Approach to the Pathogenesis and Treatment of Nonalcoholic Steatohepatitis

Abstract

Nonalcoholic steatohepatitis (NASH) represents an advanced stage of fatty liver disease developed in the absence of alcohol abuse. Its increasing prevalence in western countries, the diagnostic difficulties by noninvasive tests, and the possibility of progression to advanced fibrosis and even cirrhosis make NASH a challenge for hepatologists. NASH is frequently associated with type 2 diabetes and the metabolic syndrome, and several genetic and acquired factors are involved in its pathogenesis. Insulin resistance plays a central role in the development of a steatotic liver, which becomes vulnerable to additional injuries. Several cyclic mechanisms leading to selfenhancement of insulin resistance and hepatic accumulation of fat have been recently identified. Excess intracellular fatty acids, oxidant stress, tumor necrosis factor-␣, and mitochondrial dysfunction are causes of hepatocellular injury, thereby leading to disease progression and to the establishment of NASH. Intestinal bacterial overgrowth also plays a role, by increasing production of endogenous ethanol and proinflammatory cytokines. Therapeutic strategies aimed at modulating insulin resistance, normalizing lipoprotein metabolism, and downregulating inflammatory mediators with probiotics have promising potential. Diabetes Care 27:2057-2066, 2004N onalcoholic steatohepatitis (NASH) is a liver disease characterized by steatosis and periportal and lobular inflammation. In its initial phases, during which fat accumulates in the liver, no clinical symptoms are evident. In advanced stages, fibrosis (eventually progressing to established cirrhosis in some patients) is detectable histologically, along with a mixed inflammatory cell infiltrate, glycogen nuclei, and Mallory's hyaline (1). Because its adequate diagnosis requires histological evaluation of the liver, the prevalence of NASH is probably underestimated. Nonalcoholic fatty liver disease has been suggested to be the most common cause of chronic liver disease in the U.S., with a suggested incidence of 10 -24% in the general population and probably similar figures in Europe and Japan (2,3).Two types of NASH exist: primary NASH (which is associated with metabolic syndrome-related conditions, such as obesity, type 2 diabetes, and hyperlipemia) and secondary NASH (which occurs after obesity-related intestinal surgery, rapid weight loss in the obese, total parenteral nutrition, treatment with drugs such as amiodarone or perhexiline maleate, lipodystrophy, or Wilson's disease). Although many aspects of the disease are common to both presentations, this short review focuses mainly on the pathogenesis of primary NASH.The actual prevalence of NASH in type 2 diabetes and obesity is unknown. It is estimated that 75% of type 2 diabetic patients present some form of nonalcoholic fatty liver of different degrees. An association of NASH with hyperinsulinemia, as well as with clinical features of insulin resistance, has frequently been reported (4 -9). As far as obesity is regarded, steatosis has been reported in 70% o...

Impact of glucose tolerance on the severity of non-alcoholic steatohepatitis

“…Then, the second step is elicited by oxidative stress and cytokines occurs, resulting in an inflammatory process, hepatocellular degeneration and fibrosis. Hyperinsulinemia resulting from insulin resistance is very much involved in these first and second hits 22 . In the second hit especially, a direct link between insulin, inflammation and oxidative stress has been suggested by the observation that chronic activation of IKK‐β in ob / ob mice triggered by cytokines involved in oxidant and inflammatory stresses is associated with insulin resistance 23 .…”

Cannabinoid-1 receptor antagonists in type-2 diabetes

“…This suggests that ECS activation may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH), a common feature in overweight/obese patients with type-2 diabetes which is strongly associated with insulin resistance. 52,53 Furthermore, the fibrotic response of liver was strongly diminished by antagonism or genetic inactivation of CB1 receptors, suggesting that CB1-receptor antagonism may represent a new strategy for the treatment of liver fibrosis.…”

Infliximab reverses steatosis and improves insulin signal transduction in liver of rats fed a high-fat diet

“…In recent years, the characterization of the frequent association between NASH and hepatic insulin resistance has opened a new venue for investigation in this field (Medina et al 2004). In several tissues of the body, including the liver, insulin resistance may evolve as a consequence of proinflammatory signaling generated by cytokines produced by the enlarged adipose tissue in overnourished people (Hotamisligil 2006).…”