Cirrhosis is the formation of fibrous tissue (fibrosis) in the place of liver cells that have died due to a variety of causes, including viral hepatitis, alcohol overconsumption, and other forms of liver toxicity. Cirrhosis causes chronic liver failure.
Viral infection by hepatitis B virus (HBV) or hepatitis C virus (HCV) causes an increase of reactive oxygen species (ROS). The increase in intracellular ROS is about 10,000-fold upon chronic HBV infection and 100,000-fold after HCV infection. This increase in ROS causes inflammation and further increase in ROS. ROS cause more than 20 types of DNA damage. Oxidative DNA damage is mutagenic and also causes epigenetic alterations at the sites of DNA repair.Epigenetic alterations and mutations affect the cellular machinery that may cause the cell to replicate at a higher rate and/or result in the cell avoiding apoptosis, and thus contribute to liver disease. By the time accumulating epigenetic and mutational changes eventually cause hepatocellular carcinoma, epigenetic alterations appear to have an even larger role in carcinogenesis than mutations. Only one gene, TP53, is mutated in more than 20% of liver cancers while 41 genes each have hypermethylated promoters (repressing gene expression) in more than 20% of liver cancers.
Alcohol consumption in excess causes a build-up of acetaldehyde. Acetaldehyde and free radicals generated by metabolizing alcohol induce DNA damage and oxidative stress. In addition, activation of neutrophils in alcoholic liver disease contributes to the pathogenesis of hepatocellular damage by releasing reactive oxygen species (which can damage DNA). The level of oxidative stress and acetaldehyde-induced DNA adducts due to alcohol consumption does not appear sufficient to cause increased mutagenesis. However, as reviewed by Nishida et al., alcohol exposure, causing oxidative DNA damage (which is repairable), can result in epigenetic alterations at the sites of DNA repair. Alcohol-induced epigenetic alterations of gene expression appear to lead to liver injury and ultimately carcinoma.
Obesity is associated with higher risk of primary liver cancer. As shown with mice, obese mice are prone to liver cancer, likely due to two factors. Obese mice have increased pro-inflammatory cytokines. Obese mice also have higher levels of deoxycholic acid (DCA), a product of bile acid alteration by certain gut microbes, and these microbes are increased with obesity. The excess DCA causes DNA damage and inflammation in the liver, which, in turn, can lead to liver cancer.
According to Tilg, et al., gut microbiome could very well have an effect, be involved in the pathophysiology, on the various types of liver disease which an individual may encounter.
Particulate matter (PM) or carbon black (CB) are common pollutants. The following factors are the harmful effects of liver exposure under PM or CB. First, they have an obvious direct toxic effect on the liver. Chemicals will affect metabolism and impact liver function. Second, inflammation of liver caused by PM and CB impact lipid metabolism and fatty liver disease. Third, PM and CB can translocate from lung to liver.
PM and CB can easily translocate from lung to liver. Because they are very diverse and each has different toxicodynamics, detailed mechanisms are not clear. Water-soluble fractions of PM is the most important part for PM translocation to liver through extra-pulmonary circulation. When PM goes through blood vessel into blood, it combines with immune cells, that will stimulate innate immune responses. Pro-inflammatory cytokines will be released and cause disease progression.
^Yu HS, Oyama T, Isse T, Kitagawa K, Pham TT, Tanaka M, Kawamoto T (December 2010). "Formation of acetaldehyde-derived DNA adducts due to alcohol exposure". Chemico-Biological Interactions. 188 (3): 367–75. doi:10.1016/j.cbi.2010.08.005. PMID20813101.
^Lee SM, Kim-Ha J, Choi WY, Lee J, Kim D, Lee J, Choi E, Kim YJ (July 2016). "Interplay of genetic and epigenetic alterations in hepatocellular carcinoma". Epigenomics. 8 (7): 993–1005. doi:10.2217/epi-2016-0027. PMID27411963.