Nonalcoholic Fatty Liver Disease: From Steatosis to Cirrhosis

Abstract

Nonalcoholic steatohepatitis (NASH), the lynchpin between steatosis and cirrhosis in the spectrum of nonalcoholic fatty liver disorders (NAFLD), was barely recognized in 1981. NAFLD is now present in 17% to 33% of Americans, has a worldwide distribution, and parallels the frequency of central adiposity, obesity, insulin resistance, metabolic syndrome and type 2 diabetes. NASH could be present in one third of NAFLD cases. Age, activity of steatohepatitis, and established fibrosis predispose to cirrhosis, which has a 7-to 10-year liver-related mortality of 12% to 25%. Many cases of cryptogenic cirrhosis are likely endstage NASH. While endstage NAFLD currently accounts for 4% to 10% of liver transplants, this may soon rise. Pathogenic concepts for NAFLD/NASH must account for the strong links with overnutrition and underactivity, insulin resistance, and genetic factors. Lipotoxicity, oxidative stress, cytokines, and other proinflammatory mediators may each play a role in transition of steatosis to NASH. The present "gold standard" management of NASH is modest weight reduction, particularly correction of central obesity achieved by combining dietary measures with increased physical activity. Whether achieved by "lifestyle adjustment" or anti-obesity surgery, this improves insulin resistance and reverses steatosis, hepatocellular injury, inflammation, and fibrosis. The same potential for "unwinding" fibrotic NASH is indicated by studies of the peroxisome proliferation activator receptor (PPAR)-␥ agonist "glitazones," but these agents may improve liver disease at the expense of worsening obesity. Future challenges are to approach NAFLD as a preventive public health initiative and to motivate affected persons to adopt a healthier lifestyle. (HEPATOLOGY 2006;43:S99-S112.)

Natural history of nonalcoholic fatty liver disease: A prospective follow‐up study with serial biopsies

“…Some patients with NAFLD develop progressive fibrosis and subsequent cirrhosis with an increased risk of hepatocellular carcinoma 6. The prevalence of cirrhosis among patients with NAFLD is approximately 5%, and patients with NAFLD have an increased mortality compared to control populations 7, 8, 9.…”

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

“…Once steatosis is present, the liver becomes more susceptible to the "second-hit"; oxidative/nitrosative/nitrative stress, which is thought to be one of several stimuli for the progression from simple fatty liver to ASH or NASH. The molecular mechanism underlying how steatosis predisposes liver to transition from simple fatty liver to steatohepatitis is not clear; however, several studies point to the possibility that when hepatocytes accumulate fat the fatty acids themselves are toxic and initiate a pathological response called "lipotoxicity" [14]. Studies show that free fatty acids are toxic to hepatocytes via deregulation of lysosomal metabolism [15,16] and induction of endoplasmic reticulum stress [17,18] resulting in apoptosis.…”

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

“…Furthermore, reduced survival and higher mortality from cardiovascular and liver‐related causes have been reported among NASH patients in comparison with a reference population 4 . Several factors, including body mass index (BMI), age, hyperglycemia, dyslipidemia and hypertension, have been linked to the severity of NAFLD 5 , and the presence of diabetes, in particular, has received a great deal of attention. One previous study found that type 2 diabetes was an independent predictor of progression to fibrosis in NASH patients 6 , and the histological data of 458 Italian NAFLD patients showed that NASH was independently predicted by diabetes 7 .…”