Alcoholic liver disease

Fatty change, or steatosis, is the accumulation of fatty acids in liver cells. These 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.[6] 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 (CO
2) and water (H
2O).[7] 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, IL6 and IL8) 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.[4]

Cirrhosis is a late stage of serious liver disease marked by inflammation (swelling), fibrosis (cellular hardening) and damaged membranes preventing detoxification of chemicals in the body, ending in scarring and necrosis (cell death).[8] Between 10% to 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.[4] The production of oxidants derived from NADPH oxi- dase and/or cytochrome P-450 2E1 and the formation of acetaldehyde-protein adducts damage the cell membrane.[4] Symptoms include jaundice (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 to liver failure. Late complications of cirrhosis or liver failure include portal hypertension (high blood pressure in the portal 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 buildup of fluids in the tissues) and other complications, including hepatic encephalopathy and the hepatorenal syndrome. Cirrhosis can also result from other causes than alcohol abuse, such as viral hepatitis and heavy exposure to toxins other than alcohol. 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 with abstinence 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.

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.[10]

A 2006 Cochrane review did not find evidence sufficient for the use of androgenic anabolic steroids.[12] Corticosteroids are sometimes used; however, this is recommended only when severe liver inflammation is present.[11]

Silymarin has been investigated as a possible treatment, with ambiguous results.[13][14][15] One review claimed benefit for S-adenosyl methionine in disease models.[16]

The effects of anti-tumor necrosis factor medications such as infliximab and etanercept are unclear and possibly harmful.[17] Evidence is unclear for pentoxifylline.[11][18] Propylthiouracil may result in harm.[19]

Evidence does not support supplemental nutrition in liver disease.[20]

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.[21] 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.[22]