Soluble CD163 from activated macrophages predicts mortality in acute liver failure

University of California, San Diego, San Diego, California, United States
Journal of Hepatology (Impact Factor: 11.34). 12/2007; 47(5):671-6. DOI: 10.1016/j.jhep.2007.05.014
Source: PubMed


Soluble CD163 (sCD163) is a scavenger receptor shed in serum during inflammatory activation of macrophages. We investigated if sCD163 was increased and predicted outcome in acute liver failure (ALF).
Samples from 100 consecutive patients enrolled in the U.S. ALF Study Group for whom sera were available were collected on days 1 and 3, and clinical data were obtained prospectively. sCD163 levels were determined by ELISA.
The median level of sCD163 was significantly increased in ALF (21.1mg/l (range 3.6-74.9)) as compared to healthy controls (2.3mg/l (0.65-5.6), p<0.0001) and patients with stable liver cirrhosis (9.8mg/l (3.6-16.9), p=0.0002). sCD163 on day 1 correlated significantly with ALT, AST, bilirubin, and creatinine. sCD163 concentrations on day 3 were elevated in patients with fatal outcome of disease compared to spontaneous survivors, 29.0mg/l (7.2-54.0) vs. 14.6mg/l (3.5-67.2), respectively (p=0.0025). Patients that were transplanted had intermediate levels. Sensitivity and specificity at a cut-off level of 26mg/l was 62% and 81%, respectively.
Activated macrophages are involved in ALF resulting in a 10-fold increase in sCD163. A high level (>26mg/l) of sCD163 was significantly correlated with fatal outcome and might be used with other parameters to determine prognosis.

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Available from: Holger Jon Møller, Oct 06, 2015
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    • "Both markers remain elevated in ALF between day 1 and 3 following admission and levels correlate with severity of extra-hepatic complications and mortality. Serum levels of sCD163 were seen to diverge between day 1 and 3 in spontaneous survivors and those who died or required transplantation, with persisting macrophage activation indicative of poor prognosis [33]. Acetylated HMGB1 is secreted by monocytes and macrophages as a pro-inflammatory mediator, unlike the non-acetylated form that is more widely expressed and passively released by necrotic cells. "
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    ABSTRACT: Acute liver failure (ALF) is a condition with a high mortality and morbidity for which new treatments are desperately required. We contend that although the initial event in ALF is liver cell death, the clinical syndrome of ALF and its complications including multi-organ dysfunction and sepsis, are largely generated by the immune response to liver injury. Hepatic macrophages fulfil a diversity of roles in ALF, from pro-inflammatory to pro-resolution. Their inherent plasticity means the same macrophages may have a variety of functions depending on the local tissue environment at different stages of disease. A better understanding of the mechanisms that regulate macrophage plasticity during ALF will be an essential step towards realising the potential of immune-modulating therapies that re-orientate macrophages to promote the desirable functions of attenuating liver injury and promoting liver repair/regenerative responses. The key dynamics: temporal (early vs. late phase), regional (hepatic vs. systemic), and activation (pro-inflammatory vs. pro-resolution) are discussed and the potential for novel ALF therapies that modulate monocyte/macrophage function are described.
    Journal of Hepatology 08/2014; 61(2). DOI:10.1016/j.jhep.2014.03.031 · 11.34 Impact Factor
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    • "Recently, several authors have reported the increased serum levels of macrophage­derived factors in patients with ALF, irrespective of the trigger, which suggests that activated macrophages play an important role in the progression of ALF [11–13]. Indeed, activation of macrophages and the subsequent release of proinflammatory mediators such as cytokines (e.g., tumor necrosis factor (TNF)-α), reactive oxygen species (ROS), and eicosanoids are considered to be an early step in the pathogenesis of liver damage, because they stimulate hepatic inflammation. "
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    ABSTRACT: This study aimed to investigate the role of 5-lipoxygenase (5-LO) in acute liver failure (ALF) and changes in macrophage activation by blocking it. ALF was induced in rats by administration of D-galactosamine (D-GalN)/lipopolysaccharide (LPS). Rats were injected intraperitoneally with AA-861 (a specific 5-LO inhibitor), 24 hr before D-GalN/LPS administration. After D-GalN/LPS injection, the liver tissue was collected for assessment of histology, macrophage microstructure, macrophage counts, 5-LO mRNA formation, protein expression, and concentration of leukotrienes. Serum was collected for detecting alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (Tbil), and tumor necrosis factor- (TNF-) α . Twenty-four hours after injection, compared with controls, ALF rats were characterized by widespread hepatocyte necrosis and elevated ALT, AST, and Tbil, and 5-LO protein expression reached a peak. Liver leukotriene B4 was also significantly elevated. However, 5-LO mRNA reached a peak 8 hr after D-GalN/LPS injection. Simultaneously, the microstructure of macrophages was changed most significantly and macrophages counts were increased significantly. Moreover, serum TNF- α was also elevated. By contrast, AA-861 pretreatment significantly decreased liver necrosis as well as all of the parameters compared with the rats without pretreatment. Macrophages, via the 5-LO pathway, play a critical role in ALF, and 5-LO inhibitor significantly alleviates ALF, possibly related to macrophage inhibition.
    Research Journal of Immunology 06/2014; 2014:697560. DOI:10.1155/2014/697560
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    • "Consistent with a role in the late inflammatory response, the expression of CD163 is up-regulated in patients with liver failure. It is significantly correlated with a fatal outcome and may be used as a parameter to determine liver disease prognosis [5]. However, little is currently known of the regulatory mechanisms that influence the expression of CD163 on monocytes in liver tissues of hepatitis patients. "
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    ABSTRACT: Although patients with liver failure exhibit a generalized inflammatory-imbalance status, substantial evidence indicates that this immunosuppressive or anti-inflammatory state may be deleterious. Increased expression of CD163 (known to be involved in several anti-inflammatory functions of the immune system) in patients with liver failure is significantly correlated with a fatal outcome. However, little is known of the regulatory mechanisms that influence the expression of CD163. We assessed the expression of CD163 on monocytes from both circulating cells and the liver tissues of patients with hepatitis B induced liver failure using flow cytometry and isolated the myofibroblasts from diseased livers. The ability of human liver myofibroblasts to regulate CD163 expression on monocytes was studied in vitro. We showed that CD163+ monocytes were enriched primarily in diseased livers and that they were associated with liver myofibroblasts in the same area. Accordingly, liver myofibroblasts were significantly superior to normal skin fibroblasts in inducing the expression of CD163 on monocytes in vitro. Moreover, we found that liver myofibroblasts triggered the activation of monocytes by secreting PGE2. Inhibition of PGE2 production in liver myofibroblasts using NS-398 markedly reduced CD163 expression in vitro. These results suggest that liver myofibroblasts play a direct role in regulating the expression of CD163 on monocytes in human liver tissues and thereby may regulate monocyte function during hepatitis B induced liver failure.
    Journal of Translational Medicine 03/2014; 12(1):60. DOI:10.1186/1479-5876-12-60 · 3.93 Impact Factor
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