicine
- University of New Mexico, Division of Gastroenterology and Hepatology
- Special Hepatology Consultant to the Indian Health Service
- Northern Navajo Medical Center, Shiprock, New Mexico
Hyponatremia is a common problem in patients with advanced cirrhosis. The pathogenesis of hyponatremia in these patients is directly related to the hemodynamic changes and secondary neurohumoral adaptations that occur, resulting in an impaired ability to excrete ingested water. The severity of the hyponatremia is related to the severity of the cirrhosis . (See "Pathogenesis of ascites in patients with cirrhosis", section on 'Water retention'.)
A variety of factors can contribute to the development of hyponatremia in patients with cirrhosis. The most important factor is systemic vasodilation, which leads to activation of endogenous vasoconstrictors including antidiuretic hormone (ADH); ADH promotes the water retention that is responsible for the fall in serum sodium.
Systemic vasodilation — Systemic vasodilation plays a central role in the pathogenesis of hyponatremia in patients with cirrhosis and ascites. These patients usually have a marked reduction in systemic vascular resistance (SVR) and in mean arterial pressure and an increase in cardiac output [2-4]. The vascular territory in which the reduced SVR is most obvious is the splanchnic circulation .
The presence of vasodilation in other vascular territories is less obvious and the subject of controversy [6,7]. As an example, the factors that cause splanchnic vasodilatation may have a biphasic effect on the renal circulation. Early in the course of the disease – stable cirrhosis without ascites – the dilating substances also may influence the renal vasculature and the glomerular filtration rate may be greater than normal (150 versus 105 mL/min in one study) at this stage . With more severe disease, the splanchnic vasodilatation becomes more marked, resulting in a fall in mean arterial pressure and decreased renal perfusion, leading in some patients to the hepatorenal syndrome .
The precise mechanisms of vasodilation in cirrhosis have become better understood, with increased generation of nitric oxide and prostaglandins appearing to play an important role (algorithm 1). Nitric oxide production may be stimulated by absorbed endotoxin from the gastrointestinal tract, which is less efficiently cleared due to portal-systemic shunting and decreased reticuloendothelial cell function in cirrhosis [9,10]. (See "Pathogenesis of ascites in patients with cirrhosis".)
- Ginès P, Guevara M. Hyponatremia in cirrhosis: pathogenesis, clinical significance, and management. Hepatology 2008; 48:1002.
- KOWALSKI HJ, ABELMANN WH. The cardiac output at rest in Laennec's cirrhosis. J Clin Invest 1953; 32:1025.
- Abelmann WH. Hyperdynamic circulation in cirrhosis: a historical perspective. Hepatology 1994; 20:1356.
- Groszmann RJ. Hyperdynamic circulation of liver disease 40 years later: pathophysiology and clinical consequences. Hepatology 1994; 20:1359.
- Schrier RW, Arroyo V, Bernardi M, et al. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 1988; 8:1151.
- Fernandez-Seara J, Prieto J, Quiroga J, et al. Systemic and regional hemodynamics in patients with liver cirrhosis and ascites with and without functional renal failure. Gastroenterology 1989; 97:1304.
- Maroto A, Ginès P, Arroyo V, et al. Brachial and femoral artery blood flow in cirrhosis: relationship to kidney dysfunction. Hepatology 1993; 17:788.
- Wong F, Massie D, Colman J, Dudley F. Glomerular hyperfiltration in patients with well-compensated alcoholic cirrhosis. Gastroenterology 1993; 104:884.
- Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: a role for nitric oxide? Lancet 1991; 337:776.
- Guarner C, Soriano G, Tomas A, et al. Increased serum nitrite and nitrate levels in patients with cirrhosis: relationship to endotoxemia. Hepatology 1993; 18:1139.
- Asbert M, Ginès A, Ginès P, et al. Circulating levels of endothelin in cirrhosis. Gastroenterology 1993; 104:1485.
- Henriksen JH, Bendtsen F, Gerbes AL, et al. Estimated central blood volume in cirrhosis: relationship to sympathetic nervous activity, beta-adrenergic blockade and atrial natriuretic factor. Hepatology 1992; 16:1163.
- Arroyo V, Bosch J, Gaya-Beltrán J, et al. Plasma renin activity and urinary sodium excretion as prognostic indicators in nonazotemic cirrhosis with ascites. Ann Intern Med 1981; 94:198.
- Tsuboi Y, Ishikawa S, Fujisawa G, et al. Therapeutic efficacy of the non-peptide AVP antagonist OPC-31260 in cirrhotic rats. Kidney Int 1994; 46:237.
- Sacerdoti D, Bolognesi M, Merkel C, et al. Renal vasoconstriction in cirrhosis evaluated by duplex Doppler ultrasonography. Hepatology 1993; 17:219.
- Arroyo V, Clària J, Saló J, Jiménez W. Antidiuretic hormone and the pathogenesis of water retention in cirrhosis with ascites. Semin Liver Dis 1994; 14:44.
- Papadakis MA, Fraser CL, Arieff AI. Hyponatraemia in patients with cirrhosis. Q J Med 1990; 76:675.
- Sherlock S, Senewiratne B, Scott A, Walker JG. Complications of diuretic therapy in hepatic cirrhosis. Lancet 1966; 1:1049.
- Hilden T, Svendsen TL. Electrolyte disturbances in beer drinkers. A specific "hypo-osmolality syndrome". Lancet 1975; 2:245.
- Fenves AZ, Thomas S, Knochel JP. Beer potomania: two cases and review of the literature. Clin Nephrol 1996; 45:61.
- Angeli P, Wong F, Watson H, et al. Hyponatremia in cirrhosis: Results of a patient population survey. Hepatology 2006; 44:1535.
- Runyon BA. Ascites returns to the spotlight. Clinical Care Options for Hepatitis. http://www.clinicaloptions.com/Hepatitis.aspx (Accessed on August 26, 2014).
- Heuman DM, Abou-Assi SG, Habib A, 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.
- Biggins SW, Rodriguez HJ, Bacchetti P, et al. Serum sodium predicts mortality in patients listed for liver transplantation. Hepatology 2005; 41:32.
- Ruf AE, Kremers WK, Chavez LL, et al. Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone. Liver Transpl 2005; 11:336.
- Kim WR, Biggins SW, Kremers WK, et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med 2008; 359:1018.
- Samsca (Tolvaptan): Drug Safety Communication - FDA Limits Duration and Usage Due To Possible Liver Injury Leading to Organ Transplant or Death. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.htm (Accessed on May 20, 2013).
- Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006; 355:2099.
- Greenberg A, Verbalis JG. Vasopressin receptor antagonists. Kidney Int 2006; 69:2124.
- Verbalis JG, Goldsmith SR, Greenberg A, et al. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med 2007; 120:S1.
- Gerbes AL, Gülberg V, Ginès P, et al. Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a randomized double-blind multicenter trial. Gastroenterology 2003; 124:933.
- Wong F, Blei AT, Blendis LM, Thuluvath PJ. A vasopressin receptor antagonist (VPA-985) improves serum sodium concentration in patients with hyponatremia: a multicenter, randomized, placebo-controlled trial. Hepatology 2003; 37:182.
- Krag A, Møller S, Henriksen JH, et al. Terlipressin improves renal function in patients with cirrhosis and ascites without hepatorenal syndrome. Hepatology 2007; 46:1863.
- Higashihara E, Torres VE, Chapman AB, et al. Tolvaptan in autosomal dominant polycystic kidney disease: three years' experience. Clin J Am Soc Nephrol 2011; 6:2499.
- Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012; 367:2407.
- Forrest JN Jr, Cox M, Hong C, et al. Superiority of demeclocycline over lithium in the treatment of chronic syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med 1978; 298:173.
- Miller PD, Linas SL, Schrier RW. Plasma demeclocycline levels and nephrotoxicity. Correlation in hyponatremic cirrhotic patients. JAMA 1980; 243:2513.
- Lee J, Kim DK, Lee JW, 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.
- Yun BC, Kim WR, Benson JT, et al. Impact of pretransplant hyponatremia on outcome following liver transplantation. Hepatology 2009; 49:1610.
- Wszolek ZK, McComb RD, Pfeiffer RF, et al. Pontine and extrapontine myelinolysis following liver transplantation. Relationship to serum sodium. Transplantation 1989; 48:1006.
- Abbasoglu O, Goldstein RM, Vodapally MS, et al. Liver transplantation in hyponatremic patients with emphasis on central pontine myelinolysis. Clin Transplant 1998; 12:263.
- Bonham CA, Dominguez EA, Fukui MB, et al. Central nervous system lesions in liver transplant recipients: prospective assessment of indications for biopsy and implications for management. Transplantation 1998; 66:1596.
- Systemic vasodilation
- - Activation of endogenous vasoconstrictors
- Water retention
- PREDICTOR OF ADVERSE PROGNOSIS
- Decision to treat
- Therapeutic modalities
- - Fluid restriction
- - Correction of hypokalemia
- - Vasopressin receptor antagonists
- Do not use tolvaptan in patients with cirrhosis
- - Other
- Hypertonic saline, osmotic demyelination, and liver transplantation
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS