Italian Medicine Agency.

Infections ACLF Death Different clinical courses of acutely decompensated cirrhosis Pre-ACLF Unstable decompensated cirrhosis Stable decompensated cirrhosis 0 90 180 270 360 Days Highlights Patients with acutely decompensated cirrhosis without ACLF develop 3 different clinical courses. Patients with pre-ACLF develop ACLF within 90 days and have high systemic inflammation and mortality. Patients with unstable decompensated cirrhosis suffer from complications of severe portal hypertension. Patients with stable decompensated cirrhosis have less frequent complications and lower 1-year mortality risk.

for the CANONIC Study Investigators of the EASL Clif Consortium, Grifols Chair and the European Foundation for the Study of Chronic Liver Failure (EF Clif), Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF,

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Beside the regulation of fluid distribution, human serum albumin (HSA) carries other activities, such as binding, transport, and detoxification of many molecules. In patients with cirrhosis, HSA exhibits posttranscriptional alterations that likely affect its functions. This study aimed at identifying the structural HSA alterations occurring in cirrhosis and determining their relationship with specific clinical complications and patient survival. One hundred sixty-eight patients with cirrhosis, 35 with stable conditions and 133 hospitalized for acute clinical complications, and 94 healthy controls were enrolled. Posttranscriptional HSA molecular changes were identified and quantified by using a high-performance liquid chromatography/electrospray ionization mass spectrometry technique. Clinical and biochemical parameters were also recorded and hospitalized patients were followed for up to 1 year. Seven HSA isoforms carrying one or more posttranscriptional changes were identified. Altered HSA isoforms were significantly more represented in patients than in healthy controls. Conversely, the native, unchanged HSA isoform was significantly reduced in cirrhosis. Native HSA and most altered isoforms correlated with both Child-Pugh and Model for End-Stage Liver Disease scores. In hospitalized patients, oxidized and N-terminal truncated isoforms were independently associated with ascites, renal impairment, and bacterial infection. Finally, the native HSA and cysteinylated/N-terminal truncated isoforms were predictors of 1-year survival, with greater prognostic accuracy than total serum albumin concentration. Conclusions: Extensive posttranscriptional changes of HSA, involving several molecular sites and increasing in parallel with disease severity, occur in patients with cirrhosis. Altered isoforms are independently associated with specific clinical complications, whereas the residual, native HSA isoform independently predicts patient survival. These findings support the concept of the "effective albumin concentration," which implies that the global HSA function is related not only to its serum concentration, but also to the preservation of its structural integrity. (HEPATOLOGY 2014;60:1851-1860 Abbreviations: 2D, two-dimensional; ACLF, acute on chronic liver failure; ANOVA, analysis of variance; DM, diabetes mellitus; ESI-MS, electrospray ionization mass spectrometry; HCC, hepatocellular carcinoma; HPLC, high-performance liquid chromatography; HSA, native form of human serum albumin; HSA1CYS, cysteinylated human serum albumin; HSA1CYS-DA, cysteinylated and N-terminal truncated (-Asp-Ala) human serum albumin; HSA1CYS1GLYC, cysteinylated and glycosylated human serum albumin; HSA-DA, N-terminal truncated (-Asp-Ala) human serum albumin; HSA1GLYC, glycosylated human serum albumin; HSA-L, C-terminal truncated (-Leu) human serum albumin; HSA1SO 2 H, sulfinilated human serum albumin; LC, liquid chromatography; MELD, Model for End-Stage Liver Disease; Q-TOF, quadruple time of flight; ROC, receiver operating characteristic; SD, st...