Reviews and PerspectiveReviews in Basic and Clinical Gastroenterology and HepatologyAlcoholic Liver Disease: Pathogenesis and New Therapeutic Targets
Section snippets
Spectrum, Risk Factors, and Comorbidities
ALD presents as a broad spectrum of disorders, ranging from simple fatty liver to more severe forms of liver injury, including alcoholic hepatitis (AH), cirrhosis, and superimposed hepatocellular carcinoma (HCC) (Figure 1). Fatty liver, an early response to alcohol consumption, develops in most (more than 90%) heavy drinkers, with early-mild steatosis in zone 3 (perivenular) hepatocytes; it can also affect zone 2 and even zone 1 (periportal) hepatocytes when liver injury is more severe.
Alcoholic Fatty Liver (Steatosis)
Steatosis, the earliest response of the liver to alcohol abuse, is characterized by the accumulation of fat (mainly triglycerides, phospholipids, and cholesterol esters) in hepatocytes. Early studies indicated that alcohol consumption increases the ratio of reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide in hepatocytes, which disrupts mitochondrial β-oxidation of fatty acids and results in steatosis.24 Alcohol intake has also been shown to augment the supply
Conclusions
ALD is a major cause of advanced liver disease worldwide. Major advances in understanding its mechanisms of pathogenesis have been made at the experimental level using animal models. Translational studies, using human liver samples, have identified new therapeutic targets. However, translation of basic and translational research findings into new therapies has been modest. Future efforts should be directed toward identifying the main factors that promote disease in patients with moderate and
References (160)
- et al.
Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders
Lancet
(2009) - et al.
Alcohol and mitochondria: a dysfunctional relationship
Gastroenterology
(2002) - et al.
Advances in alcoholic liver disease
Best Pract Res Clin Gastroenterol
(2003) - et al.
Risk factors of fibrosis in alcohol-induced liver disease
Hepatology
(2002) - et al.
Excess weight risk factor for alcoholic liver disease
Hepatology
(1997) - et al.
Synergistic steatohepatitis by moderate obesity and alcohol in mice despite increased adiponectin and p-AMPK
J Hepatol
(2011) - et al.
Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease
J Hepatol
(2011) Alcohol and hepatitis virus interactions in liver pathologyComprehensive handbook of alcohol related pathology
- et al.
Effects of ethanol on lipid metabolism
J Lipid Res
(1979) - et al.
Ethanol induces fatty acid synthesis pathways by activation of sterol regulatory element-binding protein (SREBP)
J Biol Chem
(2002)
Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver
Cell Metab
Early growth response-1 transcription factor is essential for ethanol-induced fatty liver injury in mice
Gastroenterology
Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice
Gastroenterology
The role of AMP-activated protein kinase in the action of ethanol in the liver
Gastroenterology
Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury
Gastroenterology
Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model
J Hepatol
The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor alpha is inhibited by ethanol metabolismA novel mechanism for the development of ethanol-induced fatty liver
J Biol Chem
AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice
Cell Metab
Differential contributions of C3, C5, and decay-accelerating factor to ethanol-induced fatty liver in mice
Gastroenterology
Inducible nitric oxide synthase is required in alcohol-induced liver injury: studies with knockout mice
Gastroenterology
Functions of autophagy in hepatic and pancreatic physiology and disease
Gastroenterology
CYP2E1 enhances ethanol-induced lipid accumulation but impairs autophagy in HepG2 E47 cells
Biochem Biophys Res Commun
Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice
Gastroenterology
Chemokine levels in human liver homogenates: associations between GRO alpha and histopathological evidence of alcoholic hepatitis
Hepatology
Hepatic expression of CXC chemokines predicts portal hypertension and survival in patients with alcoholic hepatitis
Gastroenterology
Interleukin 8 response and oxidative stress in HepG2 cells treated with ethanol, acetaldehyde or lipopolysaccharide
Hepatol Res
Inhibition of proteasome function leads to NF-kappaB-independent IL-8 expression in human hepatocytes
Hepatology
Hepatic stellate cells primed with cytokines upregulate inflammation in response to peptidoglycan or lipoteichoic acid
Lab Invest
Lipid peroxidation contributes to immune reactions associated with alcoholic liver disease
Free Radic Biol Med
Differential inhibition of epidermal growth factor signaling pathways in rat hepatocytes by long-term ethanol treatment
Gastroenterology
Mechanisms of hepatic fibrogenesis
Gastroenterology
Alcohol induced hepatic fibrosis: role of acetaldehyde
Mol Aspects Med
Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners
Gastroenterology
Abrogation of the antifibrotic effects of natural killer cells/interferon-gamma contributes to alcohol acceleration of liver fibrosis
Gastroenterology
Hepatocellular carcinoma: epidemiology and molecular carcinogenesis
Gastroenterology
Alcohol and hepatocellular carcinoma
Gastroenterology
Liver cirrhosis mortality in the United States, 1970–2007 surveillance report #88NIAAA homepage 2010
Effects of prolonged ethanol intake: production of fatty liver despite adequate diets
J Clin Invest
Susceptibility to alcohol-related liver injury
Alcohol Alcohol Suppl
The role of gut-derived bacterial toxins and free radicals in alcohol-induced liver injury
J Gastroenterol Hepatol
Current concepts in the pathogenesis of alcoholic liver injury
FASEB J
Alcoholic liver disease
Curr Opin Gastroenterol
Alcoholic hepatitisNatural history and evaluation of prednisolone therapy
Ann Intern Med
Alcoholic liver disease
Hepatology
“Second hit” models of alcoholic liver disease
Semin Liver Dis
Genetics of alcoholic liver disease and nonalcoholic fatty liver disease
Semin Liver Dis
Drinking patterns, dependency and life-time drinking history in alcohol-related liver disease
Addiction
Variant in PNPLA3 is associated with alcoholic liver disease
Nat Genet
Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians
Hepatology
Patatin-like phospholipase domain-containing 3/adiponutrin deficiency in mice is not associated with fatty liver disease
Hepatology
Cited by (0)
Conflicts of interest The authors disclose no conflicts.