Increased Plasma Levels of Substance P and Disturbed Water Excretion in Patients with Liver Cirrhosis

Background: The pathogenesis of impaired water excretion in liver cirrhosis has not been fully elucidated. Methods: We induced an intravenous water overload of 20 ml/kg body weight in 10 cirrhotics without ascites (CLC), 11 cirrhotics with ascites (DLC), and 10 normal subjects (N) and investigated the relationship of plasma levels of substance P (SP), norepinephrine (NE), and antidiuretic hormone (ADH) to impaired water excretion. Results: Free water clearance (C_H2O) was lower in DLC (mean, 2.7 ml/min) than in N (8.3 ml/min; P < 0.001) and CLC (6.9 ml/min; P < 0.001). In DLC the creatinine clearance (CCr), maximal urine flow rate/CCr, (C_H2O-C_Na)/CCr, and mean arterial pressure (MAP) were significantly lower than in N and CLC. There was a progressive increase in basal SP, from lowest in N to CLC, to highest in DLC. Basal NE increased in CLC and DLC. Basal ADH did not differ among N, CLC, and DLC. In cirrhotics C_H2O was correlated positively with serum albumin and cholinesterase and negatively with the retention rate of indocyanine green at 15 min. Basal SP was negatively correlated with C_H2O (r = -0.71; P < 0.001) and MAP (r = -0.56; P < 0.005). Basal NE was correlated positively with basal SP (r = 0.67, P < 0.01). Conclusions: Decreased C_H2O is closely related to the severity of the liver disturbance. Decreased CCr and reduced delivery of filtrate to the ascending limb of the loop of Henle secondary to an increased sodium reabsorption in the proximal tubule may play an important role in the impairment of water excretion. The increase in SP, which has a potent vasodilatory action, and the associated enhanced activity of the sympathetic nervous system may be responsible for the mild or moderate impairment of water excretion in the absence of nonosmotic hypersecretion of ADH in cirrhotics with ascites.