Hepatic metallothionein in patients with chronic hepatitis C: relationship with severity of liver disease and response to treatment.
OBJECTIVE
Reactive oxygen species may be involved in the pathogenesis of chronic hepatitis C virus infection. Metallothionein (MT) is an essential protein for the protection of cells against reactive oxygen species. The aim of this prospective study was to assess the influence of the hepatic level and cellular distribution of MT in hepatitis C virus (HCV) infection and in the liver disease outcome.


METHODS
In liver biopsy samples of 32 patients with chronic HCV infection and of 12 control subjects, quantification of MT was performed by radioimmunoassay, MT, interleukin (IL)-1 and -6, and tumor necrosis factor (INF)-alpha mRNA by reverse transcription-polymerase chain reaction (PCR) and cellular distribution by immunohistochemistry.


RESULTS
In HCV-infected patients, MT liver protein level was 3-fold lower than in control specimens. A significant inverse linear regression between MT protein or mRNA expression and the Histological Activity Index, the necroinflammatory grade, and the stage of fibrosis was observed. MT immunostaining was located in the nucleus and cytoplasm in hepatocytes of control subjects, whereas it was mainly cytoplasmic in HCV-infected patients. Before interferon (IFN) therapy, the hepatic MT level in patients that were nonsustained responders was half that of sustained responders. Intrahepatic IL-6 and MT were simultaneously down-regulated, but no correlation was found between MT and intrahepatic cytokine mRNA expression in patients with chronic HCV infection.


CONCLUSIONS
This study shows that hepatic MT expression could reflect the severity of chronic HCV infection and could be one of the factors associated with a favorable clinical outcome in the response to interferon therapy.
Carrera
Georges
G
Laboratory of Macrophage, Inflammatory Mediators and Cellular Interactions, Institut Louis Bugnard, Centre Hospitalier Universitaire Rangueil, Toulouse Cedex, France.
Paternain
Jose Luis
JL
Carrere
Nicolas
N
Folch
Jaume
J
Courtade-Saïdi
Monique
M
Orfila
Claudine
C
Vinel
Jean Pierre
JP
Alric
Laurent
L
Pipy
Bernard
B
D000998:Antiviral Agents / Q000627:therapeutic use*; D005260:Female; D016174:Hepacivirus / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000627:therapeutic use; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011446:Prospective Studies; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000032:analysis; D012044:Regression Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000998:Antiviral Agents; D016898:Interferon-alpha; D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D012367:RNA, Viral; D014409:Tumor Necrosis Factor-alpha; D008668:Metallothionein