Алкогольная болезнь печени: патогенез, диагностика и проявления.

Alcoholic liver disease (ALD), also called alcohol related liver disease (ARLD), is a term that encompasses the liver manifestations of alcohol overconsumption, including fatty liver, alcoholic hepatitis, and chronic hepatitis with liver fibrosis or cirrhosis. It is the major cause of liver disease in Western countries, and is the leading cause of death from excessive drinking. Although steatosis (fatty liver disease) will develop in any individual who consumes a large quantity of alcoholic beverages over a long period of time, this process is transient and reversible. For patients with chronic hepatitis B, a strict adherence to abstinence is highly recommended.

Fatty change, or steatosis, is the accumulation of fatty acids in liver cells. This can be seen as fatty globules under the microscope. Alcoholism causes development of large fatty globules (macro vesicular steatosis) throughout the liver and can begin to occur after a few days of heavy drinking. Alcohol is metabolized by alcohol dehydrogenase (ADH) into acetaldehyde, then further metabolized by aldehyde dehydrogenase (ALDH) into acetic acid, which is finally oxidized into carbon dioxide and water This process generates NADH, and increases the NADH/NAD+ ratio. A higher NADH concentration induces fatty acid synthesis while a decreased NAD level results in decreased fatty acid oxidation. Subsequently, the higher levels of fatty acids signal the liver cells to compound it to glycerol to form triglycerides. These triglycerides accumulate, resulting in fatty liver.

Alcoholic hepatitis is characterized by the inflammation of hepatocytes. Between 10% and 35% of heavy drinkers develop alcoholic hepatitis (NIAAA, 1993). While development of hepatitis is not directly related to the dose of alcohol, some people seem more prone to this reaction than others. This is called alcoholic steato necrosis and the inflammation appears to predispose to liver fibrosis. Inflammatory cytokines (TNF alpha, IL 6 and IL 8) are thought to be essential in the initiation and perpetuation of liver injury and cytotoxic hepatomegaly by inducing apoptosis and severe hepatotoxicity. One possible mechanism for the increased activity of TNF α is the increased intestinal permeability due to liver disease. This facilitates the absorption of the gut produced endotoxin into the portal circulation. The Kupffer cells of the liver then phagocytose endotoxin, stimulating the release of TNF α. TNF α then triggers apoptotic pathways through the activation of caspases, resulting in cell death. Between 10% and 20% of heavy drinkers will develop cirrhosis of the liver (NIAAA, 1993). Acetaldehyde may be responsible for alcohol induced fibrosis by stimulating collagen deposition by hepatic stellate cells.

In people with alcoholic hepatitis, the serum aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio is greater than 2:1. AST and ALT levels are almost always less than 500. The elevated AST to ALT ratio is due to deficiency of pyridoxal phosphate, which is required in the ALT enzyme synthetic pathway. Furthermore, alcohol metabolite–induced injury of hepatic mitochondria results in AST isoenzyme release. Other laboratory findings include red blood cell macrocytosis (mean corpuscular volume > 100) and elevations of serum gamma glutamyl transferase (GGT), alkaline phosphatase, and bilirubin levels. Folate level is reduced in alcoholic patients due to decreased intestinal absorption, increased bone marrow requirement for folate in the presence of alcohol, and increased urinary loss. The magnitude of leukocytosis (white blood cell depletion) reflects severity of liver injury. Histologic features include Mallory bodies, giant mitochondria, hepatocyte necrosis, and neutrophil infiltration in the area around the veins. Mallory bodies, which are also present in other liver diseases, are condensations of cytokeratin components in the hepatocyte cytoplasm and do not contribute to liver injury. Up to 70% of patients with moderate to severe alcoholic hepatitis already have cirrhosis identifiable on biopsy examination at the time of diagnosis.

Not drinking further alcohol is the most important part of treatment. People with chronic HCV infection should abstain from any alcohol intake, due to the risk for rapid acceleration of liver disease. Corticosteroids are sometimes used; however, this is recommended only when severe liver inflammation is present. One review claimed benefit for S adenosyl methionine in disease models. The effects of anti tumor necrosis factor medications such as infliximab and etanercept are unclear and possibly harmful. Evidence is unclear for pentoxifylline. Propylthiouracil may result in harm. Evidence does not support supplemental nutrition in liver disease.

Although in rare cases liver cirrhosis is reversible, the disease process remains mostly irreversible. Liver transplantation remains the only definitive therapy. Today, survival after liver transplantation is similar for people with ALD and non ALD. The requirements for transplant listing are the same as those for other types of liver disease, except for a 6 month sobriety prerequisite along with psychiatric evaluation and rehabilitation assistance. Specific requirements vary among the transplant centers. Relapse to alcohol use after transplant listing results in delisting. Re listing is possible in many institutions, but only after 3–6 months of sobriety. There are limited data on transplant survival in patients transplanted for acute alcoholic hepatitis, but it is believed to be similar to that in nonacute ALD, non ALD, and alcoholic hepatitis with MDF less than 32.

The prognosis for people with ALD depends on the liver histology as well as cofactors, such as concomitant chronic viral hepatitis. Among patients with alcoholic hepatitis, progression to liver cirrhosis occurs at 10–20% per year, and 70% will eventually develop cirrhosis. Despite cessation of alcohol use, only 10% will have normalization of histology and serum liver enzyme levels. As previously noted, the MDF has been used to predict short term mortality (i. e., MDF ≥ 32 associated with spontaneous survival of 50–65% without corticosteroid therapy, and MDF < 32 associated with spontaneous survival of 90%). The Model for End Stage Liver Disease (MELD) score has also been found to have similar predictive accuracy in 30 day (MELD > 11) and 90 day (MELD > 21) mortality. Liver cirrhosis develops in 6–14% of those who consume more than 60–80 g of alcohol daily for men and more than 20 g daily for women. Even in those who drink more than 120 g daily, only 13.5% will experience a serious alcohol related liver injury. Nevertheless, alcohol related mortality was the third leading cause of death in 2003 in the United States. Worldwide mortality is estimated to be 150,000 per year.