Connective tissue growth factor, steatosis and fibrosis in patients with chronic hepatitis C.
OBJECTIVE
Both steatosis and insulin resistance have been linked to accelerated fibrosis in chronic hepatitis C. Connective tissue growth factor (CTGF) plays a major role in extracellular matrix production in fibrotic disorders including cirrhosis, and its expression is stimulated in vitro by insulin and glucose. We hypothesized that CTGF may link steatosis, insulin resistance and fibrosis.


METHODS
We included 153 chronic hepatitis C patients enrolled in the Swiss Hepatitis C Cohort Study and for whom a liver biopsy and plasma samples were available. CTGF expression was assessed quantitatively by immunohistochemistry. In 94 patients (57 with genotypes non-3), plasma levels of glucose, insulin and leptin were also measured. CTGF synthesis was investigated by immunoblotting on LX-2 stellate cells.


RESULTS
Connective tissue growth factor expression was higher in patients with steatosis (P=0.039) and in patients with fibrosis (P=0.008) than those without these features. CTGF levels were neither associated with insulinaemia or with glycaemia, nor with inflammation. By multiple regression analysis, CTGF levels were independently associated with steatosis, a past history of alcohol abuse, plasma leptin and HCV RNA levels; when only patients with genotypes non-3 were considered, CTGF levels were independently associated with a past history of alcohol abuse, plasma leptin levels and steatosis. Leptin stimulated CTGF synthesis in LX-2 cells.


CONCLUSIONS
In patients with chronic hepatitis C and steatosis, CTGF may promote fibrosis independently of inflammation. CTGF may link steatosis and fibrosis via increased leptin levels.
Hora
Caroline
C
Department of Clinical Pharmacology, University of Bern, Bern, Switzerland.
Negro
Francesco
F
Leandro
Giacchino
G
Oneta
Carl M
CM
Rubbia-Brandt
Laura
L
Muellhaupt
Beat
B
Helbling
Beat
B
Malinverni
Raffaele
R
Gonvers
Jean-Jacques
JJ
Dufour
Jean-François
JF
D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D055513:Connective Tissue Growth Factor; D005234:Fatty Liver / Q000209:etiology*; D005260:Female; D019698:Hepatitis C, Chronic / Q000150:complications*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D020738:Leptin / Q000097:blood; D008103:Liver Cirrhosis / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D013557:Switzerland
D001786:Blood Glucose; C526317:CCN2 protein, human; D017874:Immediate-Early Proteins; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D055513:Connective Tissue Growth Factor