In liver disease, several of these factors may be altered. This depends mainly on the severity of the liver disease but rarely on its etiology. Even in cirrhosis, there are remarkable differences between

the functional capacities of different metabolizing enzyme systems. In addition to changes in the intrinsic hepatic clearance, liver perfusion and especially intra- and extra-hepatic MAPK Inhibitor Library concentration shunting may significantly influence metabolism and excretion of drugs. An overall test reflecting hepatic clearance at a given stage of liver disease, similar to the glomerular filtration rate in kidney disease, does not exist. The Child–Pugh classification remains the best tool to estimate hepatic reserve and approximately determine the need for dose adjustment in cirrhotic patients. With a good understanding of the underlying pathophysiology in liver disease and the knowledge of an individual drug’s metabolic pathway, a reasonable prediction of dose adjustment is possible in most cases. “
“Whereas in most cases a fatty liver remains free of inflammation, 10%-20% of patients who have fatty liver develop inflammation and fibrosis (nonalcoholic steatohepatitis [NASH]). Inflammation may precede steatosis in certain instances. Therefore, NASH could find more reflect a disease where inflammation is followed by steatosis. In contrast, NASH subsequent to simple steatosis may be the consequence of a failure of antilipotoxic protection. In both

situations, many parallel hits derived from the gut and/or the adipose tissue may promote liver inflammation. Endoplasmic reticulum stress and related signaling networks, (adipo)cytokines, and innate immunity are emerging as central pathways that regulate key features of NASH. (HEPATOLOGY 2010;52:1836-1846) Nonalcoholic fatty liver disease 上海皓元医药股份有限公司 (NAFLD) includes a disease spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, and hepatocellular carcinoma.1 The majority of patients with NAFLD are obese or even morbidly obese and have accompanying insulin resistance.2-4 The proportion of patients with NAFLD who have NASH is

still not entirely clear but might range from 10%-20%. This is relevant because inflammation and/or fibrosis determine the long-term prognosis of this disease, whereas steatosis per se might not adversely affect outcome.5-8 Most studies indicate that 1%-3% of the Western population might have NASH. The natural history of NAFLD is still poorly understood, and in particular, it is not known why certain patients progress toward inflammation, fibrosis, and cirrhosis and why others do not. One of the burning questions in NAFLD remains which factors could be the driving forces toward a more progressive, inflammatory disease phenotype. Day and colleagues presented more than a decade ago the so-called “two-hit” model, suggesting that after a first hit (i.e., hepatic steatosis) another hit (e.g.