Nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease is emerging as the most common chronic liver condition in the Western world. It is associated with insulin resistance and frequently occurs with features of the metabolic syndrome. Disease presentation ranges from asymptomatic elevated liver enzyme levels to cirrhosis with complications of liver failure and hepatocellular carcinoma. Current treatment recommendations are limited to weight loss and exercise, although several promising medications are on the horizon. In this article we discuss the etiology, pathogenesis and diagnosis of nonalcoholic fatty liver disease as well as approaches to its management.

Fig. 1: Development of nonalcoholic hepatic steatosis. Insulin resistance enhances triglyceride (TG) lipolysis and inhibits esterification of free fatty acids (FFA) within adipose tissue. The result is increased serum FFA levels, which are taken up by the liver. Hepatic TG synthesis is driven by the increased influx of FFA and favoured by insulin upregulated lipogenic transcription factors, such as peroxisome proliferator-activated receptor gamma (PPARγ) and sterol regulatory element binding protein (SREBP)-1c. Alternative metabolism of FFA by oxidation is inhibited by insulin. TG export via very-low-density lipoproteins (VLDL) may be inhibited by decreased synthesis of apolipoprotein B (apo B) or reduced incorporation of TG with apo B by microsomal triglyceride transfer protein (MTP). See the animated figure at www.cmaj.ca/cgi/content/full/172/7/899/DC1. Photo: Mayo Clinic

Fig. 2: Left: Histologic features of fibrosis in nonalcoholic steatohepatitis (NASH). Trichrome stain of liver (magnification х 200) demonstrating macrovesicular steatosis and fibrosis, most prominent in zone 3 near the central vein (CV) of the hepatic lobule. Typically early fibrosis is pericellular and perisinusoidal, giving the appearance of “chickenwire.” Right: Histologic features of necrotic inflammation in NASH. Hematoxylin and eosin stain of liver (magnification х 400) with injured ballooned hepatocytes (B) and a mild neutrophilic infiltrate (N). Aggregations of Mallory's hyaline (MH) comprised of eosinophilic cytoskeleton filaments are also observed.