Posttranscriptional Changes of Serum Albumin: Clinical and Prognostic Significance in Hospitalized Patients With Cirrhosis
Bibliographic info
- Authors: Marco Domenicali*, Maurizio Baldassarre*, Ferdinando A. Giannone, Marina Naldi, Marianna Mastroroberto, Maurizio Biselli, Maristella Laggetta, Daniela Patrono, Carlo Bertucci, Mauro Bernardi, Paolo Caraceni (* equal contribution)
- Journal: Hepatology, 2014
- Institution: University of Bologna / S. Orsola-Malpighi Hospital, Italy
Key question
Which structural HSA alterations occur in cirrhosis, and how do they relate to specific clinical complications and 1-year patient survival?
Methods
- Sample type: Peripheral blood plasma
- Cohort: 168 patients with cirrhosis (35 stable/outpatients; 133 hospitalized for acute complications) + 94 healthy controls; followed up to 1 year
- Technique: HPLC-ESI-MS (top-down); mass range 65,800–67,100 Da for monomer isoforms
- Statistical: ANOVA + Bonferroni; Spearman rho (correlation with MELD/Child-Pugh); logistic regression; Cox proportional hazard; ROC curves; Kaplan-Meier survival
Main findings
- Seven HSA isoforms identified: native; HSA+CYS; HSA+CYS-DA; HSA+CYS+GLYC; HSA+GLYC; HSA+SO₂H (sulfinylated); HSA-DA (N-term truncated); HSA-L (C-term truncated)
- Altered isoforms elevated in cirrhosis: most abundant were cysteinylated forms (HSA+CYS, HSA+CYS-DA, HSA+CYS+GLYC) and glycated (HSA+GLYC)
- Native HSA significantly reduced in patients vs controls — the lower the native fraction, the more severe the disease (inversely correlated with MELD and Child-Pugh scores)
- No difference in truncations (HSA-DA, HSA-L) between patients and controls — ⚠️ contradicted or refined by later studies (note: baldassarre-2016-dimers finds that these monomers are consumed by homodimerization)
- Cys-34 isoforms (HSA+CYS, HSA+CYS+GLYC, HSA+SO₂H) directly correlated with MELD and most with Child-Pugh — oxidative stress drivers
- Inverse glycation correlation: HSA+GLYC inversely correlated with MELD/Child-Pugh → the biphasic pattern (glycation decreases in severe disease) established here — see el-balkhi-2025 for full explanation
- Native HSA predicts 1-year survival: the cut-off yielded by ROC was a better predictor than serum albumin concentration — seminal finding establishing that structural quality matters beyond quantity
- Complication associations (multivariate): specific isoforms independently associated with ascites, renal impairment, bacterial infection
PTMs reported
| Protein | Isoform | Modification | Δmass (Da) | Clinical association |
|---|---|---|---|---|
| HSA | Native | None | 0 | Inversely correlates with disease severity; predicts survival |
| HSA | HSA+CYS | Cysteinylation Cys34 | +119 | Elevated in cirrhosis; correlates with MELD |
| HSA | HSA+CYS-DA | CYS + N-term trunc. | +119–115 | Elevated in cirrhosis; correlates with MELD |
| HSA | HSA+CYS+GLYC | CYS + Glycation | +281 | Elevated in hospitalized > outpatients; MELD corr. |
| HSA | HSA+GLYC | Glycation | +162 | Inversely correlated with MELD (biphasic) |
| HSA | HSA+SO₂H | Sulfinylation (irreversible) | +32 | Correlates with MELD and Child-Pugh |
| HSA | HSA-DA | N-terminal truncation | −115 | No difference patient vs control in this study |
| HSA | HSA-L | C-terminal truncation | variable | No difference patient vs control in this study |
Clinical context
- Disease: Liver fibrosis / cirrhosis (compensated and decompensated stages)
- Scoring: MELD (end-stage liver), Child-Pugh (cirrhosis severity)
- Implication: Native HSA as a structural biomarker of functional albumin reserve; quantitative isoform profiling captures what total albumin measurement misses → concept of effective albumin (formalized later in baldassarre-2021-ealb and bernardi-2023)
Limitations
- Relative quantification only (%, not absolute g/L) — addressed later by lakis-2024
- Single-center (Bologna, Italy)
- No fibrosis staging (METAVIR) — only outpatient/inpatient and Child-Pugh/MELD groups
- Analysis restricted to monomer mass range; homodimers not detected (addressed in baldassarre-2016-dimers)
Connections
- HSA — seminal characterization of 7-isoform landscape in cirrhosis
- Cysteinylation — dominant PTM in cirrhosis; Cys34 as key site
- Glycation — inverse correlation with severity = biphasic concept
- Liver fibrosis / Cirrhosis — primary disease context
- el-balkhi-2025 — extends to 10 isoforms, absolute quantification, ordinal classification of METAVIR stages
- baldassarre-2016-dimers — follows up with homodimer discovery in same population
- baldassarre-2021-ealb — formalizes effective albumin concept; uses same LC-ESI-MS method
- naldi-2017-review — comprehensive methodological review citing this paper throughout
Take home notes
- This is the founding clinical paper for the HSA isoform biomarker field in liver disease. All subsequent work (Naldi 2016/2017, Baldassarre 2021, El Balkhi 2025) builds on this seminal dataset.
- The key message: native HSA fraction is the clinically predictive metric, not total albumin concentration. Everything downstream (ALBOM, effective albumin concept, PTM-CQFD) is an extension of this insight.
- The glycation inverse correlation is particularly important for interpreting el-balkhi-2025 results — in severe cirrhosis, hepatocytes lose the capacity to produce glycated albumin, so HSA+GLYC paradoxically decreases.
- Note the authors are Domenicali AND Baldassarre at equal contribution — this is the founding Bologna group that produces most of the reference literature for the ALBOM project.