Screening for biliary atresia: Swiss stool color card

We read the article by Horiguchi et al. with great interest. It is a commonly accepted dogma that inflammation induces necrosis and apoptosis of hepatocytes during liver damage. However, clinicians have found that inflammation does not always correlate with hepatocellular damage in chronic liver disease. How to explain the conflict? By using a well-established model of mice with specific deletion of signal transducer and activator of transcription 3 in myeloid cells (STAT3 / ), Horiguchi and colleagues surprisingly found more inflammatory cells, eg, neutrophils, but less necrosis/apoptosis in the liver of STAT3 / mice than in wild-type mice after carbon tetrachloride (CCl4) treatment. STAT3 mye / mice had higher hepatic STAT3 activation and became resistant to hepatic oxidative stress after CCl4 injection compared with wild-type mice. In contrast to STAT3 / mice, hepatocyte-specific STAT3 knockout (STAT3 / ) mice had more liver necrosis/apoptosis but less inflammation after CCl4 treatment compared with wild-type mice. An additional deletion of hepatocyte STAT3 in STAT3 / mice restored CCl4-induced hepatic necrosis but reduced liver inflammation. This study suggests that inflammation associated with a predominance of hepatoprotective cytokines may reduce rather than accelerate hepatocellular damage via activation of hepatocyte STAT3 in CCl4induced liver damage. The data elucidate a potential mechanism that inflammation does not always correlate with hepatocellular damage. Interestingly, the same group had also previously investigated inflammation and hepatocellular damage in the same strain of STAT3 / mice treated with concanavalin A (ConA) or ethanol. STAT3 / mice had higher inflammation concomitant with more severe hepatocellular damage compared with wild-type mice after ConA or ethanol treatment. The discrepancy between ConAand CCl4-induced liver damage in STAT3 mye / mice could be attributable to the different T helper type 1 (Th1) cytokine (IFN-c) responses in these two models. In STAT3 / mice, ConA treatment elevated serum IFN-c levels to more than 2500 pg/mL, whereas CCl4 treatment only elevated IFN-c levels to 15 pg/mL. Such high levels of IFN-c in the ConA model not only directly induce liver damage but also inhibit the hepatoprotective STAT3 signal in the liver, further promoting liver injury. In addition, ethanol consumption significantly inhibited STAT3 activation in STAT3 / mice. Thus, the protective role of STAT3 is inhibited in both models of ConA and ethanol treatment. These data suggest that the etiology of liver disease plays a critical role in determining the interplay between inflammation and hepatocellular damage. In general, the ratio between proinflammatory and anti-inflammatory factors controls the inflammatory level during liver damage; however, the fate of hepatocytes is determined by the balance between the survival and detrimental factors present within the damaged liver. For example, compared to wild-type mice, STAT3 / mice had increased pro-inflammatory cytokines, eg, IL-6, IL-1, IFN-c, and chemokines in both the liver and serum. However, proinflammatory factors do not always kill hepatocytes and some of them such as IL-6 protect rather than kill hepatocytes via activation of survival signal STAT3 in hepatocytes. Thus, inflammation is not always a direct killer of hepatocytes. Besides the dogma that inflammation leads to hepatocyte death, inflammation is also thought as the critical driver for liver fibrogenesis. However, many studies have demonstrated that inflammation does not always correlate with liver fibrosis in patients with chronic liver disease. On the other hand, it is well recognized that degradation of fibrosis needs inflammation. Thus, whether inflammation is a friend or a foe is not a simple question. Here, we have three questions for the authors: First, in patients with acute liver failure, inflammatory cells, especially monocytes and macrophages, are central to systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), and compensation anti-inflammatory response syndrome (CARS). Compared with SIRS patients, patients with MODS have similar levels of proinflammatory cytokines, but higher levels of antiinflammatory cytokines that suppressed the functions of peripheral and hepatic inflammatory cells. Similarly, in STAT3 / mice, CCl4 treatment resulted in early elevation of proinflammatory cytokines (at 12 hours after treatment), which remained at the same levels or was decreased at later time points (24 hours). In contrast, the levels of the anti-inflammatory cytokine IL-10 were higher at later time (24 hours) than earlier time (12 hours) points. The situation looks very similar to the early stage of MODS in patients with acute liver failure. It would be very interesting to further investigate the ratio of proinflammatory and anti-inflammatory cytokines/chemokines in STAT3 / mice at 36 hours after CCl4 treatment. Second, the authors investigated the relationship between inflammation and hepatocellular damage in ‘‘chronic’’ liver disease. However, the maximal CCl4 treatment time period in the present study was 72 hours, and most of data were obtained from the mice treated with CCl4 within 24 hours. It would be very interesting to investigate the inflammation and hepatocelluar damage in real ‘‘chronic liver disease’’, eg, mice subjected to 4 weeks of CCl4-treatment. Finally, we are very interested in the relationship between inflammation and fibrosis in these mice treated chronically with CCl4. Anyway, we appreciate Horiguchi and colleagues for providing such fascinating work for further discussion.