Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity, liver dysfunction and survival

Abstract

Background & aims: Impaired binding function of albumin has been demonstrated in end-stage liver disease. This and other functional disturbances of albumin may be related to oxidative stress which is believed to play an important role in the pathogenesis of liver failure as well as sepsis. The aim of the present study was to relate oxidative modification of albumin to loss of albumin binding function in advanced chronic liver failure and in sepsis.

Methods: Patients with decompensated cirrhosis or sepsis and healthy controls were investigated. Three fractions of albumin were separated by chromatography according to the redox state of cysteine-34: non-oxidized human mercaptalbumin, reversibly oxidized human non-mercaptalbumin-1, and irreversibly oxidized human non-mercaptalbumin-2 (HNA2). Binding properties of albumin site II were measured using dansylsarcosine as a ligand.

Results: Both in cirrhotic and septic patients, fractions of oxidized albumin were increased and binding capacity for dansylsarcosine was decreased. Mass spectroscopy confirmed specific oxidation of cysteine-34. In cirrhotic patients, dansylsarcosine binding correlated strongly with liver function parameters and moderately with HNA2. Baseline levels of HNA2 accurately predicted 30-day and 90-day survival in cirrhotic patients and this was confirmed in an external validation cohort.

Conclusions: Our results suggest that oxidative damage impairs binding properties of albumin. In advanced liver disease, reduced binding capacity of albumin site II is mainly related to impaired liver function. The plasma level of HNA2 is closely related to survival and may represent a novel biomarker for liver failure.

Keywords: ACLF; C-reactive protein; CRP; Cirrhosis; DS; Dansylsarcosine; HMA; HNA1; HNA2; HPLC; INR; MELD; Mercaptalbumin; Model for End-stage Liver Disease; Non-mercaptalbumin; Oxidative stress; ROC; acute-on-chronic liver failure; dansylsarcosine; high performance liquid chromatography; human mercaptalbumin; human non-mercaptalbumin1; human non-mercaptalbumin2; international normalized ratio; receiver operating characteristics.