ABSTRACT
The definable causes of nonalcoholic steatohepatitis (NASH) include jejunoileal bypass
surgery (JIB), other causes of rapid and profound weight loss in obese subjects, total
parenteral nutrition, drugs, industrial toxins, copper toxicity, and disorders characterized
by extreme insulin resistance. However, the etiopathogenesis in most cases of NASH
appears multifactorial. Obesity, type 2 diabetes, and hypertriglyceridemia are often
associated with hepatic steatosis, and although this does not invariably lead to NASH,
the fatty liver is vulnerable to hepatocellular injury initiated by reactive oxygen
species (ROS). It is critical to understand not only the triggers for hepatitis (injury
and inflammation) in NASH but also how this is perpetuated as chronic liver disease.
The present focus is on whether the biochemical processes that generate oxidative
stress lead to hepatocyte injury and secondary recruitment of inflammation or whether
inflammation is the primary mediator of liver cell injury. Insulin resistance is a
reproducible pathogenic factor in NASH. It favors accumulation of free fatty acids
in the liver and predisposes to oxidative stress by stimulating microsomal lipid peroxidases
and by the direct effects of high insulin levels in decreasing mitochondrial β-oxidation.
CYP2E1 is normally suppressed by insulin but is invariably increased in the livers
of patients with NASH. In rodent dietary models of steatohepatitis, CYP2E1 is the
catalyst of microsomal lipid peroxidation, while in Cyp 2e1 nullizygous mice, CYP4A
proteins are induced and function as alternative microsomal lipid peroxidases. Other
studies implicate activation of peroxisome proliferator-activated receptor-α (PPARα)
as leading to NASH; PPARα is a transcription factor that governs both microsomal (via
CYP4A) and peroxisomal (β-oxidation) pathways of lipid oxidation and ultimately production
of ROS. Increased lipid peroxidation is a crucial difference between the livers of
rodents with experimental NASH and those of ob/ob genetically obese mice that have uncomplicated steatosis. Administration of endotoxin,
through the release of tumor necrosis factor-α (TNF-α), provokes liver inflammation
with hepatocyte injury in the steatotic liver. This may be particularly relevant in
JIB and has been suggested as a pathogenic mechanism in primary NASH. It has been
proposed that inheriting one or more copies of the hemochromatosis gene, C282Y, promotes fibrotic progression in NASH because of increased hepatic iron deposition,
but recent studies have failed to confirm this. The relationship between the severity
of hepatitis in NASH and progression to cirrhosis implies that products of the inflammatory
infiltrate play a role in fibrogenesis. In summary, NASH can be regarded as the hepatic
consequence of the metabolic syndrome (or syndrome X). Attention should now shift
from steatosis, a generally benign process that is less evident in the advanced stages
of cirrhosis, to the mechanisms for hepatocellular injury, inflammation, and hepatic
fibrosis. In particular, the genetic, molecular, and cellular factors that ordain
and moderate fibrosis in the context of steatohepatitis will be of greatest relevance
to effective therapy and clinical outcome.
KEYWORD
Nonalcoholic steatohepatitis - pathogenesis - etiology
