Non-alcoholic fatty liver disease pathophysiology: Difference between revisions

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==Pathophysiology==
==Pathophysiology==
* The exact pathogenesis of NAFLD is not fully understood, but it is thought due to multifactorial that includes numerous genetic, dietary, metabolic and hormonal factors.
The exact pathogenesis of NAFLD is not fully understood, but is believed due to 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:
* 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.<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.
* 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.
* 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>
* By upregulating TNF-alpha expression via 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 cell 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><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>  


===Endotoxins===
===Endotoxins===
* 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>  
* Obese patients who underwent jejuno-ileal bypass surgery has the risk of developing [[bacterial endotoxins]] in the [[portal circulation]] due to small intestinal deformity.<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]].
* Increase in small bowel bacterial overgrowth due to decreased gastric motility. <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><ref>Charlton M et al. Frequency of Nonalcoholic Steatohepatitis as a Cause of Advanced Liver Disease .Liver Transpl 2001;7:608-614</ref>  
* One study found the rate of [[small bowel bacterial overgrowth]] to be present in twice as many patients with [[NASH]] as a control.
* Bacterial toxins released by this bacteria overgrowth stimulate an elevation of intra-hepatic levels of pro-inflammatory [[cytokines]], such as [[tumor necrosis factor-alpha]].
* 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><ref>Charlton M et al. Frequency of Nonalcoholic Steatohepatitis as a Cause of Advanced Liver Disease .Liver Transpl 2001;7:608-614</ref>
* Expression of TNF-alpha begins the cascade of events making liver susceptible for 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]].
* [[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>
* There is  also 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]].
* Any conditions that cause low production of adiponectin ( consuming high amounts of poly unsaturated fatty acids) results in production of TNF alpha.<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>  
* 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>


===Adenosine===
===Adenosine===
* Another pathway under investigation is [[purinergic metabolism]].  
* Alteration of  [[purinergic metabolism]] is another important pathway responsible for development of non-alcoholic liver disease.
* 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.  
* [[Adenosine]] receptor A2A is a major factor in the pathogenesis of [[cirrhosis]].<ref name="Chan" />
* 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.  
* 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.  
* Alterations in purinergic signaling induced by altered CD39 mutation 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>
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]]; [[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.
* [[adenosine]] forms a supportive link in the cell’s cascade healing response to [[inflammation]].
* 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><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><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><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>
** [[adenosine]] suppresses [[inflammation]] by enhancing [[fibrosis]].
* 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>
* CD39 deletion shifts the local population of [[cytokines]] to produce TNF alpha.<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><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><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><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>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===
===Fibroblast Growth Factor 21===
* [[Fibroblast growth factor 21]] ([[FGF21]]) has emerged as an important metabolic regulator of [[glucose]] and [[lipid]] [[metabolism]].
* [[Fibroblast growth factor 21]] ([[FGF21]]) is 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>  
* [[FGF21]] moderates or induces the [[hepatic]] response to a [[fasting]] state by [[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.
* Moreover, it is a crucial component of the hepatic lipid oxidation machinery, as 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>  
* 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>
* FGF21 is responsible for normal [[blood glucose]], [[insulin]], and [[lipid]] levels in normal individuals.
* While the present evidence is contradictory for [[FGF21]]'s role in the setting of [[fatty liver]], it is evolving.
* Low levels of FGF21 are closely associated with the [[obesity]], [[insulin resistance]], [[type two diabetes mellitus]] and [[hyperlipidemia]].<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><ref>Kliewer and Mangelsdorf. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr 2010;91(suppl):254S–7S</ref><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>
* 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>  
== Associated Conditions ==
* 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>  
* Most patients have associated features of the [[metabolic syndrome]] including [[obesity]], [[diabetes mellitus type 2]], [[hyperlipidemia]] ([[hypertriglyceridemia]]), and [[hypertension]]
* 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>
* Patients may suffer from complications of obesity such as [[obstructive sleep apnea]] , orthopedic complications, and [[polycystic ovary syndrome]].<ref>Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43:S99–S112.</ref>
 
== Microscopic Pathology ==
On microscopic histopathological analysis characteristic findings of 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.
** Characterized by cellular swelling, rarefaction of the hepatocytic cytoplasm and clumped strands of intermediate filaments.
* 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>
* [[Mallory bodies|Mallory-Denk bodies]] (MDB)
* 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>
* [[Fibrosis]]  
* The diagnosis of cryptogenic cirrhosis is usually made in patients with similar clinical characteristics to those with NAFLD spectrum disease.
* Perivenular and pericellular (peri-sinusoidal) fibrosis
* 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>


==References==
==References==

Revision as of 23:07, 22 December 2017

  • On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
https://https://www.youtube.com/watch?v=PUQFQVm96YM%7C350}}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

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.

Pathophysiology

The exact pathogenesis of NAFLD is not fully understood, but is believed due to 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.
  • By upregulating TNF-alpha expression via lysosomal pathway, free fatty acids make the liver susceptible to oxidative stress.[2]
  • 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][3]

Endotoxins

  • Obese patients who underwent jejuno-ileal bypass surgery has the risk of developing bacterial endotoxins in the portal circulation due to small intestinal deformity.[4]
  • Increase in small bowel bacterial overgrowth due to decreased gastric motility. [5][6]
  • 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.
  • There is also an inverse relationship between circulating concentrations of adiponectin and tumor necrosis factor.[7]
  • Any conditions that cause low production of adiponectin ( consuming high amounts of poly unsaturated fatty acids) results in production of TNF alpha.[8][9]

Adenosine

Fibroblast Growth Factor 21

Associated Conditions

Microscopic Pathology

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

  • Predominant lobular inflammation in form of spotty necrosis in cases where steatosis is associated with inflammation.
  • Ballooning degeneration (hallmark of steatohepatitis)
    • Characterized by cellular swelling, rarefaction of the hepatocytic cytoplasm and clumped strands of intermediate filaments.
  • Mallory-Denk bodies (MDB)
  • Fibrosis
  • Perivenular and pericellular (peri-sinusoidal) fibrosis

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. ↑ 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.
  3. ↑ "Apolipoprotein synthesis in nonalcoholic steatohepatitis - Charlton - 2002 - Hepatology - Wiley Online Library".
  4. ↑ Hocking et al. Jejunoileal bypass for morbid obesity. Late follow-up in 100 cases. NEJM 1983;308(17):995-999
  5. ↑ 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. <ref name="urlThe Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background">"The Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background".
  6. ↑ Charlton M et al. Frequency of Nonalcoholic Steatohepatitis as a Cause of Advanced Liver Disease .Liver Transpl 2001;7:608-614
  7. ↑ "Adiponectin Resistance Exacerbates Insulin Resistance in Insulin Receptor Transgenic/Knockout Mice | Diabetes".
  8. ↑ "The Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background".
  9. ↑ Nigro E, Scudiero O, Monaco ML, Palmieri A, Mazzarella G, Costagliola C, Bianco A, Daniele A (2014). "New insight into adiponectin role in obesity and obesity-related diseases". Biomed Res Int. 2014: 658913. doi:10.1155/2014/658913. PMC 4109424. PMID 25110685.
  10. ↑ 10.0 10.1 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.
  11. ↑ 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.<ref name="urlThe ATP-P2X7 Signaling Axis Is Dispensable for Obesity-Associated Inflammasome Activation in Adipose Tissue | Diabetes">"The ATP-P2X7 Signaling Axis Is Dispensable for Obesity-Associated Inflammasome Activation in Adipose Tissue | Diabetes".
  12. ↑ Kunzli BM et al. Upregulation of CD39/NTPDases and P2 receptors in human pancreatic disease. AJP-Gastrointest Liver Physiol 2007;292:223-230
  13. ↑ 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
  14. ↑ 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)
  15. ↑ Kunzli BM et al. Disordered Pancreatic Inflammatory Responses and Inhibition of Fibrosis in CD39-null mice. Gastroenterology. 2008 January ; 134(1): 292–305.
  16. ↑ Kliewer and Mangelsdorf. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr 2010;91(suppl):254S–7S
  17. ↑ 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
  18. ↑ 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
  19. ↑ Kliewer and Mangelsdorf. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr 2010;91(suppl):254S–7S
  20. ↑ 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]
  21. ↑ Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43:S99–S112.

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