The Pathogenesis Of Non-Alcoholic Fatty Liver Disease
Ian R. Wanless, MD
Department of Laboratory Medicine and Pathobiology
University of Toronto and University Hospital Network
Steatohepatitis is generally understood as the presence of large droplet steatosis accompanied by evidence
of hepatocellular necrosis, usually with ballooning, Mallory bodies, and a predominantly neutrophilic
inflammatory reaction.1,2 Although at first considered typical of alcoholic injury, an identical
histologic appearance was discovered to occur in obese patients after jejuno-ileal bypass3 and then in
obese individuals without J-I bypass.4 The term non-alcoholic steatohepatitis (NASH) was coined by
Ludwig.5 Since then, several other clinical situations have been associated with steatohepatitis,
including the direct exposure of the liver capsule to insulin,6 various insulin-resistance syndromes and
lipodystrophies,7 hypertriglyceridemia,8 wasting illnesses,9,10 and various drugs and toxins.11
These associations indicate that steatohepatitis is a non-specific hepatic response to many different
stimuli, only one of which is alcohol. The pathogenesis of NASH has been reviewed.12,13,14
Obesity, Insulin, and Weight Loss
The early studies of NASH emphasized the association with obesity. However, most patients with obesity have
elevated insulin levels with or without type II diabetes mellitus. The demonstration that insulin causes
steatohepatitis even in lean insulin-deficient individuals, when delivered to the liver through peritoneal
dialysate, indicated the importance of insulin in the pathogenesis of NASH among obese individuals.6 The
insulin effect is further supported by the inability to produce fatty liver with a choline deficient diet in
insulin-deficient rats.15 It has now been amply demonstrated that most patients with NASH have elevated
insulin levels and/or insulin resistance.16 Insulin may explain the genesis of steatohepatitis after JI
bypass surgery.6 In those patients, there is weight loss on the basis of malabsorption at the same time
that the patients are free to consume large quantities of simple sugars that are readily absorbed in the
stomach. This situation could drive up insulin levels in the face of net caloric deficit. Other situations
with wasting illnesses supported by high carbohydrate intake are associated with steatohepatitis or
The mechanism of insulin action can be understood by known effects of insulin on hepatic triglyceride
synthesis and disposal. It was demonstrated that ex vivo livers from fed and fasted rats18 differed in
their ability to oxidize lipids. This can be explained by insulin inhibition of the beta-oxidation pathway.
Other Factors Causing Cellular Injury
It is clear that insulin is an effective agent that favors retention of triglyceride in hepatocytes.
Obesity may also be an independent factor because it provides a large reservoir of lipids for mobilization
to the liver as free fatty acids. However, steatosis by itself can exist for many years without progressive
fibrosis.19 Thus it has been proposed that a "second hit" may be required to cause the hepatocellular
necrosis and inflammation that lead to cirrhosis.20
There are several possible sites for this second hit, including generalized injury to cellular membranes by
free fatty acids21 or reactive oxygen species, a more specific mitochondrial dysfunction, or the local
effects of various agents including endotoxin and TNFa.11,22 Other postulated factors are listed
in Table 1.
Steatohepatitis has been reported in association with various drugs and toxins. These include amiodarone,23
perhexilene maleate, tamoxifen,24 and petrochemicals.25 Mitochondrial injury has been documented
experimentally by actions of some of these.11,26 Abnormal mitochondrial morphology, including
paracrystalline stacks of cristae, loss of cristae, and double membranes has been demonstrated in patients
Progression to Cirrhosis
Once cellular injury has occurred, activation of hepatic fibroblasts is necessary to achieve cirrhosis.
This has been documented in biopsies with NASH.28 In addition, progression to cirrhosis is always
accompanied by obliteration of small hepatic veins. It has been suggested that this obliteration is
necessary for the development of sustained fibrosis and disturbance of hepatic architecture.29 The
release of large droplets of lipid into the sinusoids can cause sinusoidal obstruction, a phenomenon known
as lipopeliosis.30 This release may augment zone 3 ischemia and expose the small vessels to the toxic
effects of free fatty acids.
Table 1. Postulated pathogenetic factors in NASH
Excess substrate (elevated triglyceride and free fatty acid levels)
Fatty acid toxicity
Exacerbation by dietary polyunsaturated dietary lipids
Cytokines, eg. TNFa, TGFb
Endotoxin from gut
Alcohol from gut
Reactive oxygen species generated by drugs and toxins
Lipid peroxidation augmented by hemosiderosis
Mitochondrial instability from ischemia or uncoupling protein 2
Modulation of cytochromes p450
Peters RL, Gay T, Reynolds TB. Post-jejunoileal-bypass hepatic disease. Its similarity to alcoholic
hepatic disease. Am J Clin Pathol 1975;63(3):318-31.
Adler M, Schaffner F. Fatty liver hepatitis and cirrhosis in obese patients. Am J Med 1979;67(5):811-6.
Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a
hitherto unnamed disease. Mayo Clin Proc 1980;55(7):434-8.
Wanless IR, Bargman JM, Oreopoulos DG, Vas SI. Subcapsular steatonecrosis in response to peritoneal
insulin delivery: a clue to the pathogenesis of steatonecrosis in obesity. Mod Pathol 1989;2(2):69-74.
Cauble MS, Gilroy R, Sorrell MF, Mailliard ME, Sudan DL, Anderson JC, et al. Lipoatrophic diabetes and
end-stage liver disease secondary to nonalcoholic steatohepatitis with recurrence after liver
transplantation. Transplantation 2001;71(7):892-5.
Fiatarone JR, Coverdale SA, Batey RG, Farrell GC. Non-alcoholic steatohepatitis: impaired antipyrine
metabolism and hypertriglyceridaemia may be clues to its pathogenesis. J Gastroenterol Hepatol
Carr A, Miller J, Law M, Cooper DA. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction
associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy
syndrome. Aids 2000;14(3):F25-32.
Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with
analysis of risk factors. Hepatology 1990;12(5):1106-10.
Pessayre D, Berson A, Fromenty B, Mansouri A. Mitochondria in steatohepatitis. Semin Liver Dis
Sheth SG, Gordon FD, Chopra S. Nonalcoholic steatohepatitis. Ann Intern Med 1997;126(2):137-45.
Angulo P, Lindor KD. Insulin resistance and mitochondrial abnormalities in NASH: a cool look into a
burning issue. Gastroenterology 2001;120(5):1281-5.
Tilg H, Diehl AM. Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med
Poucell S, Ireton J, Valencia-Mayoral P, Downar E, Larratt L, Patterson J, et al. Amiodarone-associated
phospholipidosis and fibrosis of the liver. Light, immunohistochemical, and electron microscopic studies.
Gastroenterology 1984;86(5 Pt 1):926-36.
Cai Q, Bensen M, Greene R, Kirchner J. Tamoxifen-induced transient multifocal hepatic fatty
infiltration. Am J Gastroenterol 2000;95(1):277-9.
Cotrim HP, Andrade ZA, Parana R, Portugal M, Lyra LG, Freitas LA. Nonalcoholic steatohepatitis: a
toxic liver disease in industrial workers. Liver 1999;19(4):299-304.
Berson A, De Beco V, Letteron P, Robin MA, Moreau C, El Kahwaji J, et al. Steatohepatitis-inducing
drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes. Gastroenterology
Caldwell SH, Swerdlow RH, Khan EM, Iezzoni JC, Hespenheide EE, Parks JK, et al. Mitochondrial
abnormalities in non-alcoholic steatohepatitis. J Hepatol 1999;31(3):430-4.
Washington K, Wright K, Shyr Y, Hunter EB, Olson S, Raiford DS. Hepatic stellate cell activation in
nonalcoholic steatohepatitis and fatty liver. Hum Pathol 2000;31(7):822-8.
Wanless IR, Nakashima E, Sherman M. Regression of human cirrhosis. Morphologic features and the genesis
of incomplete septal cirrhosis. Arch Pathol Lab Med 2000;124(11):1599-607.
Ferrell L, Bass N, Roberts J, Ascher N. Lipopeliosis: fat induced sinusoidal dilatation in transplanted
liver mimicking peliosis hepatis. J Clin Pathol 1992;45(12):1109-10.