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
- Free fatty acids (FFA) play very crucial role in damaging the liver indirectly by either undergoing β-oxidation or are esterified with glycerol to form triglycerides, leading to hepatic fat accumulation.[2][3][4]
- By upregulating TNF-alpha expression via lysosomal pathway, free fatty acids make the liver susceptible to oxidative stress.[5]
- Oxidative stress inhibits the replication process in the mature hepatocytes.
- Inhibition of hepatocyte replication results in the proliferation of progenitor cell population which can also differentiates into hepatocyte-like cells.
- Progenitor cells along with hepatocyte-like cells are responsible for fibrosis and carcinogenesis in non alcoholic fatty liver.[1]
Endotoxins[6][7][8]
- Obese patients who underwent jejuno-ileal bypass surgery has the risk of developing bacterial endotoxins in the portal circulation due to small intestinal deformity.
- Increase in small bowel bacterial overgrowth due to decreased gastric motility.
- Bacterial toxins released by this bacteria overgrowth stimulate an elevation of intra-hepatic levels of pro-inflammatory cytokines, such as tumor necrosis factor-alpha.
- Expression of TNF-alpha begins the cascade of events making liver susceptible for free radical injury.
Adiponectin
- Adiponectin is an anti-atherogenic, insulin sensitizing cytokine whose secretion is decreased in obesity.[9][10][11][12]
- There is an inverse relationship between circulating concentrations of adiponectin and tumor necrosis factor.
- Any conditions that cause low production of adiponectin ( consuming high amounts of poly unsaturated fatty acids) results in production of TNF alpha.
Adenosine[13]
- Alteration of purinergic metabolism is another important pathway responsible for development of non-alcoholic liver disease.
- Adenosine receptor A2A is a major factor in the pathogenesis of cirrhosis.
- CD39 is the dominant vascular ectonucleotidase in the liver that hydrolyzes extracellular ATP and ADP to AMP which can then be converted to adenosine via ecto-5’-nucleotidase/CD73.[14]
- Alterations in purinergic signaling induced by altered CD39 mutation have major impacts upon hepatic metabolism, repair mechanisms, regeneration and associated immune responses.
- Adenosine forms a supportive link in the cell’s cascade healing response to inflammation.
- Adenosine suppresses inflammation by enhancing fibrosis.
- CD39 deletion shifts the local population of cytokines to produce TNF alpha.
Fibroblast Growth Factor 21[15]
- Fibroblast growth factor 21 (FGF21) is an important metabolic regulator of glucose and lipid metabolism.
- FGF21 moderates or induces the hepatic response to a fasting state by gluconeogenesis, fatty acid oxidation, and ketogenesis.
- Moreover, it is a crucial component of the hepatic lipid oxidation machinery, as proliferator-activated receptor activation.
- FGF21 is responsible for normal blood glucose, insulin, and lipid levels in normal individuals.
- Low levels of FGF21 are closely associated with the obesity, insulin resistance, type two diabetes mellitus and hyperlipidemia.
Associated Conditions
- Most patients have associated features of the metabolic syndrome including obesity, diabetes mellitus type 2, hyperlipidemia (hypertriglyceridemia), and hypertension
- Patients may suffer from complications of obesity such as obstructive sleep apnea , orthopedic complications, and polycystic ovary syndrome.
Microscopic Pathology
On microscopic histopathological analysis, characteristic findings of the non-alcoholic liver disease include:
- Macrovesicular steatosis
- Predominant lobular inflammation in form of spotty necrosis in cases where steatosis is associated with inflammation.
- Ballooning degeneration (hallmark of steatohepatitis)
- Mallory-Denk bodies (MDB)
- Fibrosis
- Perivenular and pericellular (peri-sinusoidal) fibrosis.
References
- ↑ 1.0 1.1 Dowman JK, Tomlinson JW, Newsome PN (2010). "Pathogenesis of non-alcoholic fatty liver disease". QJM. 103 (2): 71–83. doi:10.1093/qjmed/hcp158. PMC 2810391. PMID 19914930.
- ↑ 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). doi:10.3390/ijms17122082. PMC 5187882. PMID 27973438.
- ↑ 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. doi:10.1172/JCI34275. PMC 2254980. PMID 18317565.
- ↑ Jou J, Choi SS, Diehl AM (2008). "Mechanisms of disease progression in nonalcoholic fatty liver disease". Semin. Liver Dis. 28 (4): 370–9. doi:10.1055/s-0028-1091981. PMID 18956293.
- ↑ 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. doi:10.1002/hep.20283. PMID 15239102.
- ↑ 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. doi:10.1186/1476-9255-7-15. PMC 2873499. PMID 20353583.
- ↑ 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. doi:10.3164/jcbn.13-49. PMC 3882483. PMID 24426189.
- ↑ 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. doi:10.1186/1476-9255-7-15. PMC 2873499. PMID 20353583.
- ↑ Choi SS, Diehl AM (2008). "Hepatic triglyceride synthesis and nonalcoholic fatty liver disease". Curr. Opin. Lipidol. 19 (3): 295–300. doi:10.1097/MOL.0b013e3282ff5e55. PMID 18460922.
- ↑ 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. doi:10.1111/j.1463-1326.2009.01176.x. PMID 20415685.
- ↑ 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.
- ↑ 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. doi:10.3748/wjg.v19.i6.802. PMC 3574877. PMID 23430039.
- ↑ Robson SC, Schuppan D (2010). "Adenosine: tipping the balance towards hepatic steatosis and fibrosis". J. Hepatol. 52 (6): 941–3. doi:10.1016/j.jhep.2010.02.009. PMC 2875264. PMID 20395005.
- ↑ 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. doi:10.2337/db07-1265. PMC 2518482. PMID 18567823.
- ↑ 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. doi:10.1016/j.metabol.2014.11.009. PMID 25516477.