| Alcoholic liver disease | |
|---|---|
| Other names | Alcohol-related liver disease |
 | |
| Microscopy ofliver showing fatty change, cell necrosis,Mallory bodies | |
| Specialty | Gastroenterology |
Alcoholic liver disease (ALD), also calledalcohol-related liver disease (ARLD), is a term that encompasses theliver manifestations ofalcohol overconsumption, includingfatty liver,alcoholic hepatitis, and chronichepatitis with liverfibrosis orcirrhosis.[1]
It is the major cause ofliver disease in Western countries, and is the leading cause of death from excessive drinking.[2][3] Althoughsteatosis (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.[1] More than 90% of all heavy drinkers developfatty liver whilst about 25% develop the more severealcoholic hepatitis, and 15%liver cirrhosis.[4]
For patients with chronichepatitis B, a strict adherence to abstinence from alcohol is highly recommended.[5]
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As of 2010, known risk factors of ALD are:
The mechanism of ALD is not completely understood. 80% of alcohol passes through the liver to be detoxified. Chronic consumption of alcohol results in the secretion of pro-inflammatorycytokines (TNF-alpha,interleukin 6 andinterleukin 8),oxidative stress,lipid peroxidation, andacetaldehydetoxicity. These factors causeinflammation,apoptosis and eventuallyfibrosis of liver cells. Why this occurs in only a few individuals is still unclear. Additionally, the liver has tremendous capacity to regenerate and even when 75% ofhepatocytes are dead, it continues to function as normal.[8][failed verification]
Fatty change, orsteatosis, is the accumulation of fatty acids inliver 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.[9] Alcohol is metabolized byalcohol dehydrogenase (ADH) intoacetaldehyde, then further metabolized byaldehyde dehydrogenase (ALDH) intoacetic acid, which is finally oxidized intocarbon dioxide (CO2) and water (H2O).[10] This process generatesNADH, and increases the NADH/NAD+ ratio. A higher NADH concentration inducesfatty 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 toglycerol to formtriglycerides. These triglycerides accumulate, resulting in fatty liver.[citation needed]
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 alcoholicsteato-necrosis and the inflammation appears to predispose to liverfibrosis. 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.[7]
Cirrhosis is a late stage of serious liver disease marked byinflammation (swelling),fibrosis (cellular hardening) and damaged membranes preventing detoxification of chemicals in the body, ending in scarring andnecrosis (cell death).[11] Between 10% and 20% of heavy drinkers will develop cirrhosis of the liver (NIAAA, 1993).Acetaldehyde may be responsible for alcohol-induced fibrosis by stimulatingcollagen deposition byhepatic stellate cells.[7] The production of oxidants derived from NADPH oxi- dase and/orcytochrome P-450 2E1 and the formation of acetaldehyde-protein adducts damage thecell membrane.[7]Symptoms includejaundice (yellowing), liver enlargement, and pain and tenderness from the structural changes in damaged liver architecture. Without total abstinence from alcohol use, cirrhosis will eventually lead toliver failure. Late complications of cirrhosis or liver failure includeportal hypertension (highblood pressure in theportal vein due to the increased flow resistance through the damaged liver),coagulation disorders (due to impaired production of coagulation factors),ascites (heavy abdominal swelling due to a buildup of fluids in the tissues) and other complications, includinghepatic encephalopathy and thehepatorenal syndrome.Cirrhosis can also result from other causes than hazardous alcohol use, such asviral hepatitis and heavy exposure totoxins other thanalcohol. The late stages of cirrhosis may look similar medically, regardless of cause. This phenomenon is termed the "final common pathway" for the disease.Fatty change and alcoholic hepatitis withabstinence can be reversible. The later stages of fibrosis and cirrhosis tend to be irreversible, but can usually be contained with abstinence for long periods of time.[citation needed]
In the early stages, patients with ALD exhibit subtle and often no abnormal physical findings. It is usually not until development of advanced liver disease that stigmata of chronic liver disease become apparent. Early ALD is usually discovered during routine health examinations when liver enzyme levels are found to be elevated. These usually reflect alcoholic hepatic steatosis. Microvesicular and macrovesicular steatosis with inflammation are seen in liver biopsy specimens. These histologic features of ALD are indistinguishable from those of nonalcoholic fatty liver disease. Steatosis usually resolves after discontinuation of alcohol use. Continuation of alcohol use will result in a higher risk of progression of liver disease and cirrhosis. In patients with acute alcoholic hepatitis, clinical manifestations include fever, jaundice,hepatomegaly, and possible hepatic decompensation with hepatic encephalopathy, variceal bleeding, and ascites accumulation. Tender hepatomegaly may be present, but abdominal pain is unusual. Occasionally, the patient may be asymptomatic.[12]
In people with alcoholic hepatitis, the serumaspartate aminotransferase (AST) toalanine 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 ofpyridoxal phosphate, which is required in the ALT enzyme synthetic pathway. Furthermore, alcohol metabolite–induced injury of hepaticmitochondria results in AST isoenzyme release. Other laboratory findings include red blood cellmacrocytosis (mean corpuscular volume > 100) and elevations of serumgamma-glutamyl transferase (GGT),alkaline phosphatase, andbilirubin 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 ofleukocytopenia (white blood cell depletion) reflects severity of liver injury. Histologic features includeMallory bodies, giant mitochondria, hepatocytenecrosis, andneutrophil 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.[13]
Not drinking further alcohol is the most important part of treatment.[14] People with chronic HCV infection should abstain from any alcohol intake, due to the risk for rapid acceleration of liver disease.[13]
A 2006 Cochrane review did not find evidence sufficient for the use ofandrogenic anabolic steroids.[15] Corticosteroids are sometimes used; however, this is recommended only when severe liver inflammation is present.[14]
Silymarin has been investigated as a possible treatment, with ambiguous results.[16][17][18] One review claimed benefit forS-adenosyl methionine in disease models.[19]
The effects of anti-tumor necrosis factor medications such asinfliximab andetanercept are unclear and possibly harmful.[20] Evidence is unclear forpentoxifylline.[14][21]Propylthiouracil may result in harm.[22]
Evidence does not support supplemental nutrition in liver disease.[23]
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.[24][clarification needed] 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 withMDF less than 32.[25]
The prognosis for people with ALD depends on the liverhistology as well as cofactors, such as concomitant chronic viral hepatitis. Among patients withalcoholic hepatitis, progression toliver 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.[26] As previously noted, theMDF 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.[27] Alcoholic liver disease can lead to the development ofexocrine pancreatic insufficiency.[28]
