Epidemiology and Pathogenesis

Unlike hypernatremia, hyponatremia is very common in patients with cirrhosis and ascites. Its prevalence depends on the criteria used to define it. In a prospective study in patients with cirrhosis and ascites, the prevalence of hyponatremia, defined by a serum sodium concentration ≤135 mmol/L, was found to be 28%. Patients with cirrhosis develop two types of hyponatremia: (i) hypovolemic hyponatremia, or (ii) hypervolemic hyponatremia. Hypovolemic hyponatremia is characterized by low serum sodium associated with contraction of plasma volume, lack of edema, ascites, and prerenal renal failure. Hypervolemic or dilutional hyponatremia is due to a marked impairment of renal solute-free water excretion, resulting in a disproportionate renal retention of water with respect to sodium. As a consequence, the most stricking difference between these two conditions lies in the volume status which is reduced in hypovolemic hyponatremia and increased in hypervolemic hyponatremia. Hypervolemic hyponatremia is much more common than hypovolemic hyponatremia in patients with cirrhosis and ascites, thus, this chapter discusses to hypervolemic hyponatremia.

Clinically significant hyponatremia (serum sodium value ≤130 mmol/L) in patients with cirrhosis is associated with severe liver disease as reflected by a high Child–Pugh score, poor control of ascites, and serum creatinine value >108 μmol/L [1]. Its pathogenesis is related to a higher rate of renal retention of water in relation to sodium because of a reduction in solute-free water clearance [2–4]. The pathogenesis of water retention in cirrhosis is complex and involves several factors: increased plasma levels of vasopressin (AVP), reduced renal synthesis of prostaglandins, and reduced delivery of filtrate to the ascending limb of the loop of Henle, the diluting segment of the nephron. Patients with cirrhosis and ascites have increased plasma concentrations of AVP which are closely correlated with the reduction in solute-free water excretion [5–7]. Several studies have provided evidence that increased release [2–4] rather than reduced metabolism of AVP [8] is responsible for the increased plasma concentration of AVP in these patients. Taking into account that most patients with cirrhosis and ascites have a degree of hyponatremia and hypo-osmolality that would suppress AVP release in normal subjects [9], a nonosmotic stimulation of AVP release due to a reduction in effective circulating volume is considered the afferent factor leading to increased plasma concentration of AVP. In this context, it should be highlighted that AVP is part of the neurohumoral response to splanchnic arterial vasodilatation which also includes hyperactivation of antinatiuretic and vasopressor systems such as the renin-angiotensin-aldosterone axis and the sympathetic nervous system [9,10]. Bichet et al. [7] showed that the expansion of central blood volume by means of head-out water immersion suppressed plasma renin activity, and the plasma levels of aldosterone, norephineprine, and AVP, resulting in an improvement in both sodium and water excretion. These results were confirmed, almost 20 years later, by clinical studies that showed that in patients with hepatorenal syndrome (HRS) who responded to the prolonged administration of vasoconstrictors and albumin there was a significant improvement in plasma levels of sodium associated with a decrease in the plasma level of AVP [11,12].

The first step in the action of AVP on water excretion is its binding to V2 receptors on the basolateral membrane of the principal cells of the collecting duct. The activation of the V2 receptors stimulates adenyl cyclase via the stimulatory G protein and promotes the formation of cyclic adenosine monophosphate (cAMP). The post-cAMP events that mediate the increase in water permeability are related to the presence of a number of the water channel family that are exclusively expressed in the principal cells of the collecting duct, aquaporin-2. AVP stimulates the translocation of aquaporin-2 from sub-apical multivescicular bodies to the apical membrane [13]. According to this pathogenetic interpretation of hyponatremia in cirrhosis, urinary excretion of aquaporin-2 would be expected to be increased and not reduced as was found by Esteva-Font et al. [14]. The authors found urinary aquaporin-2 excretion in patients with cirrhosis and hyponatremia lower than in patients without hyponatremia and did not find a correlation between plasma level of AVP and urinary aquaporin-2 excretion. Nevertheless, the reduced urinary excretion of aquaporin-2 in patients with cirrhosis and hyponatremia may represent the molecular basis of the phenomenon of escaping the effects of AVP similar to that found in healthy subjects [14]. In fact, if the AVP–aquaporin-2 system was persistently activated in cirrhosis, solute-free water reabsorption would be permanently increased relative to sodium retention, and serum sodium levels would decline steadily to levels incompatible with life. Fortunately, this does not happen in clinical practice as, in most patients with cirrhosis, hyponatremia, when developed, is stable for weeks or even for a few months. Therefore, in patients with cirrhosis who develop hyponatremia, a reduced availability of aquaporin-2 may be part of a protective mechanism that counteracts the AVP-induced increase in solute-free water reabsorption in the collecting ducts and the further fall in serum sodium concentration.

Two additional factors are thought to be relevant in the pathogenesis of hyponatremia in cirrhosis: a reduced production of solute-free water due to reduced sodium delivery to the distal tubule and increased release of renal prostaglandins [15]. The former may be the consequence of a reduction in glomerular filtration rate (GFR) or an increase in sodium reabsorption in the proximal tubule [16,17]. As a consequence of its complex pathogenic mechanisms, impaired water excretion in cirrhotic patients with ascites may be induced and/or worsened by several factors including diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs) and other drugs [18–20], as well as by large-volume paracentesis if not followed by adequate plasma expansion [21], and bacterial infections. As far as diuretics are concerned, it should be stated that they can precipitate hypovolemic hyponatremia causing an excessive increase in sodium excretion and thus dehydration, as well as hypervolemic hyponatremia. With reference to the latter, it should be noted that loop diuretics may directly interfere with the urine diluting process by impairing free water generation through the inhibition of NaCl reabsorption in the thick ascending limb of the loop of Henle. On the other hand, any type of diuretic may stimulate a further release of AVP by means of a further reduction in the effective circulating volume [22]. Finally, among the drugs that can precipitate hyponatremia in cirrhosis, an acute reduction in serum sodium concentration is common during treatment with terlipressin, an AVP agonist, for severe portal-hypertensive bleeding. It develops rapidly after the start of therapy, may be severe in some patients, is associated with neurologic complications, and is usually reversible after terlipressin withdrawal [23].

Clinical Consequences and Prognostic Implications

The symptoms of hyponatremia (anorexia, apathy, nausea, vomiting) associated with cirrhosis and ascites do not differ from those of hyponatremia in other diseases in which hyponatremia is coupled with an increase in extracellular fluid volume. Few data exist on the clinical consequences of hyponatremia in patients with cirrhosis because hyponatremia almost always occurs in the setting of advanced liver failure, which causes a wide array of clinical manifestations. Nevertheless, from a clinical point of view, hyponatremia was found to be associated with a greater likelihood of hepatic encephalopathy, hepatorenal syndrome (HRS), and spontaneous bacterial peritonitis (SBP) [1]. The relationship between hyponatremia and HRS and/or SBP should probably be viewed from a pathophysiologic perspective. HRS and SBP can precipitate hyponatremia in patients with cirrhosis [24] because they are characterized by a further impairment of the effective circulating volume and, thus, to a maximal activation of all the factors that are involved in the physiopathology of hyponatremia. Nevertheless, it is also proven that hyponatremia represent a significant risk factor for the development of HRS in patients with cirrhosis [25]. Both these clinical conditions further impair the cardiocirculatory system and further increase the plasma levels of AVP, thus favoring the development of hyponatremia in patients with cirrhosis and ascites. However, the terms of the relationship must be reversed when considering encephalopathy [1], because hyponatremia appears to precipitate and aggravate hepatic encephalopathy in patients with cirrhosis. In our experience, serum levels of sodium and ammonia appear to be the major determinants of electroencephalographic abnormalities in patients with cirrhosis [26]. In addition, the existence of hyponatremia was found to be a major risk factor for the development of overt encephalopathy in all patients with cirrhosis and ascites [27], particularly in those with refractory ascites [28]. Finally, it has been observed that in patients with cirrhosis who were treated with transjugular intrahepatic portosystemic shunt, hyponatremia was a major risk factor for hepatic encephalopathy [29].