Administration of carbon tetrachloride to rats resulted in induction of hepatic fibrosis and a 60% reduction of hepatic S‐adenosylmethionine synthetase activity without producing any significant modification of hepatic levels of S‐adenosylmethionine synthetase messenger RNA. The reduction of S‐adenosylmethionine synthetase activity was corrected by treatment with S‐adenosylmethionine (3 mg/kg/day, intramuscularly). Administration of carbon tetrachloride also produced a 45% depletion of liver glutathione (reduced form) that was corrected by S‐adenosylmethionine treatment. After the rats received carbon tetrachloride, a 2.3‐fold increase in liver collagen was observed; prolyl hydroxylase activity was 2.5 times greater than that seen in controls. These increases were attenuated in animals treated with carbon tetrachloride and S‐adenosylmethionine. The attenuation by S‐adenosylmethionine treatment of the fibrogenic effect of carbon tetrachloride was associated with a decrease in the number of rats in which cirrhosis developed. (HEPATOLOGY 1992;16:1022–1027.)

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The mechanisms underlying alcohol-induced liver disease (ALD) 1 remains incompletely understood. Nevertheless, it is widely recognized that the oxidative metabolism of ethanol elicits a complex interplay of factors, including mitochondrial dysfunction, autoimmune-mediated cell injury, oxidative stress, and overproduction of inflammatory cytokines, which contribute to the development of the disease (1-4).Acetaldehyde, a product of the oxidative metabolism of ethanol, is a very reactive intermediate that has been suggested to have a pathogenic role in ALD (1, 2). Indeed, there is a correlation between acetaldehyde generation within the liver and cell injury. The impairment of the low K m mitochondrial acetaldehyde dehydrogenase in perivenous hepatocytes indicates the existence of an acetaldehyde gradient along the liver acinus being greater in the perivenous zone of the liver, the area where most of the ethanol-induced liver injury is seen in both alcoholic patients and experimental animal models (2, 5-7). Furthermore, previous in vivo and in vitro studies have revealed the ability of acetaldehyde to form covalent adducts with various proteins that are thought to lead to altered liver function and structure (1, 2). In addition to these effects, it has been shown that acetaldehyde increases the transcription of collagen in several cell types (8 -11) mediated by enhanced DNA binding of transcription factors NF-1 and SP-1 to specific sites located in the promoter of the ␣2(I) collagen gene (12, 13).In eukaryotes, regulation of gene expression can be dramatically enhanced by the binding of sequence-specific DNA-binding proteins to promoter cis-acting elements. NF-B and AP-1 are transcription factors whose role in gene regulation is widely recognized (14, 15). The DNA binding subunits of NF-B belong to a multigene family that comprise several members including p50, p65 (Rel A), c-Rel, p-52, and RelB. These proteins share a domain required for DNA binding, forming homo-and heterodimers, IB binding, and nuclear localization (15-17). On the other hand, AP-1 is a transcriptional activator composed of members of the Jun and Fos families. These proteins associate to form homo-and heterodimer complexes through a leucine zipper domain that bind to a common site (18 -21). The final step in the gene regulation of both transcription factors is the translocation of the active complex to the nuclei followed by the binding to specific DNA sequences. However, unlike the AP-1 complex, NF-B activation combines several mechanisms used by other transcription factors such as phosphorylation at specific residues of the inhibitory subunit IB followed by its degradation and translocation of the active NF-B into the nuclei. Both transcription factors become activated by a wide variety of stimuli, including growth factors, cytokines, UV irradiation, and oxidative stress (18,21,22). NF-B and AP-1 control the inducible expression of a variety of genes that are involved in immune response as well as inflammatory and cellular defense mechanisms, i...

The high levels of hyaluronic acid (HA), a glycosaminoglycan of the liver extracellular matrix, which is synthesized and degraded in the liver sinusoidal cells, have been related with a decreased function of the endothelial sinusoidal cells. The relevance of HA in alcoholic liver disease has not been sufficiently evaluated, and therefore the current study was addressed to assess whether serum HA reflects the severity of liver fibrosis and fibrogenesis as well as the potential usefulness of hyaluronic acid as a marker of early fibrosis in alcoholics with liver damage. Serum HA and aminoterminal propeptide of collagen III (PIIIP) levels, a marker of liver fibrogenesis in alcoholics with liver disease, were assessed in 45 chronic alcoholic patients (31 men and 14 women, age: 44.1 ± 1.5 years) (normal liver = 7; fatty changes = 8; fibrosis = 7; alcoholic hepatitis = 6; cirrhosis = 6; and cirrhosis plus alcoholic hepatitis = 11). The severity of liver inflammation and fibrosis were scored in liver specimens as: 0, no lesion; 1+ mild; 2+ moderate; and 3+ severe. Twenty‐seven patients (60%) had HA above normal values (1 patient with fatty changes, 3 patients with fibrosis, and all patients with alcoholic hepatitis or cirrhosis). Hyaluronic acid and (PIIIP) levels increased in parallel with the severity of liver damage. Hyaluronic acid levels were higher in those patients with more liver inflammation (0, 128 ± 38; 1+, 553 ± 141; 2+, 668 ± 259; 3+, and 1,073 ± 419 microg/L; P = .004) and of fibrosis (0, 79 ± 32; 1+, 156 ± 70; 2+, 219 ± 105; and 3+, 695 ± 114 microg/L; P < .001). Procollagen III peptide levels were related with fibrosis (0, 17 ± 1; 1+, 25 ± 6; 2+, 47 ± 13; 3+, and 55 ± 9 ng/mL; P = .002) but not with inflammation (0, 29 ± 7; 1+, 45 ± 7; 2+, 54 ± 9; 3+, and 66 ± 30 ng/mL, P: not significant). Moreover, a direct linear correlation was observed between HA and PIIIP (r = .72, P < .001). A receiver operating characteristic (ROC) curve analysis revealed that HA was similar to PIIIP levels in discriminating between alcoholics without fibrosis and those with fibrosis (area under the ROC curves) (.913 ± .042 vs. .867 ± .054; P: n.s). In conclusion, serum HA reflects the severity of liver inflammation, fibrosis, and fibrogenesis in patients with alcoholic liver disease and is useful as a marker of precirrhotic and cirrhotic stages.