Plasma endotoxin and serum cytokine levels in patients with alcoholic hepatitis: relation to severity of liver disturbance.
BACKGROUND
Endotoxin plays an important role in the initiation and aggravation of alcoholic liver disease. In this study, we evaluated plasma endotoxin levels and serum concentrations of cytokines and lipopolysaccharide binding protein (LBP) during the acute and recovery phase of patients with alcoholic hepatitis; we also explored the prognostic factors associated with a fatal outcome.


METHODS
Fourteen patients, consisting of eight patients with alcoholic hepatitis (AH), five cirrhotics with superimposed AH (LC+AH), and one patient with severe alcoholic hepatitis (SAH), were studied. Among these, two with LC+AH died of hepatic failure.


RESULTS
Plasma endotoxin levels in the acute phase were higher in patients with AH (184.4 +/- 159.4 pg/ml) and LC+AH (206.9 +/- 174.9 pg/ml) than in healthy subjects (10.4 +/- 5.5 pg/ml, p < 0.001). In particular, in one patient with SAH and one of two nonsurvivors, plasma endotoxin levels were markedly high relative to the other cases. In most survivors, plasma endotoxin levels decreased in the recovery phase, whereas they further increased at the terminal stage in one of two nonsurvivors. Serum interleukin (IL)-6 and IL-8 levels in the acute phase were significantly higher in patients with AH and LC+AH as compared with healthy subjects. These levels were especially high in nonsurvivors and in one patient with SAH. IL-10 increased in two nonsurvivors, one patient with SAH, and one with LC+AH. In the recovery phase, these cytokine levels in survivors tended to decrease, but in nonsurvivors, IL-6 remained high, and IL-8 and IL-10 further increased. Tumor necrosis factor-alpha levels were below the detection limit throughout the course in all patients. Serum lipopolysaccharide binding protein (LBP) generally was elevated in the acute phase and decreased in the recovery phase in all survivors, but in one of the nonsurvivors, LBP was elevated markedly at the terminal stage. In the acute phase, plasma endotoxin levels were correlated positively with white blood cell counts, neutrophil counts, and serum IL-8. IL-8 was correlated positively with neutrophil counts and negatively with serum cholinesterase, hepaplastin test, and serum albumin levels. IL-6 was correlated positively with white blood cell and neutrophil counts, C-reactive protein, and serum total bilirubin and negatively with hepaplastin test and serum total protein levels. Serum LBP was correlated positively with white blood cell and neutrophil counts.


CONCLUSIONS
Endotoxemia and related elevation of IL-8 may play an important role in the activation and migration of neutrophils in patients with alcoholic hepatitis. Marked elevation of inflammatory cytokines, IL-6 and IL-8, are related to severity and poor prognosis of alcoholic hepatitis. Serum LBP may serve as an index of inflammatory reaction in alcoholics.
Fujimoto
M
M
Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan.
Uemura
M
M
Nakatani
Y
Y
Tsujita
S
S
Hoppo
K
K
Tamagawa
T
T
Kitano
H
H
Kikukawa
M
M
Ann
T
T
Ishii
Y
Y
Kojima
H
H
Sakurai
S
S
Tanaka
R
R
Namisaki
T
T
Noguchi
R
R
Higashino
T
T
Kikuchi
E
E
Nishimura
K
K
Takaya
A
A
Fukui
H
H
D000209:Acute-Phase Proteins; D000210:Acute-Phase Reaction; D000328:Adult; D000368:Aged; D002097:C-Reactive Protein / Q000032:analysis; D002352:Carrier Proteins / Q000097:blood; D016207:Cytokines / Q000097:blood*; D004731:Endotoxins / Q000097:blood*; D005260:Female; D006519:Hepatitis, Alcoholic / Q000097:blood* / Q000150:complications / Q000503:physiopathology*; D006801:Humans; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D007958:Leukocyte Count; D008099:Liver / Q000503:physiopathology*; D008104:Liver Cirrhosis, Alcoholic / Q000150:complications; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D009504:Neutrophils; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002097:C-Reactive Protein; D002352:Carrier Proteins; D016207:Cytokines; D004731:Endotoxins; D016753:Interleukin-10; D015850:Interleukin-6; D016209:Interleukin-8; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D000099231:Lipopolysaccharide-Binding Protein