Academic journal article Alcohol Research

Focus On: Alcohol and the Liver

Academic journal article Alcohol Research

Focus On: Alcohol and the Liver

Article excerpt

Alcoholic liver disease (ALD)--and particularly cirrhosis--has long been one of the most prevalent and devastating conditions caused by alcohol consumption and is one of the leading causes of alcohol-related death. Liver cirrhosis is the 12th leading cause of death in the United States. The age-adjusted death rates attributed to ALD are higher in high-alcohol--consuming countries such as Spain and France and lower in countries with low alcohol consumption, with the United States ranking in between.

ALD encompasses a varied clinical and histological spectrum. On one end of the spectrum is fatty liver (steatosis), which is reversible with abstinence, and the more severe alcoholic hepatitis and fibrosis, which may or may not improve with abstinence. On the other end of the spectrum are cirrhosis (Laennec's cirrhosis) and end-stage liver disease, conditions that typically are irreversible and have a poor prognosis. In addition, continued consumption of alcohol combined with obesity can further increase a person's risk of cancer (hepatocellular carcinoma).

Steatosis may occur in 90 percent of individuals who consume more than 60 g/d of alcohol (or about five drinks per day) (Crabb 1999). In many cases, there are no clinical symptoms except for an enlarged liver (i.e., hepatomegaly), and steatosis can be reversed if alcohol consumption is stopped or significantly reduced (Mann et al. 2003). Histologically, steatosis is evidenced by an accumulation of fat molecules (i.e., lipids) in both small (i.e., microvesicular) and large (i.e., macrovesicular) droplets within liver cells.

Some biopsies from people with steatosis also show inflammatory changes, an early indicator of more serious liver disease. For example, alcoholic hepatitis is steatosis accompanied by inflammation, neutrophilic infiltration, hepatocyte necrosis, and Mallory bodies. Approximately 35 to 40 percent of alcoholic patients may progress from steatosis to fibrosis, characterized by increased deposition of extracellular matrix proteins, such as collagen, in the liver along with inflammation and, eventually, cirrhosis. Diagnosing the stage of disease is important for management and treatment of ALD. For more information, readers are referred to recently published guidelines using a data-supported approach, which address all three aspects of ALD--diagnosis, management, and therapy (O'Shea et al. 2010).

Pathophysiology: Concepts Emerging From ALD Research

The pathogenesis of ALD is multifactorial (Lieber 2004; Tsukamoto 2001). Alcohol and its toxic metabolites can damage key liver cells (primarily hepatocytes and parenchymal cells) through the excessive generation of molecules called free radicals. Particularly important are the actions of oxygen-containing free radicals known as reactive oxygen species (ROS). ROS can modify the function of essential signaling pathways in the cells, including those regulating lipid or glucose metabolism; furthermore, ROS can directly modulate proteins and DNA. Excessive levels of ROS within a cell and/or the lack of molecules that can eliminate ROS (i.e., antioxidants) lead to a state of oxidative stress.

In addition to its direct effect on the liver, alcohol can increase the "leakiness" of the intestine cell wall, allowing a harmful component of Gram-negative bacteria called endotoxin to pass more readily into the blood. The body responds to this increase in endotoxin levels by launching a coordinated immune response, marked by activation of immune cells residing in the liver (i.e., Kupffer cells). Kupffer cells are macrophages whose main role--removing bacterial and foreign proteins from the blood--is essential to the liver's primary function of cleansing the blood of foreign materials and toxic substances. When activated, Kupffer cells secrete a variety of cytokines, including tumor necrosis factor (TNF)-a and several types of interleukins (ILs). All these molecules act as inflammatory cytokines, and, as such, aid the body in fighting against invading pathogens and tissue injury and assisting in the healing process. …

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