Non-alcoholic fatty liver disease pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

Overview

The exact pathogenesis of NAFLD is not fully understood but is believed due to the interaction of multiple factors such as obesity, Insulin resistance, and metabolic syndrome. Pathogenesis of non-alcoholic liver disease can be best explained by 2 hit hypothesis. The first hit is steatosis. The second hit is controversial and is likely cause changes that leads from hepatic steatosis to hepatic inflammation and fibrosis by way of lipid peroxidation.

Pathophysiology

The exact pathogenesis of NAFLD is not fully understood but is believed due to the interaction of multiple factors.

2 hit hypothesis

Pathogenesis of non-alcoholic liver disease can be summarized by 2 hit hypothesis. According to 2 hit hypothesis:

  • The first hit results in increased fat accumulation especially triglycerides within the hepatocyte and increases the risk of liver injury.
  • On the second hit inflammatory cytokines causes mitochondrial dysfunction and oxidative stress which in turn lead to steatohepatitis and/or fibrosis.[1]

Free fatty acids

Endotoxins[6][7][8]

Adiponectin

Adenosine[13]

Fibroblast Growth Factor 21[15]

Associated Conditions

Microscopic Pathology

On microscopic histopathological analysis, characteristic findings of the non-alcoholic liver disease include:

References

  1. 1.0 1.1 Dowman JK, Tomlinson JW, Newsome PN (2010). "Pathogenesis of non-alcoholic fatty liver disease". QJM. 103 (2): 71–83. PMC 2810391Freely accessible. PMID 19914930. doi:10.1093/qjmed/hcp158. 
  2. Petta S, Gastaldelli A, Rebelos E, Bugianesi E, Messa P, Miele L, Svegliati-Baroni G, Valenti L, Bonino F (2016). "Pathophysiology of Non Alcoholic Fatty Liver Disease". Int J Mol Sci. 17 (12). PMC 5187882Freely accessible. PMID 27973438. doi:10.3390/ijms17122082. 
  3. Postic C, Girard J (2008). "Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice". J. Clin. Invest. 118 (3): 829–38. PMC 2254980Freely accessible. PMID 18317565. doi:10.1172/JCI34275. 
  4. Jou J, Choi SS, Diehl AM (2008). "Mechanisms of disease progression in nonalcoholic fatty liver disease". Semin. Liver Dis. 28 (4): 370–9. PMID 18956293. doi:10.1055/s-0028-1091981. 
  5. Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, Burgart LJ, Gores GJ (2004). "Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway". Hepatology. 40 (1): 185–94. PMID 15239102. doi:10.1002/hep.20283. 
  6. Harte AL, da Silva NF, Creely SJ, McGee KC, Billyard T, Youssef-Elabd EM, Tripathi G, Ashour E, Abdalla MS, Sharada HM, Amin AI, Burt AD, Kumar S, Day CP, McTernan PG (2010). "Elevated endotoxin levels in non-alcoholic fatty liver disease". J Inflamm (Lond). 7: 15. PMC 2873499Freely accessible. PMID 20353583. doi:10.1186/1476-9255-7-15. 
  7. Fukunishi S, Sujishi T, Takeshita A, Ohama H, Tsuchimoto Y, Asai A, Tsuda Y, Higuchi K (2014). "Lipopolysaccharides accelerate hepatic steatosis in the development of nonalcoholic fatty liver disease in Zucker rats". J Clin Biochem Nutr. 54 (1): 39–44. PMC 3882483Freely accessible. PMID 24426189. doi:10.3164/jcbn.13-49. 
  8. Harte AL, da Silva NF, Creely SJ, McGee KC, Billyard T, Youssef-Elabd EM, Tripathi G, Ashour E, Abdalla MS, Sharada HM, Amin AI, Burt AD, Kumar S, Day CP, McTernan PG (2010). "Elevated endotoxin levels in non-alcoholic fatty liver disease". J Inflamm (Lond). 7: 15. PMC 2873499Freely accessible. PMID 20353583. doi:10.1186/1476-9255-7-15. 
  9. Choi SS, Diehl AM (2008). "Hepatic triglyceride synthesis and nonalcoholic fatty liver disease". Curr. Opin. Lipidol. 19 (3): 295–300. PMID 18460922. doi:10.1097/MOL.0b013e3282ff5e55. 
  10. Polyzos SA, Kountouras J, Zavos C, Tsiaousi E (2010). "The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease". Diabetes Obes Metab. 12 (5): 365–83. PMID 20415685. doi:10.1111/j.1463-1326.2009.01176.x. 
  11. Polyzos SA, Kountouras J, Zavos C (2009). "Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines". Curr. Mol. Med. 9 (3): 299–314. PMID 19355912. 
  12. Finelli C, Tarantino G (2013). "What is the role of adiponectin in obesity related non-alcoholic fatty liver disease?". World J. Gastroenterol. 19 (6): 802–12. PMC 3574877Freely accessible. PMID 23430039. doi:10.3748/wjg.v19.i6.802. 
  13. Robson SC, Schuppan D (2010). "Adenosine: tipping the balance towards hepatic steatosis and fibrosis". J. Hepatol. 52 (6): 941–3. PMC 2875264Freely accessible. PMID 20395005. doi:10.1016/j.jhep.2010.02.009. 
  14. Enjyoji K, Kotani K, Thukral C, Blumel B, Sun X, Wu Y, Imai M, Friedman D, Csizmadia E, Bleibel W, Kahn BB, Robson SC (2008). "Deletion of cd39/entpd1 results in hepatic insulin resistance". Diabetes. 57 (9): 2311–20. PMC 2518482Freely accessible. PMID 18567823. doi:10.2337/db07-1265. 
  15. Liu J, Xu Y, Hu Y, Wang G (2015). "The role of fibroblast growth factor 21 in the pathogenesis of non-alcoholic fatty liver disease and implications for therapy". Metab. Clin. Exp. 64 (3): 380–90. PMID 25516477. doi:10.1016/j.metabol.2014.11.009. 



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