Early normalization of reduced urea synthesis capacity after direct-acting antiviral therapy in hepatitis C cirrhosis.

BACKGROUND AND AIMS: Effects of direct-acting antiviral (DAA)-treatment of chronic hepatitis C (CHC) cirrhosis on metabolic liver function are unknown but important for prognosis. Ureagenesis is an essential metabolic liver function involved in whole-body nitrogen homeostasis. We aimed to investigate the ureagenesis capacity before and immediatelyafter DAA-therapy and relate the findings to hepatic inflammation and structural changes.

METHODS: In an observational before-and-after intervention study, the ureagenesis capacity was quantified by functional hepatic nitrogen clearance (FHNC) in nine CHC patients with cirrhosis and ten healthy volunteers. Hepatic inflammation was evaluated by ALT and the macrophage activation markers sCD163 and sMR. Structural changes were estimated as liver stiffness and by portal hypertension as the hepatic venous pressure gradient (HVPG).

RESULTS: Prior to treatment, the FHNC in the patients was half of the controls (16.4 L/hour (8.2-24.5) vs. 33.4 (29.2-37.6), p=0.0004); after successful DAA-treatment, it normalized (28.4 (15.9-40.9), p=0.008 vs. baseline). DAA-treatment normalized ALT (p<0.0001), and decreased the elevated sCD163 from 5.6 mg/L (3.5-7.7) to 3.4 (2-0-4.8) (p<0.001) and sMR from 0.35 mg/L (0.21-0.49) to 0.31 (0.17-0.45) (p<0.01). Liver stiffness fell by 30% (p<0.05) but remained over the cirrhosis threshold. HVPG was not affected (p=0.59).

CONCLUSIONS: DAA-treatment restored the severely reduced ureagenesis capacity, along with amelioration of hepatic inflammation but without normalization of other cirrhosis characteristics. Our findings indicate that the anti-inflammatory effect of virus eradication independent of hepatic structural effects rapidly improves metabolic dysfunction. We suggest this effect to be an important early-onset part of the expected clinical DAA-treatment benefit.