Franz-Ludwig Dumoulin

Autoimmunity induced by interferon-α therapy for chronic viral hepatitis

Type I interferons, which are mostly alpha-interferons (either as single agents or in combination with antiviral drugs), are currently the standard therapy for chronic viral hepatitis B, B/D, and C. Side-effects are not uncommon and include exacerbation of pre-existing autoimmune disorders or the de novo induction of autoimmunity. These adverse effects are attributed to the immunomodulatory properties of type I interferons, and should be distinguished from autoimmunity associated with chronic viral hepatitis in which interferon treatment may indeed be beneficial. The major autoimmune side-effects of interferon therapy for chronic viral hepatitis are thyroid or liver disease. Therefore, screening for thyroid antibodies and auto-antibodies indicative of autoimmune hepatitis both before, during, and after interferon therapy is strongly recommended. The presence of high concentrations of thyroid auto-antibodies or antibodies associated with autoimmune hepatitis can be contraindicative to interferon therapy. However, treatment is not contraindicated in viral hepatitis (in particular chronic hepatitis C) associated with autoimmune phenomena--including low-titer thyroid antibodies or other non-organ specific auto-antibodies. If interferon-induced autoimmunity occurs, the necessity of therapy has to be balanced carefully against the risks of autoimmune disease. Further research is needed to identify the factors which determine susceptibility to interferon-associated autoimmunity in individual patients.

Early up-regulation of chemokine expression in fulminant hepatic failure

CC‐chemokines recruit and activate macrophages and T lymphocytes, the major components of inflammatory infiltrates in fulminant hepatic failure (FHF). To analyse the role of CC‐chemokines in the pathogenesis of FHF, this study examined serum levels and intrahepatic expression of MCP‐1, MIP‐1α, MIP‐1β, and RANTES in the livers and sera of patients with FHF and controls by ELISA, immunohistochemistry, and competitive RT‐PCR. Serum levels and intrahepatic expression of all chemokines studied in FHF exceeded the levels in chronic liver diseases and normal controls. Distinct patterns of expression of each chemokine were noted on Kupffer cells, sinusoidal endothelial cells, hepatocytes, lymphocytes, and bile ducts. Intrahepatic chemokine expression correlated closely with the extent of infiltration by macrophages and T lymphocytes (r = 0.65–0.95, p < 0.001). The functional relationship between intrahepatic chemokine release and infiltration was confirmed in chemotaxis assays by inhibiting chemotaxis induced by homogenates of liver tissue obtained from FHF patients with neutralizing MCP‐1, MIP‐1α, MIP‐1β, and RANTES antibodies. The time course of CC‐chemokine release was studied in the concanavalin A and the galactosamine/LPS mouse models of FHF. In both models, intrahepatic chemokine up‐regulation occurred as an early event prior to hepatic infiltration and liver damage. The data indicate that an abundant intrahepatic release of CC‐chemokines is an early and pivotal step in the pathogenesis of FHF. Copyright

Does intubation really equal death in cirrhotic patients? Factors influencing outcome in patients with liver cirrhosis requiring mechanical ventilation

Objective It is not known whether the poor outcome of ventilated cirrhotic patients is related to the severity of the underlying liver disease or to the severity of the acute illness for which ICU care is required. This study examines parameters both of chronic liver disease and of acute illness with regard to their influence on outcome in mechanically ventilated cirrhotic patients.Design and setting Retrospective observational case series in a 9-bed medical ICU in an academic tertiary care center.Patients and measurements Seventy-six consecutive cirrhotic patients who received mechanical ventilation were identified. Clinical and laboratory parameters were compared between ICU survivors and ICU deaths.Results There were 45/76 (59%) patients who died during their ICU stay. By univariate analysis, the Child-Pugh score, its components (serum bilirubin, prothrombin time), ALT, creatinine concentration, a clinical suspicion of infection, and the APACHE II score, but not the acute physiology score (APS), differed significantly between ICU survivors and ICU non-survivors. The Child-Pugh score was highly correlated to ICU mortality both in logistic regression analysis and receiver-operating characteristics analysis. Conversely, markers of acute illness, in particular the APS component of the APACHE II score, did not predict ICU survival.Conclusions Markers of advanced chronic liver disease but not of the severity of acute illness are correlated to ICU outcome in ventilated cirrhotic patients. The outcome of advanced cases (Child-Pugh score of 12 and above) is poor.

Inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) expression in fulminant hepatic failure

BACKGROUND/AIMS Inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) have important functions in inflammation and vasoregulation but their role in fulminant hepatic failure (FHF) is not well understood. METHODS Intrahepatic in situ staining and semi-quantification of iNOS and eNOS by immunohistochemistry in 25 patients with FHF, in 40 patients with chronic liver diseases (CLD) and in ten normal controls (NC). RESULTS Expression patterns of iNOS and eNOS differed. While in NC only faint iNOS expression was found in some Kupffer cells/macrophages and hepatocytes, eNOS was expressed constitutively in sinusoidal and vascular endothelial cells. In CLD, iNOS expression was induced in Kupffer cells/macrophages and hepatocytes, representing the main iNOS expressing cell types. Additionally, bile ducts, vascular endothelial cells and lymphocytes also expressed iNOS (P = 0.001). In contrast, no differences were found between eNOS expression in CLD and NC (P = 0.64). The same cell types expressed eNOS and iNOS in FHF but numbers of both were significantly enhanced, exceeding the levels seen in CLD (P < 0.001, P = 0.017). CONCLUSIONS Our data demonstrate that iNOS and eNOS are differently regulated in physiologic conditions and in liver disease. While eNOS seems to be involved in the physiological regulation of hepatic perfusion, strong upregulation of iNOS might contribute to inflammatory processes in FHF.