Non-alcoholic fatty liver disease pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
The exact pathogenesis of NAFLD is not fully understood | The exact pathogenesis of NAFLD is not fully understood, but is believed due to interaction of multiple factors such as obesity, Insulin resistance, and metabolic syndrome. Pathogenesis of non-alcoholic liver disease can be summarized by 2 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== | ==Pathophysiology== | ||
| Line 21: | Line 21: | ||
=== Free fatty acids === | === 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. | ||
* 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> | * 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. | * [[Oxidative stress]] inhibits the [[replication]] process in the mature [[hepatocytes]]. | ||
* Inhibition of hepatocyte replication results in the proliferation of progenitor | * Inhibition of [[hepatocyte]] replication results in the proliferation of [[Progenitor cells|progenitor cel]]<nowiki/>l 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.<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> | * 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=== | ||
* 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> | * [[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]].<ref>Hocking et al. Jejunoileal bypass for morbid obesity. Late follow-up in 100 cases. NEJM 1983;308(17):995-999</ref> | ||
* 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> | * 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> | ||
* Bacterial toxins released by this bacteria overgrowth stimulate an elevation of intra-hepatic levels of pro-inflammatory [[cytokines]], such as [[tumor necrosis factor-alpha]]. | * 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. | * Expression of [[TNF-alpha]] begins the cascade of events making liver susceptible for [[Free radicals|free radical injury.]] | ||
===Adiponectin=== | ===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]]. | ||
* There is | * There is 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 | Diabetes |format= |work= |accessdate=}}</ref> | ||
* 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> | * 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]].<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=== | ||
* Alteration of [[purinergic metabolism]] is another important pathway responsible for development of non-alcoholic liver disease. | * 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]].<ref name="Chan" /> | * [[Adenosine]] receptor A2A is a major factor in the pathogenesis of [[cirrhosis]].<ref name="Chan" /> | ||
* 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. | * 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. | ||
* Alterations in purinergic signaling induced by altered CD39 mutation have major impacts upon [[hepatic metabolism]], repair mechanisms, regeneration and associated [[immune]] | * 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]].<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 | 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 | Diabetes |format= |work= |accessdate=}}</ref> | ||
* Adenosine forms a supportive link in the cell’s cascade healing response to [[inflammation]]. | * [[Adenosine]] forms a supportive link in the cell’s cascade healing response to [[inflammation]]. | ||
** Adenosine suppresses [[inflammation]] by enhancing [[fibrosis]]. | ** [[Adenosine]] suppresses [[inflammation]] by enhancing [[fibrosis]]. | ||
* 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> | * 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> | ||
===Fibroblast Growth Factor 21=== | ===Fibroblast Growth Factor 21=== | ||
* [[Fibroblast growth factor 21]] ([[FGF21]]) is an important metabolic regulator of [[glucose]] and [[lipid]] [[metabolism]]. | * [[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]].<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, 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> | * 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> | ||
* FGF21 is responsible for normal [[blood glucose]], [[insulin]], and [[lipid]] levels in normal individuals. | * [[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]].<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> | * 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> | ||
| Line 64: | Line 64: | ||
* Macrovesicular [[steatosis]] | * Macrovesicular [[steatosis]] | ||
* Predominant lobular inflammation in form of spotty necrosis in cases where steatosis is associated with [[inflammation]]. | * Predominant lobular inflammation in form of spotty [[necrosis]] in cases where [[steatosis]] is associated with [[inflammation]]. | ||
* Ballooning degeneration (hallmark of [[steatohepatitis]]) | * Ballooning degeneration (hallmark of [[steatohepatitis]]) | ||
** Characterized by cellular swelling, rarefaction of the hepatocytic cytoplasm and clumped strands of intermediate filaments. | ** Characterized by cellular swelling, rarefaction of the hepatocytic [[cytoplasm]] and clumped strands of intermediate filaments. | ||
* [[Mallory bodies|Mallory-Denk bodies]] (MDB) | * [[Mallory bodies|Mallory-Denk bodies]] (MDB) | ||
* [[Fibrosis]] | * [[Fibrosis]] | ||
* Perivenular and pericellular (peri-sinusoidal) fibrosis | * Perivenular and pericellular (peri-sinusoidal) fibrosis. | ||
==References== | ==References== | ||
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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, but is believed due to interaction of multiple factors such as obesity, Insulin resistance, and metabolic syndrome. Pathogenesis of non-alcoholic liver disease can be summarized by 2 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 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
- 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.[10]
- 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.[11]
- 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.[12][13][14][10][15]
Fibroblast Growth Factor 21
- 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.[16]
- Moreover, it is a crucial component of the hepatic lipid oxidation machinery, as proliferator-activated receptor activation.[17]
- 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.[18][19][20]
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.[21]
Microscopic Pathology
On microscopic histopathological analysis characteristic findings of 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)
- 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
- ↑ 1.0 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.
- ↑ 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.
- ↑ "Apolipoprotein synthesis in nonalcoholic steatohepatitis - Charlton - 2002 - Hepatology - Wiley Online Library".
- ↑ Hocking et al. Jejunoileal bypass for morbid obesity. Late follow-up in 100 cases. NEJM 1983;308(17):995-999
- ↑ 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".
- ↑ Charlton M et al. Frequency of Nonalcoholic Steatohepatitis as a Cause of Advanced Liver Disease .Liver Transpl 2001;7:608-614
- ↑ "Adiponectin Resistance Exacerbates Insulin Resistance in Insulin Receptor Transgenic/Knockout Mice | Diabetes".
- ↑ "The Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background".
- ↑ 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.
- ↑ 10.0 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.
- ↑ 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".
- ↑ Kunzli BM et al. Upregulation of CD39/NTPDases and P2 receptors in human pancreatic disease. AJP-Gastrointest Liver Physiol 2007;292:223-230
- ↑ 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
- ↑ 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)
- ↑ Kunzli BM et al. Disordered Pancreatic Inflammatory Responses and Inhibition of Fibrosis in CD39-null mice. Gastroenterology. 2008 January ; 134(1): 292–305.
- ↑ Kliewer and Mangelsdorf. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr 2010;91(suppl):254S–7S
- ↑ 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
- ↑ 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
- ↑ Kliewer and Mangelsdorf. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr 2010;91(suppl):254S–7S
- ↑ 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]
- ↑ Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43:S99–S112.