NASH Pathophysiology

Discover new insights into the NASH Pathophysiology, with all the complexity that includes multiple parallel hits.

Overview of Pathogenesis of Nonalcoholic Steatohepatitis

An understanding of the pathogenesis and natural course of NAFL and NASH is essential. These conditions are not static, but dynamic, and may progress or regress at variable rates in different individuals or even in the same individual at different times.

Non-alcoholic steatohepatitis (NASH), resulting from a combination of adipose tissue insulin resistance, adipocytokine imbalance and systemic inflammation, is currently a major worldwide cause of chronic liver disease, contributing to cirrhotic morbidity, hepatocellular carcinoma and liver transplantation, and worsening cardiovascular disease and metabolic dysfunction.

RELATED Pathophysiology of NASH VIDEOS

RELATED Pathophysiology ARTICLES

Environmental and genetic factors promote NASH pathogenesis

Several genetic mutations have been noted to be associated with NASH and have added to the implication of lipid and glucose metabolism involvement in NAFLD progression.
The best-studied polymorphisms are mutations in genes encoding patatin-like phospholipase domain-containing protein 3 (PNPLA3), the prevalence of which differs among populations and appears to parallel that of NASH; however, the mechanism by which the effects are produced is incompletely understood.

1.Diehl AM, Day C. Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. N Engl J Med. 2017;377(21):2063-72.
2. Haas JT, Francque S, Staels B. Pathophysiology and Mechanisms of Nonalcoholic Fatty Liver Disease. Annu Rev Physiol. 2016;78:181-205.
3.Naik A, Kosir R, Rozman D. Genomic aspects of NAFLD pathogenesis. Genomics. 2013;102(2):84-95.


“Lipotoxicity” (a term coined by Unger) is caused by toxic precursors of triglycerides or their metabolites and is thought to play a central role in the pathogenesis of NASH.
According to the substrate-overload liver injury model of NASH pathogenesis, the liver’s capacity to handle the primary metabolic energy substrates, carbohydrates and fatty acids is overwhelmed, leading to the accumulation of toxic lipid species.
NASH has been described as “the sum of injury and repair responses triggered by lipotoxicity”.
Ordinarily, several regulatory mechanisms minimise the production of free fatty acid (FFA) lipotoxic metabolites. The source of hepatic FFA is adipocyte triglyceride lipolysis or hepatocyte de novo lipogenesis from excess carbohydrates and amino acids.
The former normally represents 5% of FFA but can be increased 5-fold in NASH. Excessive lipolysis or FFA synthesis increases the supply of fatty acid delivery to the liver and is controlled by several neurologic and hormonal actions, some of which can be pharmacologically modulated.

Hepatic inflammation is an important component of the process, but it is unclear whether it is a primary cause or consequence (or both) of hepatocyte injury and death.

However, lipotoxicity does not affect just the liver. Triglyceride-derived toxic lipid metabolites accumulate in ectopic tissues and lead to multiorgan dysfunction.
Dysfunctional and insulin-resistant adipocytes release toxic triglycerides metabolites from the muscles, the heart, the pancreas and the liver, leading to metabolic syndrome, T2DM, obesity and CVD.
The inflammatory and immune systems, namely macrophages, are involved as well. There is a close relationship between insulin-resistant adipocytes, dysregulated immunity and steatohepatitis.
Activated adipose tissue macrophages are important in adipose tissue FFA release, insulin resistance and subsequent liver fat deposition.
The substrate-overload liver injury model of NASH pathogenesis
The substrate-overload liver injury model of NASH pathogenesis

1.Lee Y, Hirose H, Ohneda M, Johnson JH, McGarry JD, Unger RH. Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. Proc Natl Acad Sci U S A. 1994;91(23):10878-82.
2.Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology. 2010;52(2):774-88.
3.Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24(7):908-22.
4.Unger RH. Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology. 2003;144(12):5159-65.
5.Cortez-Pinto H, Chatham J, Chacko VP, Arnold C, Rashid A, Diehl AM. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. Jama. 1999;282(17):1659-64.
6.Liss KH, Finck BN. PPARs and nonalcoholic fatty liver disease. Biochimie. 2017;136:65-74.

The inflammatory and immune systems

The inflammatory and immune systems, namely macrophages, are involved as well. There is a close relationship between insulin-resistant adipocytes, dysregulated immunity and steatohepatitis. Activated adipose tissue macrophages are important in adipose tissue FFA release, insulin resistance and subsequent liver fat deposition.

1.Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology. 2012;142(4):711-25
2. Barb D, Portillo-Sanchez P, Cusi K. Pharmacological management of nonalcoholic fatty liver disease. Metabolism. 2016;65(8):1183-95

Oxidative stress and mitochondrial dysfunction

Oxidative stress and particularly alterations in mitochondrial function are thought to be a starting point of the hepatic and extrahepatic damage in NAFLD and contribute to the generation of reactive oxygen species (ROS). Mitochondria are the primary intracellular sites of oxygen consumption and therefore are a major source of ROS generation. The equilibrium of fat and energy in hepatic cells is regulated by mitochondrial activities, including beta-oxidation of FFAs, electron transfer and production of adenosine triphosphate (ATP) and ROS. An overload of FFAs impairs mitochondrial function, altering the balance between prooxidant and antioxidant mechanisms. The incomplete or suboptimal b-oxidation leads to the accumulation of long-chain acylcarnitines, ceramides and diacylglycerols that can promote inflammation and modify insulin signalling.
Another mechanism involved in oxidative stress is the disruption of endoplasmic reticulum (ER) homeostasis, namely, ER stress.

1.Masarone M, Rosato V, Dallio M, Gravina AG, Aglitti A, Loguercio C, et al. Role of Oxidative Stress in Pathophysiology of Nonalcoholic Fatty Liver Disease. Oxid Med Cell Longev. 2018;2018:9547613.
2. Garcia-Ruiz C, Fernandez-Checa JC. Mitochondrial Oxidative Stress and Antioxidants Balance in Fatty Liver Disease. Hepatol Commun. 2018;2(12):1425-39.
3.Jelenik T, Kaul K, Sequaris G, Flogel U, Phielix E, Kotzka J, et al. Mechanisms of Insulin Resistance in Primary and Secondary Nonalcoholic Fatty Liver. Diabetes. 2017;66(8):2241-53.
4.Koliaki C, Szendroedi J, Kaul K, Jelenik T, Nowotny P, Jankowiak F, et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab. 2015;21(5):739-46.
5.Malhotra JD, Kaufman RJ. The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol. 2007;18(6):716-31.
6.Wei Y, Wang D, Gentile CL, Pagliassotti MJ. Reduced endoplasmic reticulum luminal calcium links saturated fatty acid-mediated endoplasmic reticulum stress and cell death in liver cells. Mol Cell Biochem. 2009;331(1-2):31-40


Liver inflammation in NAFLD can be triggered outside the liver such as in adipose tissue and the gut as well as inside the liver. Increased visceral adipose tissue is associated with increased infiltration of inflammatory macrophages, which triggers insulin resistance and inflammation in the adipose tissue and leads to a disturbed adipokine profile, namely high leptin and tumour necrosis factor (TNF) levels and low adiponectin levels. While adiponectin reduces insulin resistance, liver steatosis and inflammation, TNF increases insulin resistance and is pro-inflammatory.


1.Schuster S, Cabrera D, Arrese M, Feldstein AE. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol. 2018;15(6):349-64.
2. Buechler C, Wanninger J, Neumeier M. Adiponectin, a key adipokine in obesity related liver diseases. World J Gastroenterol. 2011;17(23):2801-11.
3.Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology. 2004;40(1):46-54.
4.Farrell GC, van Rooyen D, Gan L, Chitturi S. NASH is an Inflammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications. Gut Liver. 2012;6(2):149-71.
5.Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol. 2015;62(1 Suppl):S47-64.
6.Szendroedi J, Yoshimura T, Phielix E, Koliaki C, Marcucci M, Zhang D, et al. Role of diacylglycerol activation of PKCtheta in lipid-induced muscle insulin resistance in humans. Proc Natl Acad Sci U S A. 2014;111(26):9597-602.
7.Krenkel O, Tacke F. Macrophages in nonalcoholic fatty liver disease: a role model of pathogenic immunometabolism. Semin Liver Dis. 2017;37(3):189-97.


Typically, NASH is associated with some degree of hepatic fibrosis, and a small fraction of patients will develop progressive fibrosis and cirrhosis (estimated at 2% of American adults) with some further progressing to HCC. Liver biopsy studies suggest that fibrosis progresses at a rate of approximately one stage per decade, suggesting that stage 2 fibrosis will progress to cirrhosis within 20 years. However, fibrosis progression is not necessarily linear and varies from patient to patient. While NASH improvement or resolution leads to a reduction of fibrosis in some patients, in others fibrosis continues or worsens.

1.Diehl AM, Day C. Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. N Engl J Med. 2017;377(21):2063-72.
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3.Hardy T, Oakley F, Anstee QM, Day CP. Nonalcoholic Fatty Liver Disease: Pathogenesis and Disease Spectrum. Annu Rev Pathol. 2016;11:451-96.
4.Angulo P, Machado MV, Diehl AM. Fibrosis in nonalcoholic Fatty liver disease: mechanisms and clinical implications. Semin Liver Dis. 2015;35(2):132-45.
5.Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012;18(7):1028-40.
6.Verrecchia F, Mauviel A. Transforming growth factor-beta and fibrosis. World J Gastroenterol. 2007;13(22):3056-62.
7.Kanzler S, Lohse AW, Keil A, Henninger J, Dienes HP, Schirmacher P, et al. TGF-beta1 in liver fibrosis: an inducible transgenic mouse model to study liver fibrogenesis. Am J Physiol. 1999;276(4):G1059-68.
8.Dudás J, Kovalszky I, Gallai M, Nagy JO, Schaff Z, Knittel T, et al. Expression of decorin, transforming growth factor-beta 1, tissue inhibitor metalloproteinase 1 and 2, and type IV collagenases in chronic hepatitis. Am J Clin Pathol. 2001;115(5):725-35.
9.Xu F, Liu C, Zhou D, Zhang L. TGF-beta/SMAD pathway and its regulation in hepatic fibrosis. J Histochem Cytochem. 2016;64(3):157-67.
10.Gressner AM, Weiskirchen R. Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med. 2006;10(1):76-99.

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