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Editor,—The conclusions reached by Wigget al (
) about the origin and importance of tumour necrosis factor α (TNF-α) in non-alcoholic steatohepatitis (NASH) patients have failed to take into account the relationship between even modest alcohol consumption and TNF-α production and function. The authors found a lack of correlation between obesity and TNF-α levels in NASH patients and concluded that TNF-α, which they see as central to the pathogenesis of the condition, must have other sources.
We first described the strong correlation between obesity and serum TNF-α in 1998.1 Adipose tissue synthesises a number of proinflammatory cytokines.2 The negative correlation found in the Adelaide study is surprising given the findings in larger studies of non-NASH subjects and may be due to the small study numbers and not correcting for modest alcohol intake.
Alcohol consumption is considered a risk factor for the development and progression of liver disease in patients with fatty livers. We previously showed a strong negative correlation between any alcohol consumption and serum TNF-α levels in a general population sample. Modest alcohol consumption is known to suppress TNF-α production by monocytes, probably by suppressing post-transcriptional TNF-α production.3 Furthermore, alcohol also has effects on TNF-α function mediated via high density lipoprotein (HDL). Alcohol enhances HDL levels by stimulating lipoprotein lipase activity in adipose tissue.4 HDL not only inhibits TNF-α release from macrophages5 but also protects certain cells against TNF-α induced damage.6
If TNF-α is important, then modest alcohol intake should be protective via suppression of TNF-α. This raises the possibility that TNF-α is not important in early steatohepatitis.
In defining patients with NASH, alcohol consumption must be rigorously excluded. In the Adelaide study, 10 of 22 patients drank up to 20 g of alcohol per day; however, even modest amounts of alcohol have effects on TNF-α levels and function.
The known interaction between alcohol and obesity in the pathogenesis of fatty liver and steatohepatitis suggests that investigators must look to factors other than TNF-α in studying the early pathogenesis of this condition. In the same way that altered cytokine homeostasis has been implicated in alcoholic liver disease, NASH is probably caused by changes to more than one proinflammatory cytokine. Interleukin 6 (IL-6) is a proinflammatory cytokine, a hepatocyte stimulating factor, and inhibitor of hepatic apoptosis. It has been suggested that hepatic steatosis is due to the rate of hepatocyte apoptosis becoming insufficient to match the rate of hepatocyte proliferation.7 IL-6 induced liver regeneration may render the liver more susceptible to the effects of other insults. Unlike TNF-α, serum IL-6 exhibits a positive correlation with both obesity and alcohol intake (fig 1).1 8 So far IL-6 has not been studied in the aetiology of NASH.
Future studies examining the link between TNF-α and NASH will need to rigorously control for alcohol consumption and assess many other aspects of the inflammatory cytokine network.
Editor,—Our recent paper found increased small bowel bacterial overgrowth (50% versus 22%) and twofold increased systemic levels of tumour necrosis factor α (TNF-α) in patients with non-alcoholic steatohepatitis (NASH) compared with control age and sex matched subjects (
). Poullis and Mendall question the finding of elevated TNF-α levels in blood in NASH subjects and quote their own work of elevated TNF-α levels in obese, male, middle aged subjects.1-1 There was no correlation between TNF-α levels and obesity in our study whereas their study showed a correlation with obesity. How can this be explained? The question comes down to whether TNF-α is being produced predominantly in adipose tissue or in the liver, and which of these contributes to elevated systemic levels. At the moment this cannot be resolved. TNF-α will need to be investigated in liver biopsies and TNF-α levels sampled from the hepatic vein (not entirely impossible). The same should be done in animal models of obesity. In the meantime, it would be important to ascertain what proportion of obese patients have unrecognised NASH and whether this could explain the elevated TNF-α levels in obesity. Several lines of evidence suggest TNF-α is upregulated in the liver in alcoholic liver disease and presumably this is reflected by raised serum levels. We doubt therefore whether a low (<20 g/day) consumption of alcohol reduces systemic TNF-α levels but this could be formally studied. We have re-examined our data and found that there is no difference in mean TNF-α levels between those whoreported no alcohol consumption and those who drank alcohol. Finally, we would also comment from our recent work that shows that the C14-D-xylose/H2-CH4 breath test is only positive in 60–69% of cases of small bowel bacterial overgrowth,1-2 mostly because it depends on bacterial overgrowth being present on the day of testing. Thus small bowel overgrowth may have contributed even more to NASH than indicated in our paper.
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