ACETALDEHYDE-MODIFIED EPITOPES IN LIVER-BIOPSY SPECIMENS OF ALCOHOLICAND NONALCOHOLIC PATIENTS - LOCALIZATION AND ASSOCIATION WITH PROGRESSION OF LIVER FIBROSIS

Acetaldehyde, the first product of ethanol oxidation, has been shown t o stimulate collagen gene expression and to form protein acetaldehyde adducts. Because little is known about these adducts in human liver ti ssue, we assessed, with an immunohistochemical procedure, the presence and location of acetaldehyde-protein adducts in liver biopsy specimen s of alcoholic patients. In addition, we correlated the presence of ad ducts with the progression or subsequent occurrence of liver fibrosis. The group included 106 patients with high alcohol consumption (> 90 g m ethanol/day for the last 5 yr), 10 nonalcoholic patients with normal livers and 23 patients with other liver diseases. Sixty-four of the 1 06 alcoholic patients had a second liver biopsy, whose specimen was us ed to assess the progression of liver fibrosis. Polyclonal antibodies were produced against homologous low-density lipoprotein purified from rabbit serum and modified in vitro in the presence of acetaldehyde. P rotein-acetaldehyde adducts could be detected by immunohistochemistry in biopsy specimens of 90 alcoholic patients (85%), in none of the 10 nonalcoholic patients with normal livers and in 65% of the patients wi th nonalcoholic liver disease. Acetaldehyde-modified epitopes were det ected in the intracellular and extracellular compartment. Intracellula r protein-acetaldehyde adducts were localized in the cytoplasm of hepa tocytes with a more intense staining in zone 3. No correlation existed between the intensity of intracellular staining and the histologicall y assessed severity of liver disease. Extracellular acetaldehyde-modif ied epitopes were detected in 55 (52%) biopsy specimens of alcoholic p atients, with 33 of 39 (85%) patients with alcoholic hepatitis or alco holic hepatitis in cirrhosis, in none of the 10 nonalcoholic patients with normal livers and in 3 (13%) of 23 patients with other liver dise ases. Extracellular protein-acetaldehyde adducts were colocalized with in the extracellular matrix. A brighter staining was seen in areas of histologically assessed active fibrogenesis and no or low staining in the well-organized older fibrous tissue. The presence of extracellular acetaldehyde adducts in the first biopsy specimen was significantly c orrelated to progression of liver fibrosis in the second biopsy specim en (p < 0.05). The results of our study indicate that covalent crossli nks between acetaldehyde and proteins could be involved in the pathoge nesis of liver fibrosis.