Host Response to Translocated Microbial Products Predicts Outcomes of Patients With HBV or HCV Infection

Abstract

Background & Aims Chronic infection with hepatitis B or C virus (HBV or HCV) is a leading cause of cirrhosis, by unknown mechanisms of pathogenesis. Translocation of gut microbial products into the systemic circulation might increase because of increased intestinal permeability, bacterial overgrowth, or impaired clearance of microbial products by Kupffer cells. We investigated whether the extent and progression of liver disease in patients with chronic HBV or HCV infection are associated with microbial translocation and subsequent activation of monocytes. Methods In a retrospective study, we analyzed data from 16 patients with minimal fibrosis, 68 with cirrhosis, and 67 uninfected volunteers. We analyzed plasma levels of soluble CD14 (sCD14), intestinal fatty acid binding protein (I-FABP), and interleukin (IL)-6 by ELISA, and lipopolysaccharide (LPS) by the limulus amebocyte lysate assay, at presentation and after antiviral treatment. Results Compared with uninfected individuals, HCV- and HBV-infected individuals had higher plasma levels of LPS, I-FABP (indicating enterocyte death), sCD14 (produced upon LPS activation of monocytes), and IL-6. Portal hypertension, indicated by low platelet counts, was associated with enterocyte death (P=.045 at presentation, P<.0001 after therapy). Levels of sCD14 correlated with markers of hepatic inflammation (P=.02 for AST, P=.002 for ferritin) and fibrosis (P<.0001 for gamma-glutamyl transpeptidase, P=.01 for alkaline phosphatase, P<.0001 for alpha-fetoprotein). Compared to subjects with minimal fibrosis, subjects with severe fibrosis at presentation had higher plasma levels of sCD14 (P=.01) and more hepatic CD14+ cells (P=.0002); each increased risk for disease progression (P=.0009 and P=.005, respectively). Conclusions LPS-induced local and systemic inflammation are associated with cirrhosis and predict progression to end-stage liver disease in patients with HBV or HCV infection.

Reply

“…First, Sandler et al demonstrated elevated levels of sCD14 in hepatitis B virus (HBV) and HCV patients with severe fibrosis and reported a prognostic value for CD14 1 macrophages and sCD14 for disease progression in chronic viral hepatitis. 5 However, this is in contrast with the findings of Kuniholm et al In a recent study from our group, HCV patients with cirrhosis, as assessed by transient elastography, had higher levels of sCD163 and sCD206 (the shed mannose receptor), compared to those with no/mild fibrosis. However, sCD206 was inferior to sCD163 in cirrhosis prediction, 6 supporting the notion that sCD163 may be the best macrophagespecific biomarker in chronic viral hepatitis.…”

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

“…Similarly, for 98 HIV/HCV coinfected patients on virologically suppressive ART, we reported increased sCD14 levels in subjects either harboring aggressive HCV genotypes (i.e., genotypes 1 to 4) or presenting with cirrhosis (129). Furthermore, Sandler et al reported that higher sCD14 levels distinguish patients with severe liver fibrosis from those with minimal fibrosis in a cohort of hepatitis B virus (HBV)/HCV-monoinfected subjects (130). These results suggest a pathogenic role of the host response to LPS in severe HIV/HCV-related liver disease.…”

“…Although several factors have been associated with the response to anti-HCV therapy, the determinants of successful full-course peg-IFN-␣-ribavirin therapy are still poorly defined (133)(134)(135)(136)(137). Interestingly, increased plasma sCD14 levels have been proven to be independently associated with poor responses to anti-HCV treatment (129,130), thus suggesting an independent role of microbial translocation in the outcome of anti-HCV therapy. Contrasting data, however, were obtained for a cohort of ART-naïve HIV/ HCV-coinfected patients with high CD4 ϩ T-cell counts, for whom higher sCD14 levels were independently associated with a decreased risk of liver disease progression, defined as a time to Fibrosis 4 (Fib-4) score of Ͼ1.45 or liver-related death.…”

Phenotypic alterations of regulatory T cells in autoimmune hepatitis: Causal or associated with treatment and remission?

“…5 However, this is in contrast with the findings of Kuniholm et al In a recent study from our group, HCV patients with cirrhosis, as assessed by transient elastography, had higher levels of sCD163 and sCD206 (the shed mannose receptor), compared to those with no/mild fibrosis. However, sCD206 was inferior to sCD163 in cirrhosis prediction, 6 supporting the notion that sCD163 may be the best macrophagespecific biomarker in chronic viral hepatitis.…”