bility to ALD have thus far focused primarily on genes encod-SEE EDITORIAL ON PAGE 232 ing ethanol metabolizing enzymes. Results have been conflicting, but it would appear that the known polymorphisms of genes encoding the alcohol and aldehyde dehydro-Twin 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. 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. 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 [13][14][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. 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 polymorphisms have been identified in the than cumulative dose of alcohol determine which heavy TNF-a promoter; one at position 0308 17 and another at drinkers progress beyond the stage of simple steatosis. Twin position 0238. The 0308 G r A polymorphism, termed concordance studies, showing a higher concordance rate for TNF2, is strongly linked to HLA haplotypes A1, B8, and DR3 advanced alcoholic liver disease (ALD) amongst monozygotic and is independently associated with an increased suscepticompared with dizygotic twin pairs, have suggested that this bility to cerebral malaria in Gambian children. Studies with apparent inter-individual variation in disease susceptibility the TNF-a promoter linked to a reporter gene have shown is at least in part attributable to genetic factors. Because it is that the TNF2 allele leads to increased constitutive and inprobable that at least some of the injurious effects of alcohol ducible expression compared with the wild-type TNF1 alconsumption reflect either the tissue concentration of ethalele. 20 The 0238 G r A polymorphism, (TNFA-A) falls within nol or its metabolites, studies investigating genetic susceptia putative Y box, a regulative motif typical of the promoter region of major histocompatibility complex class II genes. 21 It is associated with an increased susceptibility to pulmonary Abbreviations: ASH, alcoholic steatohepatitis; ALD, alcoholic liver disease; TNF-a, tuberculosis and may also be associated with increased TNFtumor necrosis factor a; TNFA-A, the -238 G r A polymorphism.
a expression. We have sought to examine the role of both
From the Departments of