Post-Transcriptional Changes in Serum Albumin: Role in the Pathogenesis of Bacterial Infections in Cirrhosis

Besides the oncotic function Human serum Albumin (HSA) is also endowed with many other non-oncotic properties among which the antioxidant activity. Beside quantitative changes, during cirrhosis extensive post-transcriptional alterations, likely promoted by pro-inflammatory and pro-oxidant state occur to the HSA molecule.In this study we evaluated the structural and functional integrity of HSA in a large series of hospitalized patients with advanced cirrhosis. We also evaluated the relationship between alterations to the HSA molecule and clinical features as well as 1-year prognosis of patients included in the study. By using an LC-ESI-MS approach we identified several HSA isoforms characterized by one or more structural defects. These alterations mainly involved the cysteine-34 residue, the main antioxidant site of the molecule, and were mainly promoted by a pro-oxidant environment. Specific patterns of molecular alterations were found associated to the severity of cirrhosis and to the presence of clinical complication of disease, while the residual amount of the native HSA emerged as a potent predictor of 1-year mortality. The functional integrity of the N-terminal portion of the HSA molecule, provided with an indirect antioxidant activity, was evaluated by measuring the circulating level of Ischemia Modified Albumin (IMA) and IMA to serum albumin ratio (IMAr). IMA and IMAr were not associated to the severity of cirrhosis nor to the patients prognosis. Contrariwise IMA and IMAr were specifically associated to bacterial infection,showing a discriminating performance comparable to that of C-reactive protein. In conclusion this study provided evidences of clinical and prognostic relevance of HSA structural and functional alteration in patients with cirrhosis, strengthening the concept that the global function of the HSA molecule, resulting from both oncotic and non-oncotic properties, is related not only to its absolute circulating level, but also,and perhaps mainly, to its structural and functional integrity.