Alcoholic liver disease: a matter of hormones?

Abstract

See Article, pages 46–52Women are more likely than men to develop alcoholicliver disease. Although this has been known for a long time,the mechanisms underlying this gender difference are onlynow being elucidated [1,2]. The past decade has seen majoradvances in our understanding of the increased susceptibil-ity of women to develop alcoholic liver disease. First, thegroup of C.S. Lieber in New York demonstrated a gastricfirst-pass metabolism of orally ingested ethanol, which wasshown to be less in women than in men [1,3]. The lowereffectiveness in women is due to a lower alcohol dehydro-genase (ADH) activity in the gastric mucosa [3]. Therefore,consumption of the same amount of ethanol results in higherblood ethanol levels in women than in men. The gastricmucosa contains several ADH isozymes, one of which isthe type IV or s-ADH (ADH7) which is not present in theliver and has a high capacity for ethanol metabolism [1].Since estrogens increase the expression of ADH isozymes[4–6], the reason for the lower gastric s-ADH activity infemales remains to be elucidated.Another major advance in the understanding of thegender differences in susceptibility to ethanol-inducedliver injury was contributed by the group of R.G. Thurman[2,7–10]. They demonstrated that estrogens contributeimportantly to ethanol-induced liver injury. Administrationof ethanol to female rats resulted in more hepatic steatosis,inflammation and necrosis compared to male rats, despiteequal ethanol intake, metabolism and excretion [7]. Plasmaendotoxin levels were also significantly higher in femalerats than in male rats [7]. In another study they demonstratedthat treatment of female rats with estrogens increased thesensitivity to endotoxin: estrogen pre-treatment signifi-cantly increased mortality after a sublethal dose of endo-toxin [8]. The increased sensitivity to endotoxin of estrogen-treated rats is explained by increased expression of theendotoxin receptor CD14 and the pro-inflammatory cyto-kine TNF-ain Kupffer cells [8]. The sensitizing effect ofestrogen was prevented by prior elimination of the Kupffercell population [8]. Likewise, ethanol ingestion resulted in astronger activation of the inflammation-associated tran-scription factor NF-kB and a higher expression of CD14and TNF-ain livers of female rats compared to male rats[9]. Lowering estrogen levels, by subjecting female rats toovariectomy, resulted in a significant reduction of ethanol-induced liver injury including steatosis and inflammation[10]. In addition, hepatic CD14 expression as well as plasmaendotoxin levels were reduced [10]. Taken together, theseresults indicate that females are more susceptible to ethanol-induced liver damage because: (1) gastric ADH-dependentethanol metabolism is lower, resulting in higher blood etha-nol levels; (2) plasma endotoxin levels are higher after etha-nol ingestion; (3) the inflammatory response in the liver ismore severe due to an estrogen-dependent sensitization toendotoxin.In this issue of the Journal of Hepatology,Ja¨rvela¨inen etal. [11] further contribute to our understanding of the role ofestrogens in the higher susceptibility of females to ethanol-induced liver injury. Using female rats they confirmedprevious results that ethanol induced hepatic steatosis,inflammation and necrosis as well as increased expressionof CD14 and TNF-ain Kupffer cells [11]. Moreover, theydemonstrate that the estrogen antagonist toremifene reducedethanol induced hepatic inflammation and necrosis. Unex-pectedly, toremifene failed to reduce hepatic steatosis andhad no effect on the ethanol-induced hepatic expression ofCD14 and TNF-amRNA [11]. Toremifene suppressed theethanol-induced increase in the activity of the ethanol-meta-bolizing enzyme CYP2E1 and it counteracted the ethanol-induced reduction in selenium-dependent glutathione-peroxidase activity, an important anti-oxidant enzyme[11]. The findings of Ja¨rvela¨inen et al. differ from previousfindings in that the estrogen antagonist toremifene failed toreduce the expression of ethanol-induced inflammation-related genes like CD14 and TNF-a [10,11]. The reasonfor this discrepancy remains to be elucidated but couldbe related to specific differences between anti-estrogens