Dr. Nolan states1 that alcoholic liver disease is the target for earlier interventions with antiendotoxin therapy, although it is still difficult to prevent or suppress the progression of endotoxin-mediated liver injury by antiendotoxin therapy in clinical settings despite solid evidence of its effectiveness in the experimental models. Nolan refers to a study that showed a progressive rise of mean plasma endotoxin levels from 10 pg/mL in mild fatty liver to 60 pg/mL in severe cirrhosis with alcoholic hepatitis.2 However, positive correlations of endotoxin levels with the severity of liver injury do not necessarily mean the harmful effects of modest endotoxemia on the liver. A high plasma concentration of endotoxin exceeding 1,000 pg/mL is the predictor of death in hepatic failure, while the clinical implications of modest endotoxemia is unclear. Endotoxin activates tumor necrosis factor alpha (TNF-α) and nuclear factor kappa-B (NF-κB) signaling pathways, which are involved in the maintenance of the ordered balance between cell proliferation and apoptosis in the liver. Modest endotoxemia in chronic liver injury might be a response to an increased demand for TNF-α and NF-κB signaling. In such conditions, antiendotoxin therapy should be performed with caution. The gut is a reservoir of endotoxin because a single Escherichia coli contains about 2 million lipopolysaccharide (LPS) molecules per cell and 1 g of human feces contain 1.0-10 mg endotoxin.3 As mentioned in the present article, changing the gut flora with the use of prebiotics, probiotics, or both (symbiotics) seems a safe and promising approach in chronic liver disease. However, to confirm the effectiveness of probiotic or symbiotic therapy, larger randomized controlled trials would be required, because each sample size in previous trials is too small to yield level 1 evidence.4 In a small clinical trial, symbiotic-related improvement in ICGR15 was not related to endotoxin levels.5 I hope that such treatment strategies using probiotics or symbiotics for patients with chronic liver disease will be performed regardless of plasma endotoxin levels, because endotoxin activity in vitro does not actually reflect its biological toxicity in vivo.6
To the Editor:
Tetsuji Fujita M.D.*, * Department of Surgery, Jikei University School of Medicine, Tokyo, Japan.