Posttranscriptional changes of serum albumin: Clinical and prognostic significance in hospitalized patients with cirrhosis

Abstract

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...

Serum ischemic modified albumin (IMA) concentration and IMA/albumin ratio in patients with hepatitis B-related chronic liver diseases

“…Several studies have shown that posttranscriptional structural and subsequent functional alterations might occur in the structure of albumin due to several factors and new isoforms arise (21,22). These changes are minimal under physiologic conditions.…”

“…In chronic liver diseases, in addition to the decreased synthesis of albumin by the liver, concentrations of different albumin isoforms also increase due to alteration of the microenvironment within the liver or effects of several prooxidants. Some of these albumin isoforms were shown to be related to ascites, renal dysfunction, and bacterial infections in patients with chronic liver diseases (21). On the other hand, it was shown that serum concentration of naturally protected native albumin was much lower than total serum albumin concentration in cirrhotic patients and more importantly this undamaged native albumin concentration was found to be related to survival in patients with chronic liver diseases (15).…”

Effect of a Ferric Citrate Formulation, a Phosphate Binder, on Oxidative Stress in Chronic Kidney Diseases-Mineral and Bone Disorder Patients Receiving Hemodialysis: A Pilot Study

“…28) Similarly, Jalan et al found that the 1-year survival rate for liver cirrhosis patients could be predicted by the concentration of reduced HSA in their plasma. 29) Taking into consideration the fact that modified albumin molecules lack multiple functions, Domenicali et al proposed that the concentration of reduced HSA should be measured to indicate the "effective albumin concentration" as a new indicator in lieu of the conventional parameter total albumin concentration. 29) In the present study, the concentration of reduced HSA was not decreased with the administration of the ferric citrate formulation; therefore, there was no reduction in the effective albumin concentrations (from 1.92±0.22 to 2.09±0.27 (g/dL)), suggesting that the administration of the ferric citrate formulation is unlikely to increase the risk of cardiovascular disease via the induction of oxidative stress.…”

AISF-SIMTI Position Paper: The appropriate use of albumin in patients with liver cirrhosis

“…In addition to quantitative changes, HA undergoes structural and functional alterations that are probably favoured by the pro-inflammatory and pro-oxidant state of advanced cirrhosis 6,7 . Extensive post-transcriptional changes, involving several sites of the molecule, develop and increase in parallel with the disease severity 7 . Physiological functions of HA appear to be impaired, including the ability to chelate cobalt and binding and transport capacities 8 .…”

“…Physiological functions of HA appear to be impaired, including the ability to chelate cobalt and binding and transport capacities 8 . It can, therefore, be hypothesised that, in patients with cirrhosis, the global function of HA, resulting from both oncotic and non-oncotic properties, is not only related to its absolute concentration in the circulation, but also to the degree of preservation of its structural and functional integrity [5][6][7][8] . Advanced cirrhosis is characterised by two major systemic features: circulatory dysfunction and chronic inflammation.…”