Date Published: , 2017
Publisher: National Institute on Alcohol Abuse and Alcoholism
Author(s): Natalia A. Osna, Terrence M. Donohue, Kusum K. Kharbanda.
Excessive alcohol consumption is a global healthcare problem. The liver sustains the greatest degree of tissue injury by heavy drinking because it is the primary site of ethanol metabolism. Chronic and excessive alcohol consumption produces a wide spectrum of hepatic lesions, the most characteristic of which are steatosis, hepatitis, and fibrosis/cirrhosis. Steatosis is the earliest response to heavy drinking and is characterized by the deposition of fat in hepatocytes. Steatosis can progress to steatohepatitis, which is a more severe, inflammatory type of liver injury. This stage of liver disease can lead to the development of fibrosis, during which there is excessive deposition of extracellular matrix proteins. The fibrotic response begins with active pericellular fibrosis, which may progress to cirrhosis, characterized by excessive liver scarring, vascular alterations, and eventual liver failure. Among problem drinkers, about 35 percent develop advanced liver disease because a number of disease modifiers exacerbate, slow, or prevent alcoholic liver disease progression. There are still no FDA-approved pharmacological or nutritional therapies for treating patients with alcoholic liver disease. Cessation of drinking (i.e., abstinence) is an integral part of therapy. Liver transplantation remains the life-saving strategy for patients with end-stage alcoholic liver disease.
Beverage alcohol (i.e., ethanol) is chiefly metabolized in the main parenchymal cells of the liver (i.e., hepatocytes) that make up about 70 percent of the liver mass (Jones 1996). These cells express the highest levels of the major ethanol-oxidizing enzymes, alcohol dehydrogenase (ADH), which is located in the cytosol, and cytochrome P450 2E1 (CYP2E1), which resides in the smooth endoplasmic reticulum (ER) (figure 1). Hepatocytes also express very high levels of catalase, an enzyme that inhabits peroxisomes. Catalase normally carries out the detoxification of hydrogen peroxide (H2O2) to water and oxygen. However, when ethanol is present, catalase has an accessory role in ethanol metabolism by using H2O2 to oxidize ethanol to acetaldehyde. Ethanol oxidation by catalase is a relatively minor pathway in the liver, but has a larger ethanol-oxidizing function in the brain (Aragon et al. 1992).
Heavy ethanol consumption produces a wide spectrum of hepatic lesions, the most characteristic being fatty liver (i.e., steatosis), hepatitis, and fibrosis/cirrhosis (see figure 2). Steatosis is the earliest, most common response that develops in more than 90 percent of problem drinkers who consume 4 to 5 standard drinks per day over decades (Ishak et al. 1991; Lieber 2004). (A standard drink is defined as the amount of alcoholic beverage that contains approximately 0.5 fluid ounces, or about 14 grams, of pure alcohol [figure 3]). However, steatosis also develops after binge drinking, defined as the consumption of 4 to 5 drinks in 2 hours or less. Steatosis was formerly considered a benign consequence of alcohol abuse. It is characterized by the deposition of fat, seen microscopically as lipid droplets, initially in the hepatocytes that surround the liver’s central vein (i.e., perivenular hepatocytes), then progressing to mid-lobular hepatocytes, and finally to the hepatocytes that surround the hepatic portal vein (i.e., periportal hepatocytes). If the affected individual ceases drinking, steatosis is a reversible condition with a good prognosis. However, patients with chronic steatosis are more susceptible to fibrotic liver disease (Teli et al. 1995), because the presence of fat likely represents a greater risk for lipid peroxidation and oxidative damage.
As the preceding section on ethanol metabolism stated, ethanol and acetaldehyde oxidations generate higher levels of NADH, which alters the cellular redox potential and enhances lipid synthesis (i.e., lipogenesis). However, ethanol-induced redox change alone does not fully explain why the liver rapidly accumulates fat. More recent studies now strongly support the notion that ethanol-induced steatosis is multifactorial as discussed below (see figure 4).
Alcoholic hepatitis occurs in about 30 to 40 percent of individuals reporting chronic alcohol abuse. It represents the most serious form of ALD and is associated with high short-term mortality. Ballooning degeneration of hepatocytes containing Mallory-Denk bodies, infiltrating neutrophils, and fibrosis are characteristic pathologic findings indicative of hepatitis (Lefkowitch 2005). Central to the progression of alcoholic hepatitis are resident and infiltrating immune cells called macrophages, which have important roles in inducing liver inflammation. KCs, the resident macrophages in the liver, represent up to 15 percent of liver cells and 50 percent of all macrophages in the body. They reside in the liver sinusoids and provide the first line of defense, serving as potent innate immune cells. In contrast, infiltrating macrophages are recruited as immature cells from the bone marrow, and their differentiation into macrophages in the liver only occurs during inflammation.
HSCs are the key players in the development of fibrosis. These cells normally reside in the space of Disse as quiescent, lipid (retinyl-ester)-storing cells (figure 8). Following hepatic injury, HSCs undergo a complex activation process (figure 9) and become the principal source for the increased and irregular deposition of extracellular-matrix components that characterize fibrosis. Activated HSCs also contribute to the inflammatory response, coordinating the recruitment and stimulation of leukocytes by releasing chemokines and proinflammatory cytokines as well as expressing adhesion molecules. The leukocytes, in turn, not only attack and destroy hepatocytes, but also activate quiescent and activated HSCs, thereby exacerbating the fibrogenic response (Friedman 2008).
Among problem drinkers, only about 35 percent develop advanced liver disease. This is because modifiers, as listed below, exist that exacerbate, slow, or prevent ALD disease progression.
There are no FDA-approved therapies for treating patients with ALD. The following therapies currently are used for optimal ALD management.