Transcript NASH
Non alcoholic steatohepatitis (NASH) Raika Jamali M.D. Gastroenterologist and hepatologist Tehran University of Medical Sciences Steatohepatitis Is an intermediate stage in the spectrum of non alcoholic fatty liver disease (NAFLD), Simple fatty liver --> Steatohepatitis --> Cirrhosis Shows the same histopathology but occurs in the absence of excess alcohol consumption (<20 gr/day) Associated with the metabolic syndrome (insulin-resistant state): Truncal obesity, Type 2 DM, Hypertension Dyslipidemia (high TG and low HDL levels). Though strongly associated with obesity, NASH has also been demonstrated in 3% of lean individuals (generalized lipodystrophy) Epidemiology The prevalence varies based on the diagnostic test used Population-based surveys of adults >18 y with US have demonstrated fatty liver disease in 20% of the populations of Japan, Western Europe, and the US MRI: ≈34% in the general population >18 y Hispanic Americans (50%), Whites (33%), African Americans (25%) have fatty livers 80% of individuals with steatosis by MRI have normal ALT levels, Indicating that blood tests are the least sensitive tool for diagnosis Prevalence of fatty liver disease falls to 8% if elevations in ALT are used for screening NASH is the main cause of elevated liver enzymes in the Western world The true prevalence of NASH is unknown: because neither imaging tests nor blood tests reliably differentiate steatosis from more advanced stages of fatty liver disease (NASH and cirrhosis) and because liver biopsy studies show that NASH or cirrhosis sometimes occurs in individuals with normal ALT levels, Liver biopsy studies suggest: Steatosis is twice as common as NASH at least 10% of patients with NASH progress to cirrhosis over time in the adult U.S. population: Fatty liver (34%) Steatohepatitis (17%) Cirrhosis (2%) The prevalence of NAFLD in Iran was: 2.04% in a population based study in Golestan province. (2006) 2.1% in autopsies from forensic medicine of Tehran. (2006) 2.35% in healthy blood donors in Tehran. (2005) Pathobiology In the early stages of non alcoholic fatty liver disease (NAFLD), fat accumulates within hepatocytes when mechanisms that promote lipid removal (by oxidation or export) cannot keep pace with mechanisms that promote lipid import or biosynthesis. Although alcohol consumption has long been known to promote lipid biosynthesis while inhibiting lipid export, it has been appreciated only recently that the molecular mechanisms involved are very similar to those that promote steatosis in nonalcoholic fatty liver disease. Factors that modulate the evolution of NAFLD: Fatty acids Tumor necrosis factor-α (TNF-α) Adiponectin Fatty acids routinely traffic between the liver and adipose tissue. Fat and the liver are also important sources of TNF-α and adiponectin. Adiponectin reduces lipid accumulation within hepatocytes by inhibiting fatty acid import and increasing fatty acid oxidation and export. It is also a potent insulin-sensitizing agent. TNF-α antagonizes the actions of diponectin promotes hepatocyte steatosis increases mitochondrial generation of reactive oxygen species, which induce insulin resistance. promotes hepatocyte apoptosis and recruits inflammatory cells to the liver. generates oxidative and apoptotic stress that sometimes overwhelms antioxidant and antiapoptotic defenses and leads to steatohepatitis. Thus the relative risk for the development of NASH correlates with increases in TNF-α or decreases in adiponectin levels Fatty acids within hepatocytes Inhibitor κ kinase-β Nuclear transcription factor NFκB TNF-α and IL-6 insulin resistance Therefore, like adipose tissue, fatty livers also make soluble factors that circulate to distant tissues and contribute to systemic insulin resistance (the metabolic syndrome). NASH can develop in nonobese individuals. The mechanism of liver damage in nonobese and obese individuals may be similar: excessive exposure of hepatocytes to fatty acids fatty acid–inducible inflamma-tory mediators (TNF-α) reactive oxygen species. Intestinal microflora help regulate intestinal uptake of diet-derived lipids, in addition to hepatic fatty acid synthesis, the gut bacteria of some nonobese individuals might promote excessive hepatic accumulation of fatty acids, as well as exposure to other bacterial factors (e.g., lipopolysaccharide) that trigger hepatic TNF production The role of intestinal flora in the pathogenesis of alcohol-induced fatty liver disease has been well demonstrated: Experimental animals housed under germfree conditions or treated with poorly absorbed oral antibiotics are protected from alcohol-induced hepatotoxicity. Products from intestinal bacteria are thought to injure the liver by increasing hepatic production of TNF-α and reactive oxygen species because mice that are genetically deficient in either TNF-α or certain enzyme that generate reactive oxygen species are also protected from the alcoholic liver damage Progression from fatty liver disease to cirrhosis is predominately dictated by the severity of oxidant stress and the consequent necroinflammation. However, findings in animal models of steatohepatitis cast some doubt on this assumption because mice in which severe steatohepatitis develops do not uniformly progress to cirrhosis In fact, progression to cirrhosis is also poorly predicted by the gravity of the injurious insult in human fatty liver disease For example, although there is no doubt that alcohol is hepatotoxic, most lifelong heavy drinkers do not become cirrhotic Similarly, although obesity clearly increases exposure to fat-derived inflammatory mediators and is an independent risk factor for progression of alcoholic fatty liver disease to cirrhosis, some morbidly obese individuals have normal livers at the time of gastric bypass surgery Individuals in whom just steatosis develops despite constant bombardment with inflammatory factors might be better at repairing their liver damage without the development of fibrosis than those in whom NASH or cirrhosis develops. In this regard, leptin, angiotensin, and norepinephrine: promote the proliferation of hepatic stellate cells upregulate their expression of profibrogenic cytokines (TGF β) induce collagen gene expression. Conversely, adiponectin appears to inhibit the activation of hepatic stellate cells and decrease liver fibrosis. Angiotensin is an independent risk factor for advanced liver fibrosis in NASH and the suggestion,that angiotensin receptor blockade might decrease liver fibrosis and slow disease progression in patients with NASH and arterial hypertension.