Hyponatremia and Hepatorenal Syndrome Arpan Mohanty, MD, and Guadalupe Garcia-Tsao, MD Dr Mohanty is a clinical fellow in the Abstract: Hyponatremia and hepatorenal syndrome are severe Section of Digestive Diseases at Yale complications in patients with cirrhosis and ascites resulting from University School of Medicine in New circulatory abnormalities (splanchnic and systemic vasodilata- Haven, Connecticut and is affiliated with tion) that develop with portal hypertension. Both conditions are the Section of Digestive Diseases at the Veterans Administration–Connecticut associated with an increased risk of death. Hyponatremia and Health Care System in West Haven, renal failure may develop in patients with cirrhosis due to causes Connecticut. Dr Garcia-Tsao is a professor other than portal hypertension. Making an accurate differential of medicine in the Section of Digestive diagnosis is important both therapeutically and prognostically. In Diseases at Yale University School of this article, we discuss the pathophysiology, diagnosis, differential Medicine and is the chief of the Section of diagnosis, and management of hyponatremia and hepatorenal Digestive Diseases at the Veterans Adminis- tration–Connecticut Health Care System. syndrome in patients with cirrhosis. Address correspondence to: Dr Guadalupe Garcia-Tsao Section of Digestive Diseases Yale University School of Medicine One Gilbert Street, TAC, #S241-B yponatremia and hepatorenal syndrome (HRS) are severe New Haven, CT 06510 complications that occur in patients with cirrhosis and Tel: 203-737-6063 ascites and are associated with lower survival than in Fax: 203-785-7273 Hpatients with decompensated cirrhosis (eg, those who have uncom- E-mail: [email protected] plicated ascites, variceal hemorrhage, or encephalopathy).1,2 There- fore, the development of these 2 complications represents a stage of further decompensation of cirrhosis. Dilutional hyponatremia and HRS (a type of renal failure unique to patients with cirrhosis) represent manifestations of a con- tinuum of pathophysiologic events stemming from portal hyperten- sion and the resultant vasodilatation, which are the main mecha- nisms responsible for the development of ascites.3 In a prospective inception cohort study of patients with cirrhosis and new-onset ascites who were followed for a mean of 41 months, hyponatremia developed in 28% of the patients, 11% developed refractory asci- tes, and 8% developed HRS, suggesting a sequential process (from ascites to hyponatremia to refractory ascites to HRS).4 Each of these processes was associated with increasing severity of liver disease, worsening vasodilatation evidenced by decreasing mean arterial pressure (MAP), and more avid sodium retention.3 However, it is important to recognize that hyponatremia and renal failure in the patient with cirrhosis may result from conditions Keywords Hyponatremia, hepatorenal syndrome, cirrhosis, that occur in noncirrhotic patients and that result from pathophysi- ascites ologic mechanisms different from worsening portal hypertension/ 220 Gastroenterology & Hepatology Volume 11, Issue 4 April 2015 HYPONATREMIA AND HEPATORENAL SYNDROME vasodilatation. Making an accurate differential diagnosis Cirrhosis is important both prognostically and therapeutically. We therefore review the pathophysiology, diagnosis, differ- ential diagnosis, and management of hyponatremia and Portal hypertension HRS in patients with cirrhosis. Splanchnic/systemic vasodilatation Pathophysiology of Hyponatremia and Hepatorenal Syndrome Eective arterial blood volume Vasodilatation of both the splanchnic and systemic cir- culations is one of the main factors contributing to the Activation of neurohumoral systems : development of hyponatremia and HRS in cirrhosis Renin- (Figure 1). Vasodilatation occurs after portal hyperten- Aldosterone AVP Angiotensin sion has led to the formation of portosystemic collaterals when factors that have not been well elucidated (vascular Sodium Water Renal endothelial growth factor being one of them) trigger the retention retention vasoconstriction production of nitric oxide and other vasodilators.5,6 This vasodilatation leads to decreased effective arterial volume Dilutional Hepatorenal Ascites and activation of various vasoconstrictor and antinatri- hyponatremia syndrome uretic neurohumoral systems (the renin-angiotensin- aldosterone system and sympathetic nervous system), Figure 1. The pathophysiology of hyponatremia and hepa- leading to renal sodium and water retention and an torenal syndrome (HRS) in cirrhosis. Cirrhosis and portal hypertension lead to the development of splanchnic and sys- increase in intravascular volume, which in turn leads to a temic vasodilatation that causes a decrease in effective circula- hyper dynamic circulatory state. tory volume, which in turn leads to the activation of various In advanced stages of cirrhosis, progressive vasodila- vasoconstrictor and antinatriuretic neurohumoral systems tation leads not only to avid sodium retention (with for- (renin-angiotensin-aldosterone system, sympathetic nervous mation of ascites that is now refractory to diuretics) but system, and nonosmotic release of antidiuretic hormone). This also to the nonosmotic release of antidiuretic hormone or initially leads to water and salt retention increasing intravascular arginine vasopressin (AVP). The biological effects of AVP volume and allowing for the continuous formation of ascites. in increasing water reabsorption are mediated through However, with worsening cirrhosis (or with precipitant fac- G protein–coupled receptors, specifically vasopressin 2 tors), splanchnic/systemic vasodilatation worsens, leading to a (V2) receptors located on the basolateral membrane of significant increase in antidiuretic hormone release and water principal cells of the collecting ducts. When activated by retention (in excess of sodium retention) and, thereby, to dilu- tional hyponatremia. Maximal vasodilatation and activation of AVP, V2 receptors enable translocation of selective water vasoconstrictive systems (renin-angiotensin) lead to renal vaso- channels called aquaporins from the cytosol to the lumi- constriction and the development of HRS. nal plasma membrane of the collecting ducts, increasing water permeability. This increase in water reabsorption AVP, arginine vasopressin. exceeds that of sodium retention and leads to dilutional hyponatremia. V2 receptor antagonism has therefore event. However, more often than not, HRS is precipi- been a potential target for drugs used in the treatment of tated by factors that cause either a decrease in effective this dilutional hyponatremia. arterial blood volume, such as rapid fluid loss (eg, exces- Progressive vasodilatation also leads to further sive diuresis and gastrointestinal bleeding), or worsening activation of vasoconstrictive systems (mainly renin and vasodilatation induced by drugs (eg, nitrates, carvedilol, angiotensin), resulting in renal vasoconstriction and and angiotensin-converting enzyme inhibitors) or by a decreased renal blood flow. In addition, a relative decrease systemic inflammatory response (eg, infection). in cardiac output in this high-output cardiac failure state (or cirrhotic cardiomyopathy) may further contribute Hyponatremia in Cirrhosis to decreased renal blood flow.5,7,8 This decrease in renal blood flow leads to a decreased glomerular filtration rate Hyponatremia in cirrhosis has been arbitrarily defined as and a prerenal type of kidney injury (ie, HRS). a serum sodium level of less than 130 mEq/L and is pres- Hepatorenal physiology as described above may be ent in approximately one-fifth of patients with decom- present in many patients with advanced cirrhosis who pensated cirrhosis.9 It is important to note that, although may develop HRS without an obvious precipitating not meeting this definition, a serum sodium level of less Gastroenterology & Hepatology Volume 11, Issue 4 April 2015 221 MOHANTY AND GARCIA-TSAO than 135 mEq/L in patients listed for liver transplanta- mental component scores of the SF-36 questionnaire tion has been associated with increased mortality, inde- that assesses HRQOL.15 A recent study of the effect of pendent of Model for End-Stage Liver Disease (MELD) hyponatremia and hepatic encephalopathy on HRQOL score.1 In fact, the incorporation of serum sodium level demonstrated that patients with cirrhosis and hyponatre- into MELD (referred to as MELD-Na) has been shown mia but without hepatic encephalopathy have a poorer to predict survival more accurately than MELD alone10 HRQOL as measured by the Sickness Impact Profile, and will likely be used soon instead of MELD for organ despite better cognition, compared with those with con- allocation in the United States. comitant encephalopathy.16 Furthermore, in a prospective study, correction of hyponatremia was associated with Differential Diagnosis of Hyponatremia in Cirrhosis improvement in cognitive function and HRQOL.17 Hyponatremia in cirrhosis may be (1) hypervolemic or Pretransplant hyponatremia is an independent dilutional as a result of water retention (in excess of sodium predictor of short-term mortality after liver transplanta- retention) due to AVP activation secondary to vasodilata- tion.18,19 Rapid correction of hyponatremia in the postop- tion and decreased effective circulatory volume or (2) erative period can result in central pontine demyelinoly- hypovolemic as a result of sodium and fluid losses (mainly sis,20,21 a lethal neurologic complication that can result