Pathogenesis and management issues for non-alcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) has, although it is a very common disorder, only relatively recently gained broader interest among physicians and scientists. Fatty liver has been documented in up to 10 to 15 percent of normal individuals and 70 to 80 percent of obese individuals. Although the pathophysiology of NAFLD is still subject to intensive research, several players and mechanisms have been suggested based on the substantial evidence. Excessive hepatocyte triglyceride accumulation resulting from insulin resistance is the first step in the proposed 'two hit' model of the pathogenesis of NAFLD. Oxidative stress resulting from mitochondrial fatty acids oxidation, NF-kappaB-dependent inflammatory cytokine expression and adipocytokines are all considered to be the potential factors causing second hits which lead to hepatocyte injury, inflammation and fibrosis. Although it was initially believed that NAFLD is a completely benign disorder, histologic follow-up studies have showed that fibrosis progression occurs in about a third of patients. A small number of patients with NAFLD eventually ends up with end-stage liver disease and even hepatocellular carcinoma. Although liver biopsy is currently the only way to confirm the NAFLD diagnosis and distinguish between fatty liver alone and NASH, no guidelines or firm recommendations can still be made as for when and in whom it is necessary. Increased physical activity, gradual weight reduction and in selected cases bariatric surgery remain the mainstay of NAFLD therapy. Studies with pharmacologic agents are showing promising results, but available data are still insufficient to make specific recommendations; their use therefore remains highly individual.

Figure 1

Lipid metabolism within the hepatocytes. Liver lipid content is determined by the equilibrium of several processes: import of free fatty acids (FFAs) from the adipose tissue, de novo FFA synthesis in hepatocytes, beta-oxidation of FFAs, esterification of FFAs into triglycerides and export of triglycerides as very low density lipoproteins (VLDL). Hepatic steatosisis is a consequence of imbalance in those processes in favour of excessive triglyceride (TG) accumulation. FFA:free fatty acids; TG: triglycerides; VLDL: very low density lipoproteins; Apo B:apolipoprotein B.

Figure 2

Effects of insulin resistance on lipid metabolism. Insulin resistance and resulting hyperinsulinemia lead to hepatocyte lipid accumulation in the liver by several mechanisms. In adipose tissue, insulin resistance enhances triglyceride (TG) lipolysis and inhibits esterification of free fatty acids (FFAs). The result are increased circulating levels of FFAs, which are then taken up by the liver. Additionally, in hepatocytes hyperinsulinemia increases the ‘de novo’ synthesis of fatty acids and inhibits their beta oxidation. The consequence is accumulation of FFAs within hepatocytes. Hepatic TG synthesis is driven by the increased hepatocyte FFA content and favoured by insulin-mediated upregulation of lipogenic enzymes, such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and sterol regulatory element binding protein 1 (SREBP-1). Meanwhile, reduced very-low-density lipoprotein (VLDL) production and TG export may be impaired by decreased synthesis of apolipoprotein B (apo B) or reduced binding of TG to apo B by microsomal triglyceride transfer protein (MTP). The resulting accumulation of fat within the hepatocytes initiates further damage causing hepatic insulin resistance and reactive oxygen species production. (abbrevations: ↑ -icreased; ↓ -inhibits; FFA: free fatty acid; TG: triglyceride; VLDL: very low density lipoprotein; Apo B: apolipoprotein B.