Hepatocyte apoptosis by death receptors, hepatic inflammation, and fibrosis are prominent features of liver diseases. However, the link between these processes remains unclear. Our aim was to ascertain whether engulfment of apoptotic bodies by Kupffer cells promotes hepatic inflammation and fibrosis. Isolated murine Kupffer cells efficiently engulfed apoptotic bodies generated from UV-treated mouse hepatocytes. Engulfment of the apoptotic bodies, but not latex beads, stimulated Kupffer cell generation of death ligands, including Fas ligand, and tumor necrosis factor ␣ (TNF-␣). Both apoptotic body phagocytosis and death ligand generation were attenuated by gadolinium chloride, a Kupffer cell toxicant. Kupffer cells isolated from 3-day bile duct-ligated (BDL) mice were phenotypically similar to apoptotic body-"fed" Kupffer cells with enhanced death ligand expression; inhibition of hepatocyte apoptosis with a caspase inhibitor prevented this Kupffer cell activation. Consistent with a role for Kupffer cells in liver inflammation and fibrosis, gadolinium chloride attenuated neutrophil infiltration and markers for stellate cell activation. In conclusion, these findings support a model of cholestatic liver injury where Kupffer cell engulfment of apoptotic bodies promotes inflammation and fibrogenesis. (HEPATOLOGY 2003;38:1188-1198

SUMMARY:Hepatocyte apoptosis and stellate cell activation are both features of chronic liver diseases, but a relationship between these events has not been explored. In macrophages, engulfment of apoptotic bodies induces expression of transforming growth factor-␤ (TGF-␤), a profibrogenic cytokine. We examined whether a similar response occurs in stellate cells. Fluorescently labeled hepatocyte apoptotic bodies were added to cultures of primary and immortalized human stellate cells. Stellate cells, but not hepatocytes, readily engulfed apoptotic bodies in a time-dependent manner as assessed by confocal microscopy. The activation of primary and immortalized human stellate cells after incubation with apoptotic bodies, as well as their fibrogenic activity, was indicated by an increase in ␣-smooth muscle actin (primary cells), TGF-␤1, and collagen ␣1(I) mRNA (primary and immortalized cells). The profibrogenic response was dependent upon apoptotic body engulfment, because nocodazole, a microtubule-inhibiting agent, blocked both the engulfment and the increase of TGF-␤1 and collagen ␣1(I) mRNA. As described in primary rodent stellate cells, up-regulation of collagen ␣1(I) mRNA was inhibited by a PI-3K inhibitor (LY294002) and a p38 mitogen-activated protein kinase inhibitor (SB203580) in LX-1 cells. In conclusion, these data support a model in which engulfment of hepatocyte apoptotic bodies by stellate cells leads to a fibrogenic response by eliciting a kinase-signaling pathway. (Lab Invest 2003, 83:655-663).L iver fibrosis is a cardinal feature of chronic liver injury. Indeed, despite the wide array of metabolic, genetic, viral, and cholestatic pathologies causing human liver injury, fibrosis is a common, if not generic, response of the liver to these injury processes. Extensive liver fibrosis results from the deposition and accumulation of type I collagen within the liver parenchyma and is recognized clinically as cirrhosis. The clinical complications of cirrhosis include portal hypertension and chronic liver failure. For many patients with advanced liver cirrhosis, the only viable treatment option is liver transplantation, highlighting the clinical severity of this fibrotic process. Insights into the mechanisms initiating and promoting liver fibrosis are, therefore, of broad scientific and clinical importance.Activated hepatic stellate cells have been established as the source of type I collagen in the liver (de Leeuw et al, 1984;Friedman et al, 1985;McGee and Patrick, 1972). Under basal conditions, hepatic stellate cells are in a quiescent state and function to store retinoids within the liver (Blomhoff et al, 1990;Geerts, 2001). However, upon activation, these cells undergo transformation, assuming a myofibroblast morphology and expressing smooth muscle actin (Ramadori et al, 1990;Schmitt-Graff et al, 1991). These activated stellate cells secrete collagen types I and III, the principle matrix protein responsible for the development of liver fibrosis and cirrhosis (Friedman, 2000;Kent et al, 1976). Over time, activ...

BACKGROUND & AIMS: The prevalence of nonalcoholic steatohepatitis (NASH) associated hepatocellular carcinoma (HCC) is increasing. However, strategies for detection of early-stage HCC in patients with NASH have limitations. We assessed the ability of the GALAD score, which determines risk of HCC based on patient sex; age; and serum levels of a-fetoprotein (AFP), AFP isoform L3 (AFP-L3), and des-gamma-carboxy prothrombin (DCP), to detect HCC in patients with NASH. METHODS: We performed a case-control study of 125 patients with HCC (20% within Milan Criteria) and 231 patients without HCC (NASH controls) from 8 centers in Germany. We compared the performance of serum AFP, AFP-L3, or DCP vs GALAD score to identify patients with HCC using receiver operating characteristic curves and corresponding area under the curve (AUC) analyses. We also analyzed data from 389 patients with NASH under surveillance for HCC in Japan, followed for a median of 167 months. During the 5-year screening period, 26 patients developed HCC. To compensate for irregular intervals of data points, we performed locally weighted scatterplot smoothing, linear regression, and a non-linear curve fit to assess development of GALAD before HCC development. RESULTS: The GALAD score identified patients with any stage HCC with an AUC of 0.96significantly greater than values for serum levels of AFP (AUC, 0.88), AFP-L3 (AUC, 0.86) or DCP (AUC, 0.87).

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