Albuminomics

Determination of Effective Albumin in Patients With Decompensated Cirrhosis: Clinical and Prognostic Implications

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Determination of Effective Albumin in Patients With Decompensated Cirrhosis: Clinical and Prognostic Implications

Bibliographic info

  • Authors: Maurizio Baldassarre*, Marina Naldi*, Giacomo Zaccherini, Michele Bartoletti, Agnese Antognoli, Maristella Laggetta, Martina Gagliardi, Manuel Tufoni, Marco Domenicali, Katja Waterstradt, Paola Paterini, Anna Baldan, Simona Leoni, Manuela Bartolini, Pierluigi Viale, Franco Trevisani, Mauro Bernardi**, Paolo Caraceni** (* equal contribution; ** equal contribution)
  • Journal: Hepatology, 2021, vol. 74, no. 4, pp. 2058–2073; DOI available
  • Institution: University of Bologna, S. Orsola-Malpighi University Hospital; IRCCS AOU Bologna, Italy

Key question

Can the effective albumin concentration (eAlb) — the fraction of circulating albumin with preserved structural and functional integrity — be reliably measured in patients with decompensated cirrhosis, and does it predict ACLF development and 90-day mortality better than total albumin concentration (tAlb)?

Methods

  • Sample type: Plasma from hospitalized patients
  • Cohort: 319 patients with cirrhosis hospitalized for acute decompensation (AD) with/without ACLF; 18 outpatients with compensated cirrhosis; healthy controls; enrolled Feb 2010 – March 2016, S. Orsola-Malpighi Hospital, Bologna
  • Exclusion: albumin infusion in past 15 days; HCC outside Milan criteria; AAH; hematologic malignancies; NYHA>2 heart failure; COPD III-IV; organic kidney disease
  • Techniques:
    • LC-ESI-MS (top-down) for HSA isoform identification and relative quantification (MaxEnt1 deconvolution, mass range 61,500–71,500 Da)
    • Bromocresol green (BCG) for total albumin concentration (tAlb, g/dL)
    • EPR (electron paramagnetic resonance) spin-probe for albumin binding function (MedInnovation GmbH, Berlin)
    • eAlb calculation: eAlb = tAlb × (native HSA % / 100)
  • Inflammatory markers: IL-6 and TNF-α (multiplex immunoassay)
  • Severity scores: MELD, MELD-Na, Child-Pugh, CLIF-C AD scores

Main findings

Isoform landscape (11 damaged isoforms detected — more than domenicali-2014)

  • Cysteinylated isoforms (HSA+Cys; HSA+Cys+Glyc; HSA+Cys-DA) most abundant in hospitalized patients
  • Cysteinylated + glycated (HSA+Cys+Glyc) and N-term truncated + cysteinylated (HSA+Cys-DA) further elevated in ACLF vs AD
  • Glycated isoforms (HSA+Glyc; HSA+2Glyc) increased in parallel with cirrhosis severity

eAlb performance

ComparisonFinding
eAlb vs tAlb in severityeAlb declines more steeply across compensated→AD→ACLF than tAlb
eAlb vs clinical scoreseAlb correlates inversely with MELD, MELD-Na, Child-Pugh, CLIF-C AD
eAlb vs binding function (EPR)eAlb better reflects binding capacity than tAlb; tAlb in ACLF patients with same tAlb but different eAlb have very different binding functions
eAlb predicts 30-day ACLFeAlb at admission predicts 30-day occurrence of ACLF (AUROC superior to tAlb)
eAlb predicts 90-day mortalityeAlb at admission predicts 90-day mortality (AUROC superior to tAlb)

Key clinical numbers

  • tAlb: outpatients 4.2 g/dL; hospitalized 3.0 g/dL; no difference AD vs ACLF at admission (3.0 vs 2.9 g/dL)
  • ⚠️ tAlb cannot distinguish AD from ACLF at admission — eAlb can
  • eAlb formula: eAlb (g/L) = tAlb (g/L) × native HSA fraction (%)

Albumin binding function (EPR)

  • PCA applied to 6 EPR parameters → binding function correlates better with eAlb than with tAlb
  • Patients with equal tAlb but lower eAlb have worse binding function — functional implications

Clinical context

  • Disease: Decompensated Liver fibrosis / cirrhosis; ACLF
  • Key implication: tAlb measurement in clinical routine does not distinguish structurally intact from damaged albumin → eAlb introduces quality dimension; critical for guiding albumin infusion therapy
  • Therapeutic implication: target eAlb rather than tAlb for albumin supplementation decisions

Limitations

  • eAlb calculated indirectly (native HSA % × tAlb by BCG) — two-step measurement; BCG method has known limitations for accuracy in severe liver disease
  • Single center; observational
  • EPR binding function measured by specialized commercial kit — not yet routine
  • eAlb cut-off values need external validation before clinical adoption

Connections

  • HSA — isoform quantification; native fraction as structural purity index
  • Liver fibrosis / ACLF — primary disease context
  • domenicali-2014 — predecessor; establishes native HSA as survival predictor; this paper operationalizes it as eAlb
  • bernardi-2023 — perspective article on the eAlb paradigm by the same senior author (Bernardi)
  • oettl-2013 — parallel approach (HNA2 by IEC); complementary view; eAlb broader concept
  • el-balkhi-2025 — ALBOM study uses same top-down MS approach; absolute quantification by lakis-2024; clinically extends eAlb concept to fibrosis staging
  • spinella-2016-review — reviews functional albumin concept that this paper operationalizes

My take home notes

  • This is the landmark paper defining effective albumin (eAlb). The formula (eAlb = tAlb × native%) is simple but powerful — it combines the quantity (tAlb) with the quality (native fraction by LC-MS) into a single clinically interpretable value.
  • The 30-day ACLF prediction and 90-day mortality advantage of eAlb over tAlb is the key clinical result. ACLF patients with the same total albumin can have very different eAlb, predicting drastically different outcomes.
  • The EPR binding function result validates that eAlb is not just a theoretical construct — it correlates with actual measured binding capacity, which is the functional foundation of albumin’s non-oncotic roles.
  • Limitation to highlight for ALBOM: BCG method overestimates albumin in some scenarios (known colorimetric artifact) — this means eAlb derived from BCG × LC-MS% may have accuracy issues. lakis-2024 (absolute MS quantification) avoids this by directly measuring isoform concentrations in g/L.

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