Endotoxaemia in the pathogenesis of cytopenias in liver cirrhosis. Could oral antibiotics raise blood counts?
Cytopenias are frequently observed in patients with cirrhosis and are associated with increased morbidity. In particular, thrombocytopenia can impact routine care of patients with cirrhosis by potentially postponing or interfering with diagnostic and therapeutic procedures including liver biopsy and medically indicated or elective surgery. The pathogenesis of cytopenias in cirrhosis remains largely unknown. Historically, the concept of hypersplenism has long been associated with the cirrhosis-related hematological disorders but was never proven. On the other hand, intestinal bacterial overgrowth and altered gut permeability in cirrhotic patients lead to increased translocation of bacteria and endotoxin into the portal circulation. The impaired phagocytic function of the reticuloendothelial system together with the portosystemic shunting allow endotoxin to reach the systemic circulation and high concentrations of circulating endotoxin are found in cirrhotic patients even with no clinical evidence of infection and correlate with the severity of liver disease. Endotoxin activates monocytes and promotes the release of proinflammatory cytokines. Indeed, serum levels of interleukin-1, interleukin-6, tumor necrosis factor-α, and interferon-γ are elevated in patients with cirrhosis in proportion to the severity of liver disease. Endotoxaemia stimulates the vascular production of nitric oxide (NO) directly or indirectly via the cytokine cascade, and correlates with serum NO metabolite levels in cirrhosis. Several lines of evidence strongly suggest that endotoxaemia may reduce peripheral blood counts either directly or through the release of cytokines and NO. Previous studies in experimental models of cirrhosis and cirrhotic patients have demonstrated that long-term administration of oral antibiotics such as trimethoprim-sulfamethoxazole, norfloxacin, and rifaximin can reduce bacterial translocation and circulating levels of endotoxin, TNF-α, IL-6, and NO. We hypothesize that endotoxaemia plays a pivotal role in the pathogenesis of cytopenias in cirrhosis and that intestinal decontamination could raise peripheral blood counts by the suppression of endotoxaemia and the inhibition of cytokine and NO production.
Kalambokis
Georgios
G
1st Division of Internal Medicine and Hepato-Gastorenterology Unit, University Hospital, Ioannina, Greece.
Tsianos
Epameinondas V
EV
D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D019446:Endotoxemia / Q000150:complications*; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications*; D008962:Models, Theoretical; D013921:Thrombocytopenia / Q000188:drug therapy* / Q000209:etiology
D000900:Anti-Bacterial Agents