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Selected Publication:
Leber, BM.
THE ROLE OF ALBUMIN AND ENDOTOXIN IN DISEASE: FOCUS ON LIVER CIRRHOSIS, BRAIN-DEATH AND METABOLIC SYNDROME
[ Dissertation ] Medical University of Graz; 2012. pp. 87
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- Authors Med Uni Graz:
- Leber Bettina
- Advisor:
- Öttl Karl
- Stadlbauer-Köllner Vanessa
- Stiegler Philipp
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- Abstract:
- Human serum albumin (HSA) is the major plasma protein with a variety of functions. In disease HSA functions are impaired possibly due to oxidation of the molecule. One of HSAs most important functions is the ligand binding capacity of, among others, endotoxin. Endotoxins are heat stable lipopolysaccharides present on the outer membrane of Gram-negative bacteria that are recognized by means of lipopolysaccharide binding protein (LBP) in combination with CD14 and Toll-like receptor (TLR) 4. In disease, endotoxin originating from gut bacteria is present more frequently in systemic circulation due to impaired clearance ability in combination with increased gut permeability. We aimed to investigate the role of HSA and endotoxin in brain-dead organ donors (critically ill), cirrhotic patients with ascites (severely ill) and patients with metabolic syndrome (MetS; patients with suboptimal health) in combination with determination of gut permeability. Additionally we wanted to investigate the impact of endotoxin on survival of organ recipients and if endotoxin or other factors influence neutrophil function. Albumin function and binding capacity were assessed by HPLC. Endotoxin was measured by an adapted Limulus amoebocyte lysate-assay and gut permeability by RT-PCR and a differential sugar method followed by HPLC measurement. Flow cytometry was used to investigate neutrophil function, TLR expression and cytokine levels. LBP, CD14, carbonyl content of proteins (CP) and Myeloperoxidase (MPO) levels were measured by ELISA. We found increased oxidation status of HSA in brain-dead organ donors and cirrhotic patients with ascites. Albumin binding capacity was decreased in brain-dead but not in cirrhotic patients with ascites. Furthermore we found that albumin is masking endotoxin in a concentration dependent manner. Systemic endotoxin levels were detected in 16.7% of brain-dead organ donors, in 5.6% of cirrhotic patients with ascites and in none of the patients with MetS. Parameters of oxidative stress were elevated in patients when compared to healthy controls. Gut permeability was significantly elevated in patients with MetS compared to healthy controls and in brain-dead organ donors a trend towards increased gut permeability was detected in endotoxin positive when compared to endotoxin negative patients¿ samples. Furthermore neutrophil function was not different in patients with MetS compared to healthy controls. Recipient survival was significantly worse in patients with organs originating from endotoxin positive donors when compared to endotoxin negative donor organs. We conclude that in brain-dead organ donors and cirrhotic patients with ascites, albumin dysfunction may be due to oxidative stress in combination with endotoxin presence in systemic circulation. Patients with MetS are of suboptimal health with increased gut permeability but still ¿too healthy¿ to have detectable endotoxin levels in serum.