Losartan in the Prevention of Sodium Retention and Ascites in Liver Cirrhosis - a Prospective Randomized Long-Term Study

Patients with cirrhosis tend to retain sodium and water leading to the development of ascites, which in the terminal stage of decompensation cannot be eliminated despite the use of massive diuretic treatment. These decompensated patients have a very high mortality of 50 % within 3 years and morbidity, and until now no symptomatic treatment has been able to improve the prognosis.

It has been hypothesized that ascites and edema develop first due to renal sodium retention secondary to increased activity of hormones like angiotensin II and aldosterone, which may be stimulated by reduced arterial filling caused by systemic vasodilatation, and secondly due to liver fibrosis which may cause lymphatic overflow and formation of ascites.

Decreased central volume filling is believed to stimulate baroreceptors with activation of the renin-angiotensin-aldosterone system, the sympathetic nervous system and arginine vasopressin .

In cirrhotic patients systemic vasodilatation with hypotension, tachycardia, increased cardiac output and increased plasma volume has been thought to be caused by increased levels of vasodilating substances like nitric oxide (NO), but blocking NO synthesis using N(G)-monomethyl-L-arginine-acetate (L-NMMA) did not favorably influence renal sodium excretion, probably due to an important role of NOS in renal sodium handling .

It is evident that the pathophysiology of the development of excessive sodium and water retention in cirrhotic patients is insufficiently elucidated, and that an increased knowledge in this field may improve the therapeutic possibilities. Patients with cirrhosis without ascites have normal or increased glomerular filtration rate (GFR) and normal or suppressed plasma levels of renin, angiotensin II and aldosterone. Later renal blood flow and GFR may be decreased and patients have avid tubular sodium reabsorption as they can produce a virtually sodium-free urine. These functional renal changes regress after transplantation with a normal liver. Suggestions have been made that overfilling rather than central underfilling precede ascites formation. In any case blocking the mineralocorticoid receptor with spironolactone is an effective diuretic treatment in many cirrhotic patients, and this points to the importance of the distal part of the nephron in the mediation of excess sodium reabsorption.