Albuminomics

Albumin Counteracts Immune-Suppressive Effects of Lipid Mediators in Patients With Advanced Liver Disease

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Albumin Counteracts Immune-Suppressive Effects of Lipid Mediators in Patients With Advanced Liver Disease

Bibliographic info

  • Authors: Louise China, Alexander Maini, Simon S. Skene, Zainib Shabir, Yvonne Sylvestre, Romain A. Colas, Lucy Ly, Natalia Becares Salles, Vittorio Bellotti, Jesmond Dalli, Derek W. Gilroy, Alastair O’Brien
  • Journal: Gastroenterology, 2018; DOI: 10.1053/j.gastro.2018.06.035
  • Institution: University College London (UCL), London, UK; Queen Mary University of London

Key question

Does albumin infusion (20% HAS) restore immune function in patients with AD/ACLF by counteracting the immune-suppressive effects of prostaglandin E2 (PGE2) and other lipid mediators?

Methods

  • Sample type: Human plasma; monocyte-derived macrophages (MDMs) from healthy volunteers
  • Cohort: 45 of 79 patients with AD/ACLF and serum albumin <30 g/L; received 20% human albumin solution (HAS); pre- and post-treatment plasma samples
  • Design: Targeted/selected subset from a larger observational/interventional study
  • Assays:
    • MDM TNF production: LPS stimulation of healthy volunteer MDMs incubated in patient plasma (pre- vs post-HAS) — validated marker of monocyte function
    • PGE2 binding capacity of plasma: measured as % PGE2 bound to albumin
    • EP1-3/EP4 receptor antagonists (AH6809 + MF498): pan-PGE2 receptor blockade to confirm PGE2 mechanism
    • Lipid mediator metabolomics: LC-MS/MS (selected 10 pairs pre/post from top recruiting site)
    • Cytokine multiplex (BD cytometric bead array)
    • LPS detection (HEK293 cell assay)

Main findings

  1. Patients with AD/ACLF have elevated PGE2 and other lipid mediators — PGE2 is bioavailable (not protein-bound) due to reduced and dysfunctional albumin
  2. Pre-treatment: MDM TNF production suppressed in presence of patient plasma (immune dysfunction confirmed)
  3. HAS infusion (20%): mean >14% increase in MDM TNF production → partial restoration of monocyte function
  4. PGE2 binding improved after HAS: mean 8.7% increase in % PGE2 bound (95% CI 5.2–12.1%, p<0.0001) — functional albumin infused with HAS has better PGE2 binding capacity
  5. Functional binding improvement confirmed independent of concentration: at fixed albumin concentration (18 g/L), post-treatment plasma bound more PGE2 than pre-treatment → the improvement is in albumin quality, not just quantity
  6. PGE2 receptor blockade (EP1-3 + EP4) mimics HAS effect: confirms PGE2 is the key mediator of immune suppression → albumin works by binding/inactivating PGE2
  7. Commercial 20% HAS: binds PGE2 less than healthy volunteer plasma — ⚠️ commercial albumin preparations may be partially oxidized/damaged during manufacturing

Mechanistic model

AD/ACLF → liver dysfunction → reduced albumin synthesis + increased albumin oxidation
↓
Less functional albumin → more bioavailable PGE2 (not bound/inactivated)
↓
PGE2 binds EP receptors on monocytes/macrophages → TNF suppression → immune dysfunction
↓
HAS infusion → functional albumin binds/inactivates PGE2 → monocyte function restored

Clinical context

  • Disease: AD/ACLF — Liver fibrosis decompensated cirrhosis; highest mortality setting
  • Implication: Immune dysfunction in AD/ACLF is partly explained by PGE2-mediated suppression driven by insufficient functional albumin — reversible by HAS infusion
  • Therapeutic pathway: 20% HAS infusion improves monocyte/macrophage function via PGE2 sequestration — supports non-oncotic therapeutic rationale for albumin in AD/ACLF

Connections

  • HSA — functional albumin as PGE2 scavenger/sequestrant
  • Liver fibrosis / ACLF — disease context
  • alcaraz-quiles-2018 — complementary: oxidized albumin (HNA1) drives TNF/IL production via p38 MAPK; China 2018 shows that restoring functional albumin reverses PGE2-driven immune suppression; together they define a cycle
  • fernandez-2019 — parallel approach; Pilot-PRECIOSA + INFECIR-2; IL-6 suppression by albumin infusion
  • spinella-2016-review — reviews albumin’s immunomodulatory role including PGE2 inactivation
  • baldassarre-2021-ealb — eAlb concept: low eAlb = insufficient functional albumin to inactivate PGE2

My notes

  • The finding that commercial 20% HAS has lower PGE2 binding than healthy plasma is clinically important — it implies that commercially available albumin preparations may be partially oxidized during manufacturing/storage, reducing their therapeutic efficacy.
  • The MDM TNF assay (monocyte-derived macrophage TNF production) is an elegant functional readout of immune dysfunction — not PTM-based but captures a functional consequence of albumin dysfunction.
  • This paper connects perfectly with alcaraz-quiles-2018: oxidized albumin drives inflammation via p38 MAPK; insufficient functional albumin allows PGE2 to escape and suppress immunity. Two opposing mechanisms driven by the same albumin dysfunction.
  • UCL group (O’Brien, Gilroy, Dalli) is the leading UK group on albumin immunology. Complementary to Bologna/Graz groups.

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