Abnormalities of Neutrophil Phagocytosis, Intracellular Killing and Metabolic Activity in Alcoholic Cirrhosis and Hepatitis

Abstract

Neutrophil functions of phagocytosis and intracellular killing of bacteria were examined in 40 patients with alcoholic cirrhosis of whom 18 had a superimposed acute alcoholic hepatitis. In 65% of these, defective neutrophil phagocytosis was demonstrable, and in 62.5% there was a defect of intracellular killing of either Staphylococcus aureus or Escherichia coli. Studies of the patients' serum failed to reveal inhibitors of neutrophil function. Additional assays of superoxide (O₂ ^-) and hydrogen peroxide production, hexose monophosphate shunt activity, degranulation and cellular levels of granule enzymes and glutathione revealed that these neutrophil defects are caused by both reduced production of superoxide and defects of degranulation. The hydrogen peroxide/superoxide molar ratio was raised in patients' neutrophils, and the strong inverse correlation found between the value of this ratio and intracellular levels of reduced glutathione would be consistent with thehypothesis that the neutrophils from patients with cirrhosis are unable to detoxify hydrogen peroxide effectively and that this is a result of reduced levels of glutathione in the cells. The consequent increase in oxidant stress, both intra–and extracellularly, may be the cause of phagocytic and degranulation defects. The reduced responsesof patients' neutrophils may be caused by previous exposure of the cells to activating stimuli in circulation, as evidenced by depleted intracellular levels of granule enzymes and glutathione. Neutrophils from the patients with a superimposed acute alcoholic hepatitis had depressed phagocytosis in the early stages of incubation but, on the whole, neutrophils from these patients had a greater capacity for ingestion and killing of bacteria than neutrophils from patients with cirrhosis alone. Other neutrophil functions and metabolic activities were also significantly better than in patients with cirrhosis alone, and the reason for this may lie in the greater proportion of young neutrophils in the circulation of patients with superimposed acute alcoholic hepatitis. The exhaustion of the neutrophils' bactericidal capacity in severe alcoholic liver disease, most marked in patients with cirrhosis alone, could be a significant factor in the well–described increased susceptibility of these patients to bacterial infection.