Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis

Abstract

bility to ALD have thus far focused primarily on genes encod-SEE EDITORIAL ON PAGE 232 ing ethanol metabolizing enzymes. 3 Results have been conflicting, but it would appear that the known polymorphisms of genes encoding the alcohol and aldehyde dehydroTwin concordance studies suggest that genetic factors play genase enymes and the ethanol-inducible cytochrome P450, a role in determining why only a minority of heavy drinkers CYP2E1, play only a minor role in the Caucasian populadevelop hepatitis and cirrhosis. Tumor necrosis factor a tion. [5][6][7] These results have led to a search for alternative ''can-(TNF-a) has emerged as the ''final common pathway'' in the didate genes'' potentially involved in determining individual pathogenesis of alcohol-related hepatic necro-inflammation.susceptibility to advanced ALD. We have examined the frequency of the two recently de-The cytokine tumor necrosis factor a (TNF-a) has recently scribed polymorphisms of the TNF-a promoter in 150 paemerged as an important mediator of hepatic necro-inflamtients with biopsy-proven alcoholic liver disease and 145 mation associated with excessive alcohol intake. 8 Investigahealthy volunteers. There was a significant excess of the rare tion of the role of TNF-a and other cytokines in alcoholic allele (TNFA-A; G 0238 r A) at position 0238 in patients with steatohepatitis was first stimulated by the striking similarity steatohepatitis compared with controls or patients without observed between the metabolic complications of ASH and this lesion. This is consistent with previous suggestions that the metabolic effects of cytokines, including TNF-a. 8 Inthe TNFA-A allele, which falls within a putative Y regulation creased TNF-a production by peripheral blood monocytes box of the TNF-a promoter, is associated with increased TNFand Kupffer cells has been shown in patients with ASH and a expression. No differences were observed for the polymoranimal models of alcoholic liver injury. 9,10 Several investigaphism at position 0308. (HEPATOLOGY 1997;26:143-146.)tors have shown increased plasma levels of TNF-a activity in patients with ASH 11-15 and some have shown a correlation In common with other end-organ complications of alcohol with liver function and mortality. 11,14 TNF-a is cytotoxic to abuse, severe liver disease develops in only a minority of sensitized hepatocytes and has been implicated as a proximal heavy drinkers. In several biopsy studies alcoholic steatohepmediator in experimental liver injury induced by Propionibacatitis (ASH), characterized by steatosis and necroinflammaterium acnes, galactosamine, lead and endotoxin, and ischtion, is present in 6% to 30% of heavy drinkers, with estabemia-reperfusion. 8 In humans, reversible hepatitis is one of lished cirrhosis in less than 20%. 1 Although some evidence the toxicities of human recombinant TNF-a administered for supports a dose-response relationship between alcohol contherapy to cancer patients. 16 sumption and risk of disease, 2 it is clear that factors other Recently, two polymorphi...

Biochemical evaluation of antihyperglycemic and antioxidative effects of Morinda citrifolia fruit extract studied in streptozotocin-induced diabetic rats

“…Oxidative stress from reactive lipid peroxidation, peroxisomal b-oxidation, and recruited inflammatory cells are the other potential explanations for elevated aminotransferase in insulin resistance. The insulinresistant state is also characterized by an increase in proinflammatory cytokines such as tumor necrosis factor-a (TNF-a), which may also contribute to hepatocellular injury (Grove et al, 1997). Thus, the observed increase in the activities of ALT, AST, and ALP in serum of diabetic rats may primarily be due to leakage of these enzymes from liver cytosol into bloodstream as a consequence of the hepatotoxic effect of STZ (El-Demerdash et al, 2005).…”

Polymorphisms of Promoter Region ofTNF-αGene in Iranian Azeri Turkish Patients with Behçet’s Disease

“…A number of single nucleotide polymorphisms (SNPs) in TNF-α promoter region have been identified, of which we chose to genotype TNF-α -857T/C and TNF-α -238G/A polymorphisms. It has been shown that the -857C and- 238A alleles cause an increase in TNF-α production (1314). The implication of these polymorphisms in susceptibility to several autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, and systemic lupus erythematosus, has been assessed (151617).…”

TNFα is required for cholestasis-induced liver fibrosis in the mouse

“…For example, increased TNFα levels are found in patients with PBC [6], chronic viral hepatitis [7], fulminant hepatic failure [8], and negatively correlate with survival in patients with alcoholic liver disease [9]. In addition, TNFα levels are elevated in the serum of patients with alcoholic liver cirrhosis [10] and polymorphisms in the TNFα gene are associated with advanced fibrosis in alcoholic steatohepatitis [11]. Further, TNFα aggravates liver fibrosis induced by schistosomiasis in humans [12].…”