Adiponectin has antilipogenic and anti-inflammatory effects, while tumor necrosis factor ␣ (TNF-␣) reduces insulin sensitivity and has proinflammatory effects. We examined (1) the extent to which hypoadiponectinemia and TNF-␣ activation are features of nonalcoholic steatohepatitis (NASH) and (2) whether serum levels of these markers correlate with the severity of histological changes in 109 subjects with nonalcoholic fatty liver disease (NAFLD), including 80 with NASH and 29 with simple steatosis. By multivariate analysis, subjects with NASH had reduced adiponectin level and increased TNF-␣ and soluble TNF receptor 2 (sTNFR2)-but not leptin levels, compared with controls matched by age, sex, and body mass index; these differences were independent of the increased insulin resistance (by homeostasis model [HOMA-IR]) in NASH. When compared with simple steatosis, NASH was associated with lower adiponectin levels and higher HOMA-IR, but there were no significant differences in the levels of TNF-␣ and sTNFR2. The majority of subjects with steatohepatitis (77%) had adiponectin levels less than 10 g/mL and HOMA-IR greater than 3 units, but only 33% of those with pure steatosis had these findings. HOMA-IR and low serum adiponectin were also independently associated with increased grades of hepatic necroinflammation. In conclusion, hypoadiponectinemia is a feature of NASH independent of insulin resistance. Reduced adiponectin level is associated with more extensive necroinflammation and may contribute to the development of necroinflammatory forms of NAFLD.
(HEPATOLOGY 2004;40:46 -54.) N onalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury in many countries. The spectrum encompasses simple fatty liver (steatosis), which is generally nonprogressive, 3 and nonalcoholic steatohepatitis (NASH), which can lead to cirrhosis and liver failure. Insulin resistance is central to the pathogenesis of NAFLD, and recent data indicate that NASH should be considered the hepatic manifestation of the insulin resistance syndrome. 6,8 -10 However, while steatosis appears very common, NASH is not universal among those with the insulin resistance syndrome. It is therefore important to discern what factors in the host metabolic milieu modulate the development of NASH, and, in particular, the transition from steatosis to steatohepatitis.
Adipose tissue secretes several bioactive proteins, or adipokines, that regulate hepatic and peripheral glucose and lipid metabolism. These adipokines include leptin, tumor necrosis factor ␣ (TNF-␣), resistin, and adiponectin. Although resistin inhibits insulin action in animal models, its expression is not increased in human subjects with insulin resistance or type 2 diabetes. We recently suggested that raised serum leptin levels in NASH may be a reflection of the failure of leptin to stimulate hepatic lipid turnover, that is, hepatic leptin resistance. 14 Likewise, raised serum TNF-␣ levels have been demonstrated in several studies of fatty liver disease. TNF-␣ interferes with insulin signaling, thereby favoring steatosis, and may play a proinflammatory role in the pathogenesis of NASH. 17 However, these earlier reports of TNF-␣ levels in NAFLD failed to match control subjects for adipos-