Abstract
Although granulocyte dysfunction is known to occur in cirrhosis, in vivo studies of granulocyte lifespan have not previously been performed. The normal circulating granulocyte survival half‐time (G − t ½), determined using indium‐111 (111In)‐radiolabeled granulocytes, is ~7 h. In this pilot study, we aimed to measure the in vivo G − t ½ in compensated alcohol‐related cirrhosis. Sequential venous blood samples were obtained in abstinent subjects with alcohol‐related cirrhosis over 24 h post injection (PI) of minimally manipulated 111In‐radiolabeled autologous mixed leukocytes. Purified granulocytes were isolated from each sample using a magnetic microbead‐antibody technique positively selecting for the marker CD15. Granulocyte‐associated radioactivity was expressed relative to peak activity, plotted over time, and G − t ½ estimated from data up to 12 h PI. This was compared with normal neutrophil half‐time (N − t ½), determined using a similar method specifically selecting neutrophils in healthy controls at a collaborating center. Seven patients with cirrhosis (six male, aged 57.8 ± 9.4 years, all Child‐Pugh class A) and seven normal controls (three male, 64.4 ± 5.6 years) were studied. Peripheral blood neutrophil counts were similar in both groups (4.6 (3.5 − 5.5) × 109/L vs. 2.8 (2.7 − 4.4) × 109/L, respectively, P = 0.277). G − t ½ in cirrhosis was significantly lower than N − t ½ in controls (2.7 ± 0.5 h vs. 4.4 ± 1.0 h, P = 0.007). Transient rises in granulocyte and neutrophil‐associated activities occurred in four patients from each group, typically earlier in cirrhosis (4–6 h PI) than in controls (8–10 h), suggesting recirculation of radiolabeled cells released from an unidentified focus. Reduced in vivo granulocyte survival in compensated alcohol‐related cirrhosis is a novel finding and potentially another mechanism for immune dysfunction in chronic liver disease. Larger studies are needed to corroborate these pilot data and assess intravascular neutrophil residency in other disease etiologies.
Highlights
Advanced forms of alcohol-related liver disease are associated with high rates of bacterial and fungal sepsis, which are a frequent cause of hospitalization and death in patients with cirrhosis (Verma et al 2006)
Defects in neutrophil function have been reported in various forms of chronic and acute-onchronic liver disease, this pilot study is the first to report the in vivo measurement of granulocyte lifespan in cirrhosis
Normal intravascular neutrophil residency time determined from the recovered neutrophil fraction of radiolabeled mixed leukocytes was shorter than previously reported
Summary
Advanced forms of alcohol-related liver disease are associated with high rates of bacterial and fungal sepsis, which are a frequent cause of hospitalization and death in patients with cirrhosis (Verma et al 2006). In part, this relates to defects in neutrophil function, including impaired phagocytic capacity and high resting oxidative burst (Mookerjee et al 2007). Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society
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