The human body, the liver, performs many tasks, such as processing food into energy, removing harmful substances from the blood, and reserving iron and vitamins for future use. Importantly, the liver breaks down alcohol molecules and removes them from the body. Excess alcohol can damage or destroy liver cells if the person drinks more than the liver can process (30 grams or more per day).1
Alcoholic liver disease (ALD) represents a broad spectrum of disorders, ranging from simple fatty liver to more severe forms of liver injury, including alcoholic hepatitis, cirrhosis, fibrosis, and superimposed hepatocellular carcinoma. Interestingly, while more than 90% of heavy drinkers develop fatty liver, only 35% of this population develops more severe forms of ALD. Unfortunately, among those who develop ALD, symptoms often present only after severe, life-threatening liver disease has developed.1
There are three main types of alcohol-related liver disease: alcoholic fatty liver disease, alcoholic hepatitis, and alcoholic cirrhosis. The last is the most serious form of the liver diseases. Many heavy drinkers will progress from fatty liver disease to alcoholic hepatitis to alcoholic cirrhosis over time. However, some heavy drinkers may develop cirrhosis without first acquiring alcoholic hepatitis. Since susceptibility to the toxic effects of alcohol may vary by many factors including age, gender, genetics, and coexistent medical conditions, individuals should discuss alcohol use with their physician.2
Complications from alcohol-related liver disease usually occur after years of heavy drinking, and overconsumption of alcohol is the major cause of liver disease in Western countries. Although steatosis (fatty liver) 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.2
In this article, we briefly review signs and symptoms, pathophysiology, diagnosis, and treatment of this serious medical problem.
SIGNS AND SYMPTOMS
The signs and symptoms of ALD differ depending on the stage of liver damage and the severity of the disease.3
Alcoholic Fatty Liver Disease (Steatosis)
People with alcoholic fatty liver disease are typically asymptomatic. ALD is a major cause of chronic liver disease worldwide. Alcoholic-related liver deaths account for up to 48% of cirrhosis-associated deaths in the United States. Research on ALD has been rapidly growing since it was reported that alcohol is a true hepatotoxin that causes hepatocellular damage.3
Alcoholic fatty liver disease results from the deposit of fat (mainly triglycerides, phospholipids, and cholesterol esters) in liver cells, and it is the earliest stage of ALD. There are usually no symptoms. If symptoms do occur, they may include fatigue, weakness, and discomfort in the upper-right abdomen. Liver enzymes may be elevated, but tests of liver function are often normal. Many heavy drinkers have fatty liver disease. Alcoholic fatty liver disease may be reversible with abstinence from alcohol.3
Alcoholic hepatitis (AH) is a syndrome characterized by inflammation of the liver due to hepatocellular injury and is characterized by fat deposition in liver cells, inflammation, and mild scarring of the liver. AH develops in patients with steatosis and is usually associated with progressive fibrosis. Symptoms may include loss of appetite, nausea, vomiting, abdominal pain, fever, and jaundice. Liver enzymes are typically elevated, and tests of liver function may be abnormal. Up to 35% of heavy drinkers develop alcoholic hepatitis, and of these 55% already have cirrhosis.3
AH can be mild or severe. Mild AH may be reversed with abstinence. Severe AH may occur suddenly and lead to serious complications, including liver failure and death.
Alcoholic cirrhosis, the most advanced type of alcohol-induced liver injury, is characterized by severe scarring and disruption of the normal structure of the liver in which hard scar tissue replaces soft, healthy tissue. Between 10% and 20% of heavy drinkers develop cirrhosis. Symptoms of cirrhosis may be similar to those of severe AH. Patients who develop cirrhosis may report jaundice, weakness, peripheral edema, abdominal distention, or symptoms of GI bleeding such as hematemesis or melena. Cirrhosis is the most advanced type of alcohol-related liver disease and is not reversible with abstinence. However, abstinence may improve the symptoms of liver disease and prevent further damage.3
Ethanol metabolism–associated oxidative stress, glutathione depletion, abnormal methionine metabolism, malnutrition, and ethanol-mediated induction of gut endotoxins have important roles in the pathogenesis of ALD. Alcohol intake has also been shown to augment the supply of lipids to the liver from the small intestine, increasing mobilization of fatty acids from adipose tissue and uptake of fatty acids by the liver. This will subsequently prime and sensitize hepatocytes to injury. In hepatocytes, ethanol is primarily metabolized into acetaldehyde (a carcinogen with mutagenic properties) by alcohol dehydrogenase in the cytosol, cytochrome P450 in microsomes, and catalase in peroxisomes.4
Acetaldehyde is rapidly metabolized into acetate by aldehyde dehydrogenase in the mitochondria. While acetaldehyde is highly toxic to hepatocytes, acetate has no direct hepatotoxicity, but it is believed to regulate the inflammatory response in patients with AH via the up-regulation of proinflammatory cytokines in macrophages.4
It is reported that the phenomenon of autophagy (a normal physiological process in the body that deals with destruction of cells in the body) has an important role in removing lipid droplets in hepatocytes. Long-term alcohol consumption inhibits autophagy, while short-term alcohol exposure activates autophagy by generating reactive-oxygen species during the early stages of alcohol liver injury. The inhibitory and stimulatory effects of ethanol on autophagy require further studies.4
Hepatocyte apoptosis is an important pathologic feature of human ALD. Apoptosis results from multiple mechanisms, including ethanol-mediated hepatotoxicity, induction of oxidative stress, and inhibition of survival genes (c-Met).4
Physical examination findings in patients with ALD range from a normal physical examination to evidence of cirrhosis with hepatic decompensation. Patients with steatosis may have a normal examination or hepatomegaly. Patients with cirrhosis may have spider angioedema, peripheral edema, or hepatic encephalopathy.5
There are no modern diagnostic tools to assess individual susceptibility to the development of ALD, and the pathogenesis of ALD in humans is incompletely understood. As a consequence, no new drugs for ALD have been successfully developed since the early 1970s, at which time the use of corticosteroids was proposed for the treatment of severe AH. The poor understanding of ALD has resulted from the lack of experimental models of advanced ALD and from difficulties in performing clinical trials in patients with active addiction.3 As a result, there is an urgent need to develop new pathophysiology-oriented therapies.
There are several characteristic laboratory abnormalities in patients with ALD, but none are diagnostic. The classic finding is moderately elevated transaminases, with an aspartate aminotransferase to alanine aminotransferase ratio >1 and often >2. Often, the gamma-glutamyl transpeptidase is elevated in patients with ALD. Other laboratory tests include serum albumin level, coagulation studies, hepatitis B surface antigen, antibodies to hepatitis C virus, and liver biopsy.6
Despite the profound economic and health impact of ALD, little progress has been made in the management of patients with this severe clinical condition. Patients with ALD are most commonly treated with approaches to eliminate alcohol intake; continued alcohol ingestion is the single most important risk factor for progression of the disease. Referral to rehabilitation programs, in combination with family support, is usually necessary. Some patients also require specific pharmacologic treatment.1,2
Disulfiram, an irreversible inhibitor of alcohol dehydrogenase, is frequently prescribed to treat alcoholism, but it is not recommended for patients with advance ALD because of potential severe hepatotoxicity. Anticraving drugs (e.g., acamprosate) are effective at preventing relapses, but some of them are hepatotoxic.3
The drug Baclofen has recently been found to be effective in maintaining abstinence and is safe even for cirrhotic patients. The drug naltrexone (an opioid antagonist) has been shown to reduce relapse with modest efficacy.3,7
There are no approved antifibrotic drugs to prevent disease progression in patients with modest ALD. The extent of liver fibrosis can be estimated by liver biopsy analysis or measurement of serum markers.3
Patients with severe AH could be admitted to an ICU. The airway should be protected in patients with acute alcoholic intoxication, and the use of benzodiazepines is contraindicated in these patients. Due to the potential risk of encephalopathy among these patients, the use of B-complex vitamins is often necessary. Patients with AH are predisposed to develop severe infections, and early use of empiric antibiotics is advised.3,8
The use of steroids in AH is controversial based on individual and meta-analysis studies. Nevertheless, The American Association for the Study of Liver Diseases practice guidelines recommend the use of steroids for patients with severe AH due to hepatic encephalopathy. During therapy, patients must be monitored for the evidence of infection due to corticosteroid treatment. Infection can occur in almost 25% of patients during therapy and is associated with a poor prognosis. Severe acute AH is associated with significant lymphocyte corticosteroid insensitivity, which can be overcome by theophylline administration. This drug improves the efficacy of corticosteroids in treating AH.8
In patients who cannot use steroids, pentoxifylline is given. This drug is a phosphodiesterase inhibitor that blocks the transcription of TNF-alfa to decrease serum levels of the gene product, and it has been shown to reduce mortality in patients with severe AH due to hepatorenal syndrome. However, pentoxifylline was not effective as rescue therapy for patients who did not respond to treatment with corticosteroids.8
Nutrition therapy is also important. Alcoholic patients often experience protein calorie malnutrition, which can cause bacterial infections. Nutrition support in AH improves liver function and might increase survival times based on short-term follow-up studies. Androgen corticosteroids have been used in attempts to improve the nutritional status of patients with AH.9
S-Adenosylmethionine (SAMe) is a methyl donor that has been shown to protect liver injury via multiple mechanisms, such as antioxidant functions, mitochondrial function, and down regulation of TNF-alfa. While an early study showed that SAMe as a supplemental agent may significantly reduce mortality and the need for liver transplantation in ALD, some other scientists believe more studies are needed to establish its pharmacologic effects.3,9
Since ALD is associated with increased levels of oxidative stress, a number of antioxidants (such as vitamin E and silymarin) have been used to improve the survival times of patients with AH, but no potential benefit was observed compared with controls.3
Liver transplantation has been used in patients with decompensated ALD as the last resort. Outcomes are equal to or better than those obtained from end-stage liver disease from other causes. As a result, several liver transplant centers have proposed that this be a rescue option for patients with severe AH who do not respond to medical therapy and are unlikely to survive.9
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