Biomarkers of Macrophage Activation and Immune Danger Signals Predict Clinical Outcomes in Alcoholic Hepatitis

Abstract

Although mortality due to acute alcoholic hepatitis (AH) correlates with Model for End-Stage Liver Disease (MELD) scores, biomarkers are critically needed to manage this disease. Increases in inflammatory markers and macrophage activation are associated with acute AH and could be potential biomarkers of clinical events and/or mortality. We enrolled 89 clinically diagnosed AH patients in four US academic medical centers. Plasma from AH patients had a significant increase in gut microbial translocation indicators (endotoxin, bacterial 16S ribosomal DNA) and host response indicators (soluble cluster of differentiation 14 [sCD14] and lipopolysaccharide binding protein [LBP]) compared to controls. Patient MELD score and Glasgow Alcoholic Hepatitis score (GAHS) correlated with endotoxin levels. AH patients also had a significant increase in high mobility group protein 1 (HMGB1), a sterile danger signal molecule, and osteopontin (OPN), a multifunctional phosphoprotein involved in neutrophil activation, compared to controls. Increased levels of OPN positively correlated with increasing MELD score, GAHS, and LBP levels. Consistent with these results, AH patients had significantly increased circulating levels of macrophage activation (sCD163 and sCD206) markers compared to healthy controls, and sCD163 and sCD206 significantly and positively correlated with OPN, HMGB1, and LBP levels as well as with MELD score and GAHS. These findings indicate a connection between microbial translocation, immune cell activation, and AH severity. Plasma sCD14, OPN, sCD163, and sCD206 levels were significantly higher in nonsurvivors than survivors. In multivariate regression models, we identified sCD14, sCD163, and OPN as independent predictors of 90-day mortality, infection, and organ failure development, respectively. Conclusion: Our study suggests that sCD14, LBP, OPN, sCD163, and sCD206 are biomarkers to indicate severity and predict clinical outcomes in AH. (Hepatology 2019;70:1134-1149).A lcoholic liver disease (ALD) is responsible for 0.9% of all deaths worldwide and is a leading cause of liver-related morbidity and mortality. (1) The clinical spectrum of ALD encompasses steatosis, alcoholic steatohepatitis, alcoholic fibrosis, and cirrhosis. Acute alcoholic hepatitis (AH) is the most severe form of ALD and carries a high mortality. (2,3) Heavy alcohol consumption leads to changes in lipid metabolism, causing lipid accumulation in hepatocytes and release of danger-associated molecular patterns (DAMPs) that, in combination with gut-derived pathogen-associated molecular patterns

Recent advances in alcohol-related liver disease (ALD): summary of a Gut round table meeting

“…Recent studies found that biomarkers such as cytokeratin-18 fragments, soluble cluster of differentiation 14, lipopolysaccharide binding protein (LBP), osteopontin (a multifunctional phosphoprotein involved in neutrophil activation) and circulating levels of macrophage activation sCD163 and sCD206t can indicate severity and predict clinical outcomes in AH helping the management of the disease 54 55…”

Emerging Noninvasive Biomarkers, and Medical Management Strategies for Alcoholic Hepatitis: Present Understanding and Scope

“…Some of the advantages of the MELD score over the DF are the use of INR as compared to prothrombin time, and the use of serum creatinine to include renal function, which plays an important role in the prognosis of AH patients [16]. Several studies have estimated that MELD may be equivalent to or even better than the DF as a prognostic marker of AH [26][27][28].…”

“…Surface proteins have numerous functions including acting as a receptor, transport channel, enzyme activity and intracellular identification and interaction. In the liver, CD glycoproteins are mainly detected on Kupffer cells [28]. Some markers like CD163 are also released in response to the bacterial stressors like lipopolysaccharides (LPS), which are detectable in the plasma making this marker relatively easy to measure [71].…”

Serum levels of bone sialoprotein correlate with portal pressure in patients with liver cirrhosis

“…So far, biomarkers of systemic inflammation and infection have performed fairly well to distinguish patients with a stable disease course from those at higher risk of decompensation [2][3][4]. Moreover, biomarkers of macrophage activation and immune danger signals were demonstrated to predict outcome in patients with decompensated liver cirrhosis, especially in patients with alcoholic hepatitis [5].…”

“…OPN levels positively correlated with total bilirubin, Model for End-Stage Liver Disease (MELD) score, MELD-Na score and monocyte count. Moreover, OPN was identified as an independent risk factor for mortality in ACLF and reflected macrophage activation in patients with liver cirrhosis and alcoholic hepatitis [5]. Since many analyses suggested comparable features of different SIBILINGs when tested on their function as a biomarker for a specific disease condition [15], we hypothesized that BSP might also represent a previously unrecognized marker in the context of liver cirrhosis.…”