HANS POPPER HEPATOPATHOLOGY SOCIETY

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
Toronto, Ontario
Email: ian.wanless@utoronto.ca

Introduction
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 steatosis.10,17

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 with NASH.16,27

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
      Insulin resistance
      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
      Inadequate cytoprotection
      Modulation of cytochromes p450

References

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