Twenty to 40% of patients with steatosis will progress to fibrosis, of which 8–20% will develop cirrhosis.[12, 13] As in other liver diseases, patients with cirrhosis are at risk for hepatic decompensation (ascites, variceal bleeding, and encephalopathy) and hepatocellular carcinoma (HCC) (Fig. 1). Although the most important risk factor for ALD is the absolute amount of alcohol intake, multiple other factors play a role in host susceptibility.[14] Women are at greater risk of ALD, as are Mexican and black non-Hispanic Americans for reasons that

are not well understood.[15-17] Obesity may potentiate the hepatotoxic effects of alcohol, presumably through mechanisms similar to those that result in non-alcoholic steatohepatitis.[18, 19] Smoking and selleck kinase inhibitor the pattern of alcohol use are also associated with the increased risk of ALD.[14, 20, 21] Genetic factors are also important in host susceptibility to ALD. Polymorphisms in the genes encoding NFκB subunits, interleukin (IL)-1β and IL-1 receptor antagonists, IL-2, IL-6, and IL-10 may modify ALD progression.[22] Genetic variation in components of lipopolysaccharide (LPS)-induced intracellular pathways, such as CD14 and toll-like receptor (TLR) 4, may also be associated with ALD.[23]

Variations in PNPLA3, which encodes patatin-like phospholipase domain-containing protein 3, strongly and reproducibly influence the progression of ALD.[24-26] To date, there are no large-scale, well-designed, genome-wide association Daporinad studies for ALD. Such a study will Selleck CHIR-99021 be vital in advancing the field of ALD and identifying new targets for therapy.

Steatosis is the first response of the liver to alcohol abuse. It is defined histologically as the deposition of fat in hepatocytes. Alcohol intake increases NADH/NAD+ in hepatocytes, thereby disrupting fatty acid oxidation and leading to steatosis development.[27] It also increases fatty acid and triglyceride synthesis, enhances hepatic influx of free fatty acids from adipose tissue and chylomicrons from the intestinal mucosa, increases hepatic lipogenesis, decreases lipolysis, and damages mitochondria and microtubules, resulting in accumulation of very-low-density lipoprotein (VLDL).[28-32] Alcohol upregulates lipogenic enzymes through upregulation of sterol regulatory element-binding protein 1c (SREBP-1c)[33] and downregulation of peroxisome proliferator-activated receptor (PPAR)-α.[34, 35] In addition, alcohol downregulates adenosine monophosphate-activated protein kinase (AMPK). AMPK inactivates acetyl-CoA carboxylase, which, through its effects on malonyl-CoA and carnitine palmitoyltransferase 1, leads to reduced fatty acid synthesis and increased fatty acid oxidation, promoting steatosis.[36, 37] Steatohepatitis is characterized by steatosis, a superimposed inflammatory infiltrate of predominantly polymorphonuclear leukocytes and hepatocellular damage.