It is well known that heavy drinking increases the risk of alcohol-related liver disease (ALD). This disease is characterized by the development of steatosis, inflammation, hepatocyte necrosis, and apoptosis, which then lead to development of fibrosis and cirrhosis. The mechanisms for liver fibrosis have been dramatically elucidated in the last several decades but are still not fully understood (innate). Chronic inflammation is the most important contributor to ALD which involve macrophages, T cells, and fluid-phase component in the progression.
Hepatocyte is the primary site for alcohol metabolism. When a person drinks too much alcohol till the tissue alcohol levels exceed 10 mmol/L concentrations, there will be an increase in reactive oxygen species (ROS) level and also decrease in glutathione (GSH) level. These changes may then lead to lipid peroxidation, which refers to the oxidative degradation of lipids. If not terminated fast enough, there will be damage to the cell membrane, which consists mainly of lipids. Unfortunately, when the level of ROS keeps rising above a certain limit, it then cannot be removed efficiently by antioxidant system and this will be a major contributor to a liver damage (S De Minicis and DA Brenner, 2007). This is because, ROS are able to cause damage to the DNA, interfere with physiological processes such as mitochondrial respiratory chain and also enhancing oxidative stress. Oxidative stress is an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage.2
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Hepatocytes have 3 mechanisms to metabolize alcohol. First, alcohol is converted to acetaldehyde, catalyses by alcohol dehydrogenase (ADH), which then lead to production of ROS. Moreover, the microsomal ethanol-oxidizing system (MEOS), located on the endoplasmic reticulum (ER), which consists of ethanol-inducible cytochrome P450 2E1 (CYP2E1), also converts alcohol to acetaldehyde and generates ROS. Induction of Cyp2E also results in direct damage to hepatocytes, contributing to inflammation. Additionally, during the generation of ROS, NADH interferes with the electron transfer system in mitochondria, which facilitate ROS generation. NADH also enhances synthesis of fatty acids and inhibits their oxidation, and promotes development of steatosis. Once alcohol is metabolized into acetaldehyde, aldehyde dehydrogenase (ALDH) plays it roles to convert acetaldehyde to acetate. However, alcohol also can be directly converted to acetate by catalase in peroxisomes. In overloaded system, excess acetaldehyde will react with mitochondria GSH, causing decrease in antioxidant defense and lead to increase in oxidative stress. Severe oxidative stress can cause cell death and even moderate oxidation can trigger apoptosis, while more intense stresses may cause necrosis.
Innate immunity initiate immediate defense against pathogens, tissue injury, and malignancy without recognition of foreign antigen. Jeong et al (2007) report that there is increasing evidence suggest that liver's immune system is predominantly comprises of innate immunity. There is also evidence indicates that liver fibrosis is controlled by a variety of components of innate immunity system including humoral factors (complement 5), phagocytic cells (macrophages), lymphocytic cells, and pattern recognition receptor (Toll-like receptor,TLR). By using genetic mapping technique, Hillebrandt et al (2005) identified that 44.7 Mb region on mouse chromosome 2 containing a gene that is responsible for the development of liver fibrosis, and further studies showed this gene is the complement 5 (C5) gene.
Kendrick et al (1989) proposed that direct action of alcohol on final common pathway of cytokine gene transcriptional regulation by histone acetylation will enhance inflammatory cytokine response. One of their findings shows significant augmentation of IL6, IL8 and TNF-α release, following lipopolisaccharide (LPS) exposure. There is also an increase level of cytokine mRNA. This support their hypothesis that exposure to alcohol will increase level of inflammatory cytokine gene transcription. Furthermore, the authors also state that, from the tests that they have done, there is evidence that shows alcohol metabolism by mononuclear cells is associated with increase in histone acetylation, simultaneously with cytokine enhancement.
Constitutive production of cytokines is low or absent in healthy livers (Hamdi et al 2007). Chronic consumption of alcohol enhances the secretion of TNF-α by monocytes or macrophages. Activation of innate immune system by LPS emerges as key factor triggering ALD. Besides that, alcohol intake increases translocation of LPS from the gut lumen into the portal blood. Patients with alcoholic cirrhosis have higher endotoxin levels. This may results in activation of Kupffer cells, to produce chemokines (IL-8, MCP-1), proinflammatory cytokines (TNFa, IL-1), reactive oxygen species (ROS), and transforming growth factor b (TGFß). In addition, activation of baseline nuclear regulatory factor kB (NF-kB) is a key abnormality in the mediation of cytokine disturbance in ALD. It initiate the stimulation of NF-kB-dependent gene transcription which common cause of activation of Toll-like receptors 4, 2, and 6 and are essential to the initiation of an inflammatory response.
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FIGURE 1. Currently accepted model of the pathomechanisms of alcoholic hepatitis.
The rate of ATP synthesis in liver cells exposed to ethanol is typically reduced. Chronic alcohol consumption depresses the activity of all mitochondrial complexes, except complex II,[84, 85] as several abnormalities in mitochondrial respiratory chain have been described in experimental models of chronic ethanol intoxication. These include: decreased activity and heme content of cytochrome oxidase, impaired electron transport and proton translocation through complex I, decreased cytochrome b content in complex III and reduced function in ATP synthase complex. As a result, the energy metabolism of liver cells can be severely impaired and this would lead to tissue damage.
Energy metabolism can also be altered by hypoxia. Chronic ethanol administration definitely enhances the oxygen uptake rate by liver cells because of the need of its metabolization, which mainly occurs in the centrilobular area of the liver lobule. In such circumstances, the liver blood flow increases, but such an increase does not match the requirements deriving from exalted ethanol metabolism. Thus, centrilobular hypoxia ensues, which can be responsible for liver injury.[91-93] Centrilobular hypoxia can be further enhanced by the ethanol-induced changes in liver blood flow. In fact, ethanol infusion in a model of rat liver perfusion exerts a dose-dependent increase in portal pressure secondary to intrahepatic vasoconstriction. Such hemodynamic changes are mediated by an imbalance between nitric oxide/endothelin-1 interaction, as ethanol-induced vasoconstriction is inhibited by endothelin-1 antiserum and enhanced by nitric oxide synthase inhibitor L-NMMA.[93, 95] Thus, at high-ethanol blood levels, hypoxia might ensue from the combination of reduced perfusion and increased oxygen demand. When blood ethanol levels subsequently decline, lobular perfusion is restored and this can lead to reperfusion injury.