The relationship between sodium retention, hyperactivity of the neurohumoral vasoactive systems, and ascites formation in cirrhosis is intriguing and still remains a subject of interest and debate. According to the most widely accepted theory, the so-called peripheral arteriolar vasodilatation hypothesis of sodium retention and ascites formation in cirrhosis, the predominant mechanism in the pathogenesis of these abnormalities is the presence of persistent systemic arterial vasodilation leading to arterial hypotension, low peripheral resistance, high cardiac output, and decreased effective arterial blood volume.1 These circulatory abnormalities are detected by arterial and cardiopulmonary baroreceptors which in turn initiate the homeostatic activation of the endogenous neurohumoral systems aimed at maintaining arterial pressure within normal or near normal levels. In the kidneys however homeostatic activation of the vasoactive and sodium retaining systems promotes tubular sodium reabsorption and sodium retention.1 Because the splanchnic vasculature is a major site of arteriolar vasodilatation in cirrhosis, it is not surprising that extravasation of the fluid retained by the kidneys occurs mainly in this compartment, leading to the formation of ascites.

The renin-angiotensin-aldosterone (RAAS) and sympathetic nervous (SNS) systems, together with atrial natriuretic peptide (ANP), are the main endogenous neurohumoral systems involved in sodium homeostasis. The RAAS is one of the most extensively investigated endogenous vasoactive systems in cirrhosis because it is markedly activated in patients with sodium retention.2 ,3 Plasma renin activity and plasma aldosterone levels closely correlate with urinary sodium excretion and in many decompensated cirrhotic patients they reach extraordinarily high values, with levels being higher in patients with marked sodium retention.2 ,3 The SNS is another key factor involved in the pathogenesis of sodium retention and ascites formation in cirrhosis. In fact, noradrenaline concentrations are consistently found to be increased in patients with sodium retention and ascites.2 ,3 On the other hand, endogenous natriuretic substances such as ANP inhibit tubular sodium reabsorption and counteract the antinatriuretic and renal vasoconstrictor effects of the RAAS and SNS.2

Whereas in decompensated cirrhosis the mechanisms underlying sodium retention are quite well established, in preascitic cirrhosis this question remains elusive. Patients with preascitic cirrhosis (patients without a history of ascites or diuretic use) usually do not exhibit sodium retention.2 Moreover, the activities of the RAAS and SNS, estimated by plasma renin activity and circulating levels of aldosterone and noradrenaline, respectively, are consistently found to be either normal or decreased in preascitic cirrhotic patients.2 These patients however present subtle abnormalities in renal sodium handling leading to an expanded circulatory blood volume but without causing ascites or oedema. Indeed, the existence of an altered renal sodium metabolism in preascitic cirrhotic patients can be readily uncovered by administering a sodium overload or following mineralocorticoid treatment.2Therefore, and although not clinically evident, preascitic cirrhotic patients encounter a positive sodium balance which presumably is a homeostatic mechanism to compensate for the reduced effective arterial blood volume due to arteriolar vasodilation present in this condition.

In this issue of Gut 4, Wonget al examine the status of sodium homeostasis in preascitic cirrhosis by investigating renal sodium handling in 16 biopsy proven cirrhotic patients without ascites submitted to a high sodium diet (200 mmol/day) for five weeks (see page847). The results obtained show that daily sodium intake of 200 mmol results in weight gain and a positive sodium balance for three weeks, returning to a complete sodium balance thereafter. These findings indicate that despite continued high sodium intake, preascitic cirrhotic patients eventually reach a new steady state of sodium balance thereby preventing fluid retention and the development of ascites. As significant suppression of the RAAS and SNS, as estimated by plasma renin activity and aldosterone and noradrenaline levels, respectively, is observed in preascitic cirrhotic patients submitted to a high sodium diet for more than three weeks, the new state of sodium balance is presumably reached at the expense of intravascular volume expansion. In fact, elevated plasma ANP levels, a surrogate marker of an expanded blood volume, is consistently found in these patients during the course of the study. Interestingly, preascitic cirrhotic patients do not exhibit renal resistance to the diuretic and natriuretic effects of ANP, and thus increased plasma levels of ANP apparently contribute to the establishment of a new sodium balance in this condition. This scenario is completely different to that usually found in decompensated cirrhotic patients who show marked sodium retention despite the existence of elevated ANP plasma levels.5 ,6 Finally, it is noteworthy that at the end of the study period (that is, after five weeks on a high sodium diet), when patients have already reached a new steady state level of sodium balance and plasma renin activity and plasma aldosterone levels do not differ significantly from baseline, noradrenaline levels still remain suppressed. This is not consistent with previous investigations by the same group reporting that plasma noradrenaline levels are not suppressed in preascitic cirrhotic patients submitted to an oral sodium load of 200 mmol/day for one week.6 ,7 These controversial results could be interpreted as that evaluation of sodium homeostasis in cirrhosis without ascites is best performed over extended study periods rather than following acute or short term treatments.

In summary, the study by Wong and colleagues4 indicates that preascitic cirrhotic patients retain sodium when challenged with a high sodium intake. However, at this stage of disease, cirrhotic patients are still able to re-establish a new steady state of sodium balance mainly due to elevated levels of ANP and inhibition of the RAAS and SNS, thus preventing further development of sodium retention and ascites formation. Altogether these observations contribute to a significant advancement in our knowledge on the mechanisms underlying the disturbed sodium homeostasis of patients with preascitic cirrhosis.