21 The possible involvement of mitochondria in causation of T2D and fatty liver disease remains intriguing,32–35 but we are not aware of congenital mitochondrial disorders (Alpers syndrome, mitochondrial DNA depletion syndrome) causing other than macrovesicular or microvesicular steatosis, cirrhosis or acute liver failure, not NASH.36 None-the-less, we do think consideration needs to be given to the

fact that microvesicular steatosis is observed in some cases of NASH, and mitochondrial crystalline inclusions are commonly noted, particularly in severer cases;34,35 the implications will GSK-3 inhibitor be discussed in Part 2. The list of causes of fatty liver that are not NAFLD/NASH presented in Cassiman and Jaekman’s Table 1, as in a 2001 review,2 is less than 100. Individually they are exceedingly rare, < 1 per 10 000 population, versus 2000–4000 per 10 000 for NAFLD Pembrolizumab concentration and 700–1300 per 10 000 for NASH. So one hundred of them could not account for even 5% of NAFLD cases. It also does not seem logical

to us to exclude childhood monogenetic obesity syndromes (Bardet-Biedl, Alström, Prader-Willi syndromes) as causes of NASH when the associated metabolic factors (over-nutrition, obesity, insulin resistance, T2D, dyslipidemia) are identical to NASH, as discussed later. While we think it unlikely that even a minority of cases presently diagnosed as NAFLD will turn out to be syndromes based on single gene mutations, we agree that only a minority of ‘the metabolically challenged’ (those with over-nutrition) will develop cirrhosis; individual susceptibility to NASH versus SS is a key issue in pathogenesis.2–5 However, we note with irony that the authors

cite a review written by two of us as evidence in favor of ‘the magical two-hit hypothesis’ (sic) for progression from MCE ‘NAFLD to NASH’ (sic, mis-using above terminology).21 In that review,4 we actually canvassed strongly, as we do here, the evidence against metabolic factors being self-limiting, and against the cytokine basis of a two-hit hypothesis. Like others in this field (including Day who proposed the two-hit hypothesis),[C Day, personal communication, EASL Single Topic Conference on NAFLD, Bologna, September 2009] we no longer think this is a helpful concept. This review will explore the evidence for what seems to us intuitively more plausible, the lipotoxicity concept of NASH pathogenesis. While NAFLD is near universal among the obese (body mass index [BMI] > 30 kg/m2 in Europeans, > 25 kg/m2 in Asians), the interaction between obesity and NAFLD is more nuanced. The most striking correlates are with visceral fat accumulation and insulin resistance. As such, ‘metabolically obese, normal weight’ individuals may exhibit features of NAFLD in the absence of obesity but in association with an abnormal metabolic phenotype. But there appears to be a reproducible connection between NAFLD and over-nutrition—energy intake that exceeds energy utilization.