Table 4.

Alcoholic liver disease and the 5-hit working hypothesis with a tentative cascade of events. Hypothetical steps of the five hits leading to end-stage alcoholic liver disease. Adapted from a previous report [25] and reproduced with permission of the PublisherTaylor & Francis (Didcot, UK).

First Hit.	The first hit is dependent on ADH and occurs at low alcohol levels through the generation not only of NADH + H+ leading to an increased NADH + H+/NAD+ ratio, which stimulates hepatic fatty acid synthesis [22] and increases α-glycerophosphate-trapping fatty acids [22,33], but also of acetaldehyde, which impairs hepatic mitochondrial functions including hepatic mitochondrial fatty acid oxidation [22]. This first hit fully explains at least in part the development of alcoholic fatty liver.
Second Hit.	The second hit is classified as a transition from alcoholic fatty liver to alcoholic steatohepatitis, most likely triggered by the increased production of acetaldehyde via MEOS [22,23] and of reactive oxygen species (ROS) with its capacity for irreversible covalently binding to cellular macromolecules, including membrane proteins and phospholipids [45,50,56,92,152,205,231,234,237,244,245,246,247,248,249,250,251,252]. These injurious alterations at the molecular and cellular level cause some necrosis, apoptosis, and inflammatory cells in the fatty liver, justifying the term alcoholic steatohepatitis, as it includes toxic hepatitis in steatosis [25]. Further stages are characterized by perisinusoidal and pericentral fibrosis due to participation of non-hepatocytes such as Kupffer cells, stellate cells, and sinus endothelial cells. Mediators such growth factors, interferons, interleukins, tumor necrosis factor and endotoxins, as well as hepatic iron, are considered as possible active promoters of liver injury, but considering the multiplicity of proposed mediators, it is difficult to predict how they interact with each other and modify the course of liver injury.
Third Hit.	The third hit initiates a more severe liver injury stage, whereby alcoholic steatohepatitis is the precursor in most, but certainly not all patients with alcoholic hepatitis. Steatosis is no more a characteristic feature, but is now replaced by necrosis, apoptosis, and inflammation. At this stage, injury becomes more severe and presents with more fibrosis and as a self-perpetuating process, immunity aspects gain additional relevance, because alcohol modifies the innate and adapted immune system, which may explain the individual differences of susceptibility for ALD. With the third hit, the disease may approach a point of no return.
Fourth Hit.	The fourth hit is dominated by increased fibrosis, due to increased collagen formation. This allows for a clinically unrecognizable transition from alcoholic hepatitis with fibrosis to irreversible cirrhosis. However, AC can also develop without ASH or AH.
Fifth Hit.	In rare cases, a fifth hit initiates the development of a hepatocellular carcinoma (HCC), mostly occurring in patients with cirrhosis. This final hit scenario of carcinogenesis is triggered by acetaldehyde and ROS through the generation of DNA adducts, which promote mutagenesis, and interference with methylation, synthesis, and repair of DNA. Suggested is a possible role of SIRT1. These overall events will enhance AHCC susceptibility, keeping in mind that ethanol itself is not a carcinogenetic chemical.