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...

Adoption of the Model for End-stage Liver Disease (MELD) to select and prioritize patients for liver transplantation represented a turning point in organ allocation. Prioritization of transplant recipients switched from time accrued on the waiting list to the principle of "sickest first". The MELD score incorporates three simple laboratory parameters (serum creatinine and bilirubin, and INR for prothrombin time) and stratifies patients according to their disease severity in an objective and continuous ranking scale. Concordance statistics have demonstrated its high accuracy in stratifying patients according to their risk of dying in the short-term (three months). Further validations of MELD as a predictor of survival at various temporal end-points have been obtained in independent patient cohorts with a broad spectrum of chronic liver disease. The MELD-based liver graft allocation policy has led to a reduction in waitlist new registrations and mortality, shorter waiting times, and an increase in transplants, without altering overall graft and patient survival rates after transplantation. MELD limitations are related either to the inter-laboratory variability of the parameters included in the score, or to the inability of the formula to predict mortality accurately in specific settings. For some conditions, such as hepatocellular carcinoma, widely accepted MELD corrections have been devised. For others, such as persistent ascites and hyponatremia, attempts to improve MELD's predicting power are currently underway, but await definite validation.

Summary Background Alcoholic liver disease has a known aetiology but a complex and incompletely known pathogenesis. It is an extremely common disease with significant morbidity and mortality, but the reason why only a relatively small proportion of heavy drinkers progress to advanced disease remains elusive. Aim To recognize the factors responsible for the development and progression of alcoholic liver disease, in the light of current knowledge on this matter. Methods We performed a structured literature review identifying studies focusing on the complex pathogenetic pathway and risk factors of alcoholic liver disease. Results In addition to the cumulative amount of alcohol intake and alcohol consumption patterns, factors such as gender and ethnicity, genetic background, nutritional factors, energy metabolism abnormalities, oxidative stress, immunological mechanisms and hepatic co‐morbid conditions play a key role in the genesis and progression of alcoholic liver injury. Conclusions Understanding the pathogenesis and risk factors of alcoholic liver disease should provide insight into the development of therapeutic strategies.

Our new diagnostic algorithm demonstrated significantly higher sensitivity and comparable specificity than those of the AASLD imaging criteria for HCC in patients with cirrhosis evaluated using Gd-EOB-DTPA MRI, even for lesions ≤2 cm. Moreover, this diagnostic algorithm allowed evaluating other lesions which could arise in a cirrhotic liver, such as early HCC and HGDN.

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