Non-alcoholic fatty liver disease pathophysiology
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Editor in Chief: Elliot Tapper, M.D., Beth Israel Deaconess Medical Center, C. Michael Gibson, M.S., M.D. [1]
Overview
The exact cause is still unknown. However both obesity and insulin resistance likely play a strong role in this disease process. 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.[1] Oxidative stress, hormonal imbalances, endotoxemia and mitochondrial abnormalities may all be potential causes.
Pathophysiology
Insulin Resistance
Clinicopathologic studies in patients with NAFLD have confirmed that insulin resistance is a cause and not a result of liver disease. For example, 75% of NAFLD/NASH patients – lean or obese – having insulin resistance while only 7.5% of patients with Hepatitis C are insulin resistant.[2] In another study, a fasting glucose >110 mg/dL was the most predictive feature of NAFLD.[3]
Comorbid Liver Disease
The evidence for oxidative stress as a second-hit comes from many sources. For example, as in hemochromatosis liver disease, any degree of iron overload engenders enhanced free radical production in the liver. As many as 31% of patients with NASH have been discovered to have C282Y mutations of the HFE gene for hemochromatosis(compared to a prevalence of less than 12.5% in the general population).[4] Similarly, while 2-3.6% of the population have the profibrotic MZ alpha-1 antitrypsin deficiency phenotype, it is present in as many as 16.7% of NASH patients requiring liver transplantation.[5]
Endotoxins
One of the original theories of NASH pathogenesis derived from clinical experience involving obese patients who developed cirrhosis after a jejuno-ileal bypass.[6] 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 control. Furthermore, some degree of steatohepatitis can even be reversed after treatment with metronidazole. [7]
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.[8]. 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.[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] 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.[11]
Secondly, adenosine appears to be a critical supportive link in the cell’s cascade of responses to inflammation;[12] 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.[13][14] CD39 deletion shifts the local population of cytokines toward the pro-inflammatory and non-fibrinogenic (e.g. interferon gamma).[15]
Thirdly, in CD39 knockout models of hepatitis and pancreatitis, there is a marked decrease in fibrogenesis.[16] And adenosine receptor A2A is a major factor in the pathogenesis of cirrhosis.[13]
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.[17] Moreover, it is a crucial component of the hepatic lipid oxidation machinery. This probably occurs as a function of proliferator-activated receptor activation. [18].
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.[19] 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.[20] 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.[21]
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).[22] In animal studies conducted by the same group, they were able to show that hypouricemic medications reduced hepatic steatosis and hyperlipidemia.[23]
References
- ↑ Berson A, De Beco V, Lette´ron P, Robin MA, Moreau C, El KahwajiJ, Verthier N, Feldmann G, Fromenty B, Pessayre D. Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes. Gastroenterology 1998;114:764–774.
- ↑ Chitturi S, Abeygunasekera S, Farrell GC, et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002;35:373–379
- ↑ Marchesini G, Brizi M, Bianchi G, et al.Metformin in nonalcoholic steatohepatitis. Lancet 2001;358:893–894
- ↑ George DK, Goldwurm S, Macdonald GA, Cowley LL, Walker NI, Ward PJ, Jazwinska EC, Powell LW. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 1998;114:311–318.
- ↑ Charlton M et al. Frequency of Nonalcoholic Steatohepatitis as a Cause of Advanced Liver Disease .Liver Transpl 2001;7:608-614
- ↑ 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, endotoxaemia, and tumour necrosis factor α in the pathogenesis of non-alcoholic steatohepatitis. Gut 2001;48:206-211
- ↑ Anania. Adiponectin and Alcoholic Fatty Liver: Is It, After All, About What You Eat? Hepatology 2005;42(3):530-532
- ↑ You M, Considine RV, Leone TC, Kelly DP, Crabb DW. Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice. Hepatology 2005;42:568-577.
- ↑ 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. Frontiers Biosci 2008; 13, 2588-2603
- ↑ Enjyoji, K et al. Deletion of Cd39/Entpd1 Results in Hepatic Insulin Resistance. Diabetes. 2008; 57:2311–2320
- ↑ 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
- ↑ 13.0 13.1 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.
- ↑ 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. Upregulation of CD39/NTPDases and P2 receptors in human pancreatic disease. AJP-Gastrointest Liver Physiol 2007;292:223-230
- ↑ 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]