EASL Clinical Practice Guidelines

Pathogenesis of ALD

The spectrum of ALD includes simple steatosis, alcoholic steatohepatitis (ASH), progressive fibrosis, cirrhosis, and the development of hepatocellular cancer (HCC). Although many individuals consuming more than 60 g of alcohol per day (e.g. 1/2 a bottle of wine or more than 1 L of beer) develop steatosis, only a minority of the patients with steatosis progress to ASH and 10–20% eventually develop cirrhosis [65]. Genetic and non-genetic factors modify both the individual susceptibility and the clinical course of ALD [2]. The mechanisms of ALD are not completely understood. Most studies have been performed in rodents with chronic alcohol intake (e.g. Tsukamoto-French model or Lieber–DiCarli diet). However, these models basically induce moderate liver disease and non-severe fibrosis or liver damage develops. Few studies have been performed so far in livers from patients with ALD. These translational studies are needed to develop novel targeted therapies for these patients [2]. The pathogenesis varies in different stages of the disease.

Alcoholic fatty liver

There are four main pathogenic factors: (1) Increased generation of NADH caused by alcohol oxidation, favouring fatty acid and triglyceride synthesis, and inhibiting mitochondrial β-oxidation of fatty acids [66]. (2) Enhanced hepatic influx of free fatty acids from adipose tissue and of chylomicrons from the intestinal mucosa [66]. (3) Ethanol-mediated inhibition of adenosine monophosphate activated kinase (AMPK) activity [67] resulting in increased lipogenesis and decreased lipolysis by inhibiting peroxisome proliferating-activated receptor α (PPARa) [68] and stimulating sterol regulatory element binding protein 1c (SREBP1c) [69]. (4) Damage to mitochondria and microtubules by acetaldehyde, results in a reduction of NADH oxidation and the accumulation of VLDL, respectively [66].

Alcoholic steatohepatitis

Alcoholic fatty livers can develop parenchymal inflammation (mainly by PMN cells) and hepatocellular damage, a prerequisite for progress to fibrosis and cirrhosis. In cases of severe ASH episodes in patients with an advanced disease, ASH may cause profound liver damage, increased resistance to blood flow and it is also associated with a poor prognosis [70]. Various factors may contribute to the development of ASH (1) Acetaldehyde-induced toxic effects. It binds to proteins [71] and to DNA [72] resulting in functional alterations and protein adducts, which activate the immune system by forming autoantigens. It also induces mitochondria damage and impairs glutathione function, leading to oxidative stress and apoptosis [73]. (2) Reactive oxygen species (ROS) generation and the resulting lipid peroxidation with DNA adduct formation [74]. Main sources of ROS include CYP2E1-dependent MEOS, mitochondrial electron transport system of the respiratory chain, NADH-dependent cytochrome reductase, and xanthine oxidase [[75], [76]]. Moreover, chronic alcohol intake markedly up-regulates CYP2E1, which metabolizes ethanol to acetaldehyde and parallels the generation of ROS and hydroxyl–ethyl radicals [77]. (3) Pro-inflammatory cytokines. Alcohol metabolites and ROS stimulate signaling pathways such as NFκB, STAT-JAK, and JNK in hepatic resident cells, leading to the local synthesis of inflammatory mediators such as TNFα and CXC chemokines (e.g. interleukin-8), as well as osteopontin [78]. Alcohol abuse also results in changes in the colonic microbiota and increased intestinal permeability, leading to elevated serum levels of lipopolysaccharides [79] that induce inflammatory actions in Kupffer cells via CD14/TLR4 [80]. The resulting inflammatory milieu in the alcoholic liver leads to PMN infiltration, ROS formation and hepatocellular damage. (4) Impaired ubiquitin–proteasome pathway leading to hepatocellular injury and hepatic inclusions of aggregated cytokeratins (i.e. Mallory–Denk bodies) [81].

Fibrosis progression

Patients with ASH may develop progressive fibrosis [82]. In ALD, the fibrotic tissue is typically located in pericentral and perisinusoidal areas. In advanced stages, collagen bands are evident and bridging fibrosis develops. This condition precedes the development of regeneration nodules and liver cirrhosis. The cellular and molecular mechanisms of fibrosis in ALD are not completely understood [83]. Alcohol metabolites such as acetaldehyde can directly activate hepatic stellate cells (HSC), the main collagen-producing cells in the injured liver. HSC can also be activated paracrinally by damaged hepatocytes, activated Kupffer cells and infiltrating PMN cells. These cells release fibrogenic mediators such as growth factors (TGFβ1, PDGF), cytokines (leptin, angiotensin II, interleukin-8, and TNFα), soluble mediators (nitric oxide), and ROS. Importantly, ROS stimulate pro-fibrogenic intracellular signaling pathways in HSC including ERK, PI3K/AKT, and JNK [84]. They also up-regulate TIMP-1 and decrease the actions of metalloproteinases, thereby promoting collagen accumulation. Cells other than HSC can also synthesize collagen in ALD. They include portal fibroblasts and bone-marrow derived cells. Whether other novel mechanisms such as epithelia-to-mesenchymal transition of hepatocytes also play a role in liver fibrosis is under investigation [85].

Suggestions for futures studies

  1. Experimental models of severe ALD with hepatocellular damage and fibrosis are needed.
  2. Translational studies with human samples of patients at different stages of ALD are required to identify new therapeutic targets.
  3. Studies assessing liver regeneration in severe ALD should be performed.