Hepatic glutathione deficiency in chronic hepatitis C: quantitative evaluation in patients who are HIV positive and HIV negative and correlations with plasmatic and lymphocytic concentrations and with the activity of the liver disease.
OBJECTIVE
Reduced glutathione (GSH) is decreased in patients affected by chronic hepatitis C (CHC) as well as in patients who are HIV positive. Because the liver is the most important source of plasmatic GSH, we measured the concentrations of GSH in the liver (H-GSH) of patients with CHC who were either HIV positive or negative, correlating it to the concentrations of GSH in plasma (P-GSH) and in peripheral blood mononuclear cells (PBMCs) (L-GSH), to the replication activity of hepatitis C virus (HCV) in PBMCs, to the activity of the liver disease, and to the state of immunodeficiency in patients who were HIV positive.


METHODS
One hundred, five patients with serologically and histologically demonstrated CHC (55 HIV positive and 50 HIV negative) entered the trial. Fifty-one healthy individuals made up a control group for P-GSH and L-GSH concentrations. H-GSH concentration was determined by high performance liquid chromatography on liver specimens obtained by ultrasound-guided biopsy according to the method described by Reed et al. The concentrations of P-GSH and L-GSH were determined according to the method described by Suarez et al. The detection of HCV RNA strands in PBMCs was performed according to the method described by Qian et al. Histological findings and degree of fibrosis were scored according to the numerical scoring system proposed by Scheuer and by Knodell et al.


RESULTS
H-GSH, P-GSH, and L-GSH were significantly reduced in patients affected by CHC compared with healthy controls (p < 0.001). H-GSH and particularly L-GSH were more significantly reduced in patients who were HIV positive compared with those who were HIV negative (p < 0.001), without significant correlation with the values of the T cell subset CD4+. The reductions in H-GSH, P-GSH, and L-GSH were significantly correlated to the replication activity of HCV in PBMCs (p < 0.001) and to the grade of activity of the liver disease assessed by the values of ALT (p < 0.001) and by histological and fibrosis scores of CHC (p < 0.001). In both groups of patients with CHC, H-GSH, P-GSH, and L-GSH were more reduced in patients addicted to drugs than in patients who were not addicted.


CONCLUSIONS
In patients with CHC, particularly those who are HIV positive, a systemic depletion of GSH is present. This depletion may be a factor underlying the resistance to interferon therapy and, in patients who are HIV positive, to antiretroviral drugs, fostering HCV and/or HIV replication. This may represent the biological basis for GSH replacement therapy.
Barbaro
G
G
Department of Emergency Medicine, University La Sapienza, Rome, Italy.
Di Lorenzo
G
G
Soldini
M
M
Parrotto
S
S
Bellomo
G
G
Belloni
G
G
Grisorio
B
B
Barbarini
G
G
D000328:Adult; D002908:Chronic Disease; D005260:Female; D005978:Glutathione / Q000097:blood / Q000172:deficiency* / Q000378:metabolism; D018023:HIV Seronegativity; D006679:HIV Seropositivity / Q000150:complications*; D006526:Hepatitis C / Q000150:complications* / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D009994:Osmolar Concentration; D019966:Substance-Related Disorders / Q000150:complications
D005978:Glutathione