Non-alcoholic fatty liver disease pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: 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 it is thought due to multifactorial that includes numerous genetic, dietary, metabolic and hormonal 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.
- 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 (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.[2]
- 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.[1]
- 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
- 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).[3]
Endotoxins
- One of the original theories of NASH pathogenesis derived from clinical experience involving obese patients who developed cirrhosis after a jejuno-ileal bypass.[4]
- 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. [5][6]
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.[7]
- 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.[8]. [9]
Adenosine
- 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.[10]
- 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.
- CD39 deletion shifts the local population of cytokines toward the pro-inflammatory and non-fibrinogenic (e.g. interferon gamma).[11][12][13][14]
- Thirdly, in CD39 knockout models of hepatitis and pancreatitis, there is a marked decrease in fibrogenesis.[15]
- Adenosine receptor A2A is a major factor in the pathogenesis of cirrhosis.[14]
Fibroblast Growth Factor 21
- 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.[16]
- Moreover, it is a crucial component of the hepatic lipid oxidation machinery.
- This probably occurs as a function of proliferator-activated receptor activation. [17]
- 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.[18]
- 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.[19]
- 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.[20]
Uric Acid
- 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).[21]
- In animal studies conducted by the same group, they were able to show that hypouricemic medications reduced hepatic steatosis and hyperlipidemia.[22]
Associated Conditions
- 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. [23]
- As awareness of this condition spreads, it has been regarded as a major cause of cryptogenic cirrhosis of the liver.[24]
- 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. [25]
- 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.[26][25]
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.
- ↑ 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)
- ↑ 14.0 14.1 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.
- ↑ 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
- ↑ 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
- ↑ 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.
- ↑ 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.
- ↑ Clark JM, Diehl AM. Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. JAMA 2003;289:3000-4. PMID 12799409.
- ↑ 25.0 25.1 Caldwell SH, Oelsner DH, Iezzoni JC. Cryptogenic Cirrhosis: Clinical Characterization and Risk Factor for Underlying Disease. Hepatology 1999;29(3);664-69
- ↑ Yoshioka Y, Hashimoto E, Yatsuji S. “NASH: cirrhosis, hepatocellular carcinoma and burnt-out NASH.” J Gastroenterol 2004;39;1215-1218