The cause of ascites in patients with cirrhosis is not established. Elevated plasma renin activity and norepinephrine concentration (PNC) in patients with cirrhosis and ascites have suggested that vascular """"""""underfilling"""""""" is the initiating factor. Total blood volume (BV) is not reduced in such patients, but mean arterial pressue (MAP) and systemic vascular resistance (SVR) are often low, suggesting that """"""""effective"""""""" arterial underfilling may be present. However, the mechanism by which arterial volume contraction might occur is not established. An alternative hypothesis is that renal sodium retention is caused by impaired liver metabolic function, ascites"""""""" as plasma volume expands. We offer a mechanism of sodium retention in cirrhosis that combines features of both the underfilling and overflow proposals. We suggest that the first step in ascites formation is development of portal hypertension. This results in portal-systemic shunting of pancreatic glucagon (PG). PG is a potent dilator of splanchnic arterioles. Arterial pressure falls. This activates renal sympathetic neurons and stimulates tubular reabsorption of sodium. Repletion of arterial BV is prevented by overflow of ascites from the splanchnic venous circulation. Total BV eventually returns to normal or even becomes elevated owing to expansion of the volume of blood in the portal vein and inferior vena cava. Splanchnic sympathetic neuropathy secondary to chronic alcoholism contributes to impaired splanchnic vasoregulation in some patients. We will test this mechanism by conducting biannual evaluation of its component parts in 25 patients with moderate-advanced alcoholic liver disease as they undergo spontaneous changes in disease activity over the 5 year period of the study. The advantage of this method of study is that each patient serves as his own control, eliminating the variation associated with intergroup comparisons. The evaluation will include measurement of: 1) sodium balance; 2) total BV; 3) PNC and its response to postural change (an indicator of regional or """"""""effective"""""""" blood volume); 4) mean arterial pressure and systemic vascular resistance (reflections of arterial BV); 5) left atrial size (central BV); 6) portal-systemic shunt fraction; 7) plasma concentration of PG; 8) sympathetic and parasympathetic nervous system function; and 9) liver metabolic capacity.
