Is non-alcoholic steatohepatitis caused by alcohol?

As opposed to ALD, the defi nition of NAFLD and NASH generally allows the daily use of <20 g alcohol. This defi nition particularly in alcohol-sensitive patients ignores the contribution of even low amounts of alcohol to the pathogenesis of NAFLD/ NASH and at the same time in somewhat relaxed attitude towards the recommended <20 g daily alcohol restriction. In fact, the recommendation of alcohol restriction in patients of NAFLD/ NASH should be an Epidemiology

with liver cryptogenic liver fi brosis or cirrhosis NASH appears to be the underlying cause.
Excessive importation of free fatty acids (FFA) can result from either increased delivery of triglycerides to the liver (as seen with obesity and rapid weight loss), or from excessive conversion of carbohydrates and proteins to triglycerides (e.g., secondary to overfeeding or total parenteral nutrition).
Insulin resistance has a key role in the development of hepatic steatosis and, potentially, steatohepatitis. Obesity and type 2 diabetes, conditions associated with peripheral insulin resistance, are frequently observed in patients with (NAFLD).
Resistin and leptin are adipose tissue-derived proteins that may have an important physiological role in the development of insulin resistance. Overexpression of resistin in a mouse model led to glucose intolerance, hyperinsulinemia, and impaired suppression of FFA levels. Further, leptin defi ciency is associated with massive overweight in mice and humans.

Can nash be caused by alcohol
As opposed to ALD, the defi nition of NAFLD and NASH generally allows the daily use of <20 g alcohol. This absolute alcohol abstinence. This view is strongly supported by a recent publication demonstrating that the moderate alcohol use of 10-19 g/ day doubles the risk of advanced liver disease as compared to a daily alcohol use of 0-9 g [6]. Therefore, only alcohol abstinence would scientifi cally justify the term NAFLD/ NASH.
Recently, intestinal microbiota have been implicated as a potential source of hepatotoxic oxidative injury and changes in the microbiome have been shown to play a role in lipotoxicity and pathogenesis of NAFLD. Studies suggest that the specifi c composition of intestinal microbiota may play a role in both the infl ammatory and fi brosis responses in patients with NAFLD [7]. Among 57 patients with biopsy-proven NAFLD, those with Bacteroides genus counts in the second and third tertile had a 2-fold increase in NASH compared with those with lower Bacteroides counts who were found to also have an abundance of Prevotella bacteria. With respect to fi brosis stage, those with Ruminococcus counts in the third tertile were found to have a 2-fold increase in stage 2 or greater fi brosis compared with those with lower levels of Ruminococcus. Specifi c gut microbiome signatures were linked to the severity of NAFLD and degree of fi brosis in additional studies [8,9]. A specifi c microbial metabolite, 3-(4-hydroxyphenyl) lactate, correlated signifi cantly with hepatic fi brosis and specifi c bacterial species (Firmicutes, Bacteroidetes, and Proteobacteria) [8]. One proposed mechanism pertains to the endogenous production of alcohol and acetaldehyde. Colonic bacteria and yeast possess an enormous metabolic capacity for generating both ethanol and acetaldehyde, and can oxidize ethanol to high levels of acetaldehyde, even at low ethanol concentrations. Acetaldehyde is easily absorbed into the portal system, The most compelling evidence for a contribution of alcohol to NAFLD/ NASH has recently been provided by Yuan, et al. [10]. In an individual with a severe NASH the authors discovered an ultrahigh blood alcohol concentration (BAC) of about 400 mg/ L after the consumption of a high-carbohydrate, alcoholfree diet. Further analyses revealed the endogenous alcohol production by a Klebsiella pneumoniae (Kpn) strain through fermentation of glucose/ sucrose (glucose-fructose dimer). This clinical situation was termed‚ Autobrewing syndrome' (ABB) caused by a high-alcohol (HiAlc) producing Kpn strain (Figure 1). The patient eventually recovered after dietary changes and antibiotic treatment.
The further investigation of a cohort of patients with NAFLD identifi ed a strong association between disease severity and the existence HiAlc Kpn isolates. In a HiAlc-Kpn-induced mouse model of fatty liver disease (FLD) the authors demonstrated that HiAlc-Kpn might be an important cause for NAFLD via the induction of endogenous alcohol production. Finally, transplant of HiAlc-Kpn into mice was shown to cause NAFLD. Taken together, these data provide compelling evidence that HiAlc-Kpn exist in humans and can be associated with the development of NAFLD/ NASH (Figure 2).

Summary and recommendations
In NALFD/ NASH alcohol abstinence is to be recommended because the intake of even low daily amounts of acohol (< 20 g) can carry the risk of an advanced liver disease [6] while 10-19 g alcohol per day doubles the risk of advanved liver disease as compared to 0-9 g daily alcohol inake, Recent data further suggest that the intestinal microbiome can play a major role inthe pathogenesis of NAFLD/ NASH