Non-alcoholic fatty liver disease pathophysiology: Difference between revisions

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__NOTOC__
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{{Non alcoholic fatty liver disease}}
{{Non alcoholic fatty liver disease}}
'''Editor in Chief''': Elliot Tapper, M.D., Beth Israel Deaconess Medical Center, [[User:C Michael Gibson |C. Michael Gibson, M.S., M.D.]] [mailto:charlesmichaelgibson@gmail.com]
{{CMG}}; {{AE}} {{MKK}}


==Overview==
==Overview==
The exact pathogenesis of NAFLD is not fully understood.It is thought that NAFLD is the caused by either obesity, Insulin resistance, and metabolic syndrome. The exact reasons and mechanisms by which this disease progresses from [[steatosis]] to [[steatohepatitis]] and [[fibrosis]] is a subject of much research and debate. The prevailing wisdom comes from the so-called ‘two-hit hypothesis.’ The first hit is [[steatosis]]. The second hit is controversial and is likely numerous; likely any injury which causes a change that leads from [[hepatic steatosis]] to [[hepatic]] [[inflammation]] and [[fibrosis]] by way of [[lipid peroxidation]].
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==
==Pathophysiology==
* The exact pathogenesis of NAFLD is not fully understood, But It is thought that pathophysiology of NAFLD  is multifactorial that includes numerous genetic, dietary, metabolic and hormonal factors.
The exact pathogenesis of NAFLD is not fully understood but is believed due to the interaction of multiple factors.
* According to the 2 hit hypothesis NAFLD is described as follows
 
** The first hit resulting in increased fat accumulation especially triglycerides within the hepatocyte and increases the risk of liver injury.  
=== <u>2 hit hypothesis</u> ===
** On the second hit inflammatory cytokines causes mitochondrial dysfunction and oxidative stress which in turn lead to steatohepatitis and/or fibrosis.<ref name="pmid19914930">{{cite journal |vauthors=Dowman JK, Tomlinson JW, Newsome PN |title=Pathogenesis of non-alcoholic fatty liver disease |journal=QJM |volume=103 |issue=2 |pages=71–83 |year=2010 |pmid=19914930 |pmc=2810391 |doi=10.1093/qjmed/hcp158 |url=}}</ref>.
Pathogenesis of non-alcoholic liver disease can be summarized by 2 hit hypothesis. According to 2 hit hypothesis:
* 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.
* The first hit results in increased fat accumulation especially triglycerides within the hepatocyte and increases the risk of liver injury.  
* Now there is new evidence that FFA is directly causing the liver damage by increasing the oxidative stress by upregulation of TNF-alpha expression via a lysosomal pathway.<ref name="pmid15239102">{{cite journal |vauthors=Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, Burgart LJ, Gores GJ |title=Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway |journal=Hepatology |volume=40 |issue=1 |pages=185–94 |year=2004 |pmid=15239102 |doi=10.1002/hep.20283 |url=}}</ref>
* On the second hit inflammatory cytokines causes mitochondrial dysfunction and oxidative stress which in turn lead to steatohepatitis and/or fibrosis.<ref name="pmid19914930">{{cite journal |vauthors=Dowman JK, Tomlinson JW, Newsome PN |title=Pathogenesis of non-alcoholic fatty liver disease |journal=QJM |volume=103 |issue=2 |pages=71–83 |year=2010 |pmid=19914930 |pmc=2810391 |doi=10.1093/qjmed/hcp158 |url=}}</ref>  
 
=== 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.<ref name="pmid27973438">{{cite journal |vauthors=Petta S, Gastaldelli A, Rebelos E, Bugianesi E, Messa P, Miele L, Svegliati-Baroni G, Valenti L, Bonino F |title=Pathophysiology of Non Alcoholic Fatty Liver Disease |journal=Int J Mol Sci |volume=17 |issue=12 |pages= |year=2016 |pmid=27973438 |pmc=5187882 |doi=10.3390/ijms17122082 |url=}}</ref><ref name="pmid18317565">{{cite journal |vauthors=Postic C, Girard J |title=Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice |journal=J. Clin. Invest. |volume=118 |issue=3 |pages=829–38 |year=2008 |pmid=18317565 |pmc=2254980 |doi=10.1172/JCI34275 |url=}}</ref><ref name="pmid18956293">{{cite journal |vauthors=Jou J, Choi SS, Diehl AM |title=Mechanisms of disease progression in nonalcoholic fatty liver disease |journal=Semin. Liver Dis. |volume=28 |issue=4 |pages=370–9 |year=2008 |pmid=18956293 |doi=10.1055/s-0028-1091981 |url=}}</ref>
* By [[Upregulation|upregulating]] [[TNF-alpha]] expression via [[Lysosomal enzymes|lysosomal]] pathway, [[free fatty acids]] make the [[liver]] susceptible to [[oxidative stress]].<ref name="pmid15239102">{{cite journal |vauthors=Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, Burgart LJ, Gores GJ |title=Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway |journal=Hepatology |volume=40 |issue=1 |pages=185–94 |year=2004 |pmid=15239102 |doi=10.1002/hep.20283 |url=}}</ref>


* Oxidative stress inhibits the replication process in the mature hepatocytes, Results in the proliferation of progenitor (oval ) cell population and later they differentiate into hepatocyte-like cells. Now both the oval and hepatocyte-like cells play a very important role in the process of fibrosis and hepatocellular carcinogenesis.<ref name="pmid19914930">{{cite journal |vauthors=Dowman JK, Tomlinson JW, Newsome PN |title=Pathogenesis of non-alcoholic fatty liver disease |journal=QJM |volume=103 |issue=2 |pages=71–83 |year=2010 |pmid=19914930 |pmc=2810391 |doi=10.1093/qjmed/hcp158 |url=}}</ref>
* [[Oxidative stress]] inhibits the [[replication]] process in the mature [[hepatocytes]].
* Alterations in MTP/apoB synthesis and secretion have been implicated as one of the  potential mechanisms in the pathogenesis of NAFLD which in turn leads to a decreased capacity for lipid export
* Inhibition of [[hepatocyte]] replication results in the proliferation of [[Progenitor cells|progenitor cel]]<nowiki/>l population which can also differentiates into hepatocyte-like cells.  
* Normally triglycerides are transported from the liver in the form of VLDL particles which are then formed by the incorporation of triglyceride into apolipoprotein B (apoB) by microsomal transfer protein (MTP).<ref name="urlApolipoprotein synthesis in nonalcoholic steatohepatitis - Charlton - 2002 - Hepatology - Wiley Online Library">{{cite web |url=http://onlinelibrary.wiley.com/doi/10.1053/jhep.2002.32527/abstract |title=Apolipoprotein synthesis in nonalcoholic steatohepatitis - Charlton - 2002 - Hepatology - Wiley Online Library |format= |work= |accessdate=}}</ref>
* Progenitor cells along with hepatocyte-like cells are responsible for [[fibrosis]] and [[carcinogenesis]] in non alcoholic fatty liver.<ref name="pmid19914930">{{cite journal |vauthors=Dowman JK, Tomlinson JW, Newsome PN |title=Pathogenesis of non-alcoholic fatty liver disease |journal=QJM |volume=103 |issue=2 |pages=71–83 |year=2010 |pmid=19914930 |pmc=2810391 |doi=10.1093/qjmed/hcp158 |url=}}</ref>  


===Endotoxins===<ref>Charlton M et al. Frequency of Nonalcoholic Steatohepatitis as a Cause of Advanced Liver Disease .Liver Transpl 2001;7:608-614</ref>
===Endotoxins<ref name="pmid20353583">{{cite journal |vauthors=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 |title=Elevated endotoxin levels in non-alcoholic fatty liver disease |journal=J Inflamm (Lond) |volume=7 |issue= |pages=15 |year=2010 |pmid=20353583 |pmc=2873499 |doi=10.1186/1476-9255-7-15 |url=}}</ref><ref name="pmid24426189">{{cite journal |vauthors=Fukunishi S, Sujishi T, Takeshita A, Ohama H, Tsuchimoto Y, Asai A, Tsuda Y, Higuchi K |title=Lipopolysaccharides accelerate hepatic steatosis in the development of nonalcoholic fatty liver disease in Zucker rats |journal=J Clin Biochem Nutr |volume=54 |issue=1 |pages=39–44 |year=2014 |pmid=24426189 |pmc=3882483 |doi=10.3164/jcbn.13-49 |url=}}</ref><ref name="pmid203535832">{{cite journal |vauthors=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 |title=Elevated endotoxin levels in non-alcoholic fatty liver disease |journal=J Inflamm (Lond) |volume=7 |issue= |pages=15 |year=2010 |pmid=20353583 |pmc=2873499 |doi=10.1186/1476-9255-7-15 |url=}}</ref>===
One of the original theories of [[NASH]] pathogenesis derived from clinical experience involving [[obese]] patients who developed [[cirrhosis]] after a [[jejuno-ileal bypass]].<ref>Hocking et al. Jejunoileal bypass for morbid obesity. Late follow-up in 100 cases. NEJM 1983;308(17):995-999</ref> This sort of intestinal deformity may increase the concentration of [[bacterial endotoxins]] in the [[portal circulation]], which in turn may cause an elevation of intrahepatic levels of pro-inflammatory [[cytokines]], including [[tumor necrosis factor-alpha]]. One study found the rate of [[small bowel bacterial overgrowth]] to be present in twice as many patients with [[NASH]] as a control. Furthermore, some degree of [[steatohepatitis]] can even be reversed after treatment with [[metronidazole]]. <ref>Wigg AJ et al. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxemia, and tumor necrosis factor α in the pathogenesis of non-alcoholic steatohepatitis. <nowiki><ref name="urlThe Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background"></nowiki>{{cite web |url=https://www.hindawi.com/journals/grp/2016/2862173/ |title=The Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background |format= |work= |accessdate=}}</ref>
* [[Obese]] patients who underwent [[Jejuno-ileal bypass|jejuno-ileal bypass surgery]] has the risk of developing [[bacterial endotoxins]] in the [[portal circulation]] due to [[Small intestine|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 radicals|free radical injury.]]


===Adiponectin===
===Adiponectin===
Many groups have implicated variations in different metabolic pathways. One of the principle pathways under investigation is that which is affected by [[adiponectin]]. [[Adiponectin]] is an anti-atherogenic, [[insulin]] sensitizing [[cytokine]] whose secretion is decreased in [[obesity]]. One study found an inverse relationship between circulating concentrations of [[adiponectin]] and [[tumor necrosis factor]].<ref name="urlAdiponectin Resistance Exacerbates Insulin Resistance in Insulin Receptor Transgenic/Knockout Mice | Diabetes">{{cite web |url=http://diabetes.diabetesjournals.org/content/56/8/1969 |title=Adiponectin Resistance Exacerbates Insulin Resistance in Insulin Receptor Transgenic/Knockout Mice &#124; Diabetes |format= |work= |accessdate=}}</ref> Another implication of the research on [[adiponectin]] is that different dietary fats have variable effects on [[adiponectin]] levels, with [[polyunsaturated fatty acids]] leading to decreased levels and more [[hepatic]] [[inflammation]]. Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice.<ref name="urlThe Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background">{{cite web |url=https://www.hindawi.com/journals/grp/2016/2862173/ |title=The Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background |format= |work= |accessdate=}}</ref>. <ref name="pmid25110685">{{cite journal |vauthors=Nigro E, Scudiero O, Monaco ML, Palmieri A, Mazzarella G, Costagliola C, Bianco A, Daniele A |title=New insight into adiponectin role in obesity and obesity-related diseases |journal=Biomed Res Int |volume=2014 |issue= |pages=658913 |year=2014 |pmid=25110685 |pmc=4109424 |doi=10.1155/2014/658913 |url=}}</ref>
* [[Adiponectin]] is an anti-atherogenic, [[insulin]] sensitizing [[cytokine]] whose [[secretion]] is decreased in [[obesity]].<ref name="pmid18460922">{{cite journal |vauthors=Choi SS, Diehl AM |title=Hepatic triglyceride synthesis and nonalcoholic fatty liver disease |journal=Curr. Opin. Lipidol. |volume=19 |issue=3 |pages=295–300 |year=2008 |pmid=18460922 |doi=10.1097/MOL.0b013e3282ff5e55 |url=}}</ref><ref name="pmid20415685">{{cite journal |vauthors=Polyzos SA, Kountouras J, Zavos C, Tsiaousi E |title=The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease |journal=Diabetes Obes Metab |volume=12 |issue=5 |pages=365–83 |year=2010 |pmid=20415685 |doi=10.1111/j.1463-1326.2009.01176.x |url=}}</ref><ref name="pmid19355912">{{cite journal |vauthors=Polyzos SA, Kountouras J, Zavos C |title=Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines |journal=Curr. Mol. Med. |volume=9 |issue=3 |pages=299–314 |year=2009 |pmid=19355912 |doi= |url=}}</ref><ref name="pmid23430039">{{cite journal |vauthors=Finelli C, Tarantino G |title=What is the role of adiponectin in obesity related non-alcoholic fatty liver disease? |journal=World J. Gastroenterol. |volume=19 |issue=6 |pages=802–12 |year=2013 |pmid=23430039 |pmc=3574877 |doi=10.3748/wjg.v19.i6.802 |url=}}</ref>
 
* There is an inverse relationship between circulating concentrations of [[adiponectin]] and [[tumor necrosis factor]].
===Adenosine===
* Any conditions that cause low production of [[adiponectin]] ( consuming high amounts of [[Polyunsaturated fatty acids|poly unsaturated fatty acids]]) results in production of [[TNF alpha]].  
Another pathway under investigation is [[purinergic metabolism]]. CD39 is the dominant vascular (and immune cell) [[ectonucleotidase]] in the [[liver]] that hydrolyzes [[extracellular]] [[ATP]] and [[ADP]] to [[AMP]] which can then be converted to [[adenosine]] via [[ecto-5’-nucleotidase]]/CD73. Alterations in purinergic signaling induced by altered CD39 expression have major impacts upon [[hepatic metabolism]], repair mechanisms, regeneration and associated [[immune]] responses.<ref>Beldi G, et al. The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism.3, Varying levels of CD39 and [[adenosine]] have thus been implicated in the spectrum of [[NAFLD]]/[[NASH]] phenotypes.  
Based on knockout studies, the experimental evidence is mounting in support of a major role for both CD39 and [[adenosine]] in the development of [[steatosis]], [[inflammation]] and, later, [[fibrosis]]. Firstly, the deletion of CD39 and thus the local reduction of [[adenosine]] results in [[hepatic]] [[insulin resistance]] and increased serum levels of several inflammatory [[cytokines]]. Deletion of Cd39/Entpd1 Results in Hepatic Insulin Resistance.<nowiki><ref name="urlThe ATP-P2X7 Signaling Axis Is Dispensable for Obesity-Associated Inflammasome Activation in Adipose Tissue | Diabetes"></nowiki>{{cite web |url=http://diabetes.diabetesjournals.org/content/61/6/1471 |title=The ATP-P2X7 Signaling Axis Is Dispensable for Obesity-Associated Inflammasome Activation in Adipose Tissue &#124; Diabetes |format= |work= |accessdate=}}</ref>


Secondly, [[adenosine]] appears to be a critical supportive link in the cell’s cascade of responses to [[inflammation]];<ref>Haschemi A, Wagner O, Marculescu R, Wegiel B, Robson SC, Gagliani N, Gallo D, et al. Cross-regulation of carbon monoxide and the [[adenosine]] A2A receptor in macrophages. J. Immunol. 2007;178;5921-5929</ref> [[adenosine]] suppresses [[inflammation]] and, as [[inflammation]], tissue repair and scarring are closely linked events, it enhances [[fibrosis]] by increasing matrix formation in healing insulted tissues and facilitating regeneration.<ref name="Chan">Chan ES, Montesinos MC, Fernandez P, Desai A, Delano DL, Yee H, Reiss AB, et al. [[adenosine]] A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis. Br J Pharmacol 2006;148:1144-1155.</ref><ref>Montesinos MC et al. Wound healing is accelerated by agonists of [[adenosine]] A2 (G alpha s-linked) receptors. J. Exp. Med.1997;186:1615–162010-11)</ref> CD39 deletion shifts the local population of [[cytokines]] toward the pro-inflammatory and non-fibrinogenic (e.g. [[interferon gamma]]).<ref>Kunzli BM et al. Upregulation of CD39/NTPDases and P2 receptors in human pancreatic disease. AJP-Gastrointest Liver Physiol 2007;292:223-230</ref>
===Adenosine<ref name="pmid20395005">{{cite journal |vauthors=Robson SC, Schuppan D |title=Adenosine: tipping the balance towards hepatic steatosis and fibrosis |journal=J. Hepatol. |volume=52 |issue=6 |pages=941–3 |year=2010 |pmid=20395005 |pmc=2875264 |doi=10.1016/j.jhep.2010.02.009 |url=}}</ref>===
* 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 [[Adenosine monophosphate|AMP]] which can then be converted to [[adenosine]] via [[Ectonucleotidase|ecto-5’-nucleotidase]]/CD73.<ref name="pmid18567823">{{cite journal |vauthors=Enjyoji K, Kotani K, Thukral C, Blumel B, Sun X, Wu Y, Imai M, Friedman D, Csizmadia E, Bleibel W, Kahn BB, Robson SC |title=Deletion of cd39/entpd1 results in hepatic insulin resistance |journal=Diabetes |volume=57 |issue=9 |pages=2311–20 |year=2008 |pmid=18567823 |pmc=2518482 |doi=10.2337/db07-1265 |url=}}</ref>  
* Alterations in [[Purinergic metabolism|purinergic signaling]] induced by altered CD39 mutation have major impacts upon [[Hepatic metabolism, regulation, and excretion|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]].


Thirdly, in CD39 knockout models of [[hepatitis]] and [[pancreatitis]], there is a marked decrease in [[fibrogenesis]].<ref>Kunzli BM et al. Disordered Pancreatic Inflammatory Responses and Inhibition of Fibrosis in CD39-null mice. Gastroenterology. 2008 January ; 134(1): 292–305. </ref>[[Adenosine]] receptor A2A is a major factor in the pathogenesis of [[cirrhosis]].<ref name="Chan" />
===Fibroblast Growth Factor 21<ref name="pmid25516477">{{cite journal |vauthors=Liu J, Xu Y, Hu Y, Wang G |title=The role of fibroblast growth factor 21 in the pathogenesis of non-alcoholic fatty liver disease and implications for therapy |journal=Metab. Clin. Exp. |volume=64 |issue=3 |pages=380–90 |year=2015 |pmid=25516477 |doi=10.1016/j.metabol.2014.11.009 |url=}}</ref>===
* [[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]].


===Fibroblast Growth Factor 21===
== Associated Conditions ==
[[Fibroblast growth factor 21]] ([[FGF21]]) has emerged as an important metabolic regulator of [[glucose]] and [[lipid]] [[metabolism]]. Essentially, [[FGF21]] moderates or induces the [[hepatic]] response to a [[fasting]] state: [[gluconeogenesis]], [[fatty acid oxidation]], and [[ketogenesis]].<ref>Kliewer and Mangelsdorf. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr 2010;91(suppl):254S–7S</ref> Moreover, it is a crucial component of the hepatic lipid oxidation machinery. This probably occurs as a function of proliferator-activated receptor activation. <ref>Badman MK et all. Hepatic Fibroblast Growth Factor 21 Is Regulated by PPARa and Is a Key Mediator of Hepatic Lipid Metabolism in Ketotic States. Cell Metabolism 2007;5:426–437</ref>
* 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]].


While the present evidence is contradictory for [[FGF21]]'s role in the setting of [[fatty liver]], it is evolving. In one study, supplemental, recombinant [[FGF21]] was given to mice and resulted in reduced [[blood glucose]], [[insulin]], and [[lipid]] levels and reversed [[hepatic steatosis]]. [[FGF21]] also dramatically improved [[hepatic]] and peripheral [[insulin sensitivity]].<ref>Xu, J et al. Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice. Diabetes 58:250–259, 2009</ref> At the same time, studies in humans have shown that circulating [[FGF21]] concentrations were increased in subjects who were either [[overweight]] or had [[type 2 diabetes]] or [[impaired glucose tolerance]].<ref>Kliewer and Mangelsdorf. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr 2010;91(suppl):254S–7S</ref> The most recent study has shown that while [[FGF21]] levels are associated with [[BMI]] in humans, they are not nutritionally regulated. It may only be a marker of - not causally linked to - [[NAFLD]].<ref>Dushay J, Chui PC, Gopalakrishnan GS, Varela-Rey M, Crawley M, Fisher FM, Badman MK, Martinez-Chantar ML, Maratos-Flier E. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology. 2010 Aug;139(2):456-63</ref>
== Microscopic Pathology ==
On microscopic histopathological analysis, characteristic findings of the non-alcoholic liver disease include:
* Macrovesicular [[steatosis]]


===Uric Acid===
* Predominant lobular [[inflammation]] in form of spotty [[necrosis]] in cases where [[steatosis]] is associated with [[inflammation]].
Another candidate in the pathophysiology of [[NAFLD]] is [[uric acid]]. While it remains to be seen whether [[uricemia]] is causal or a marker of disease, a hypothesis generating paper from China implicates [[uric acid]] in [[NAFLD]]. A population-based prospective study in China to found that 11.80% (813/6890) subjects developed NAFLD over 3 years of follow-up. Interestingly, the incidence of [[NAFLD]] increased with progressively higher baseline serum [[uric acid]] levels (7.2%, 9.5%, 11.5%, 13.8%, and 17.2% in quintile 1, quintile 2, 3, 4 and 5, respectively).<ref>Xu C, Yu C, Xu L, Miao M, Li Y (2010) High Serum Uric Acid Increases the Risk for Nonalcoholic Fatty Liver Disease: A Prospective Observational
Study. PLoS ONE 5(7): e11578.</ref> In animal studies conducted by the same group, they were able to show that [[hypouricemic medications]] reduced [[hepatic steatosis]] and [[hyperlipidemia]].<ref>Xu CF, Yu CH, Xu L, Sa XY, Li YM. Hypouricemic therapy: A novel potential therapeutic option for nonalcoholic fatty liver disease.Hepatology. 2010 Jun 11. [Epub ahead of print]</ref>


===Associated Conditions===
* Ballooning [[degeneration]] (hallmark of [[steatohepatitis]])
The disease is most closely associated with the increasing [[obesity]], [[insulin resistance]], [[type two diabetes mellitus]] and [[hyperlipidemia]] [[endemic]] to the developed world. Roughly half of all patients with NAFLD, however, do not meet criteria for [[metabolic syndrome]]. <ref>Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43:S99–S112.</ref>As awareness of this condition spreads, it has been regarded as a major cause of cryptogenic [[cirrhosis]] of the liver.<ref name="Clark">Clark JM, Diehl AM. Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. ''JAMA'' 2003;289:3000-4. PMID 12799409.</ref> The diagnosis of cryptogenic cirrhosis is usually made in patients with similar clinical characteristics to those with NAFLD spectrum disease. Cryptogenic cirrhotics tend to be women, aged 63 (+/- 11) years who are obese and [[type 2 diabetics]]. <ref name="Caldwell">Caldwell SH, Oelsner DH, Iezzoni JC. Cryptogenic Cirrhosis: Clinical Characterization and Risk Factor for Underlying Disease. Hepatology 1999;29(3);664-69</ref> Moreover, there are case reports of patients with [[NASH]] who received serial [[liver biopsies]] where there was a progression to [[cirrhosis]] with a dissapearance of the histologcal stigmatia of [[NASH]]. Without the index [[biopsy]], these patients' [[cirrhosis]] would have been classified as cryptogenic.<ref>Yoshioka Y, Hashimoto E, Yatsuji S. “NASH: cirrhosis, hepatocellular carcinoma and burnt-out NASH.” J Gastroenterol 2004;39;1215-1218</ref><ref name="Caldwell">Caldwell SH, Oelsner DH, Iezzoni JC. Cryptogenic Cirrhosis: Clinical Characterization and Risk Factor for Underlying Disease. Hepatology 1999;29(3);664-69</ref>
** Characterized by cellular swelling, rarefaction of the hepatocytic [[cytoplasm]] and clumped strands of intermediate [[filaments]].
* [[Mallory bodies|Mallory-Denk bodies]] (MDB)
* [[Fibrosis]]  
* Perivenular and pericellular (peri-sinusoidal) [[fibrosis]].


==References==
==References==

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Risk calculators and risk factors for Non-alcoholic fatty liver disease pathophysiology

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. doi:10.1093/qjmed/hcp158. PMC 2810391. PMID 19914930.
  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). doi:10.3390/ijms17122082. PMC 5187882. PMID 27973438.
  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. doi:10.1172/JCI34275. PMC 2254980. PMID 18317565.
  4. ↑ 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.
  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. doi:10.1002/hep.20283. PMID 15239102.
  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. doi:10.1186/1476-9255-7-15. PMC 2873499. PMID 20353583.
  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. doi:10.3164/jcbn.13-49. PMC 3882483. PMID 24426189.
  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. doi:10.1186/1476-9255-7-15. PMC 2873499. PMID 20353583.
  9. ↑ 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.
  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. doi:10.1111/j.1463-1326.2009.01176.x. PMID 20415685.
  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. doi:10.3748/wjg.v19.i6.802. PMC 3574877. PMID 23430039.
  13. ↑ 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.
  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. doi:10.2337/db07-1265. PMC 2518482. PMID 18567823.
  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. doi:10.1016/j.metabol.2014.11.009. PMID 25516477.

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