Initial stages of ALD may be asymptomatic apart from hepatomegaly and slightly elevated liver function tests [6]. In contrast, alcoholic hepatitis almost always presents with symptoms that may range from mild to severe and life-threatening [4]. Fever, fatigue, jaundice, nausea, pain in the right upper quadrant, weight loss and hepatomegaly are usually seen [6], while ascites, variceal bleeding and encephalopathy are encountered in more severe forms. Signs of liver failure, including spider nevi and bleeding, together with impaired synthetic function of the liver may be observed in this stage [11]. Liver cirrhosis may start asymptomatically, but eventually, severe injury leads to portal hypertension, hepatosplenomegaly, upper gastrointestinal bleeding, ascites, esophageal varices and Wernicke-Korsakoff syndrome in some cases [4]. Renal failure due to reduced renal blood flow, as a part of hepatorenal syndrome may develop, together with various metabolic changes that can be fatal if left untreated.

Initial suspicion toward ALD can be made through patient history that may reveal heavy alcohol consumption, but patients may not always reveal such information, in which case friends and family should be asked as well. The majority of cases present in advanced stages of the disease, which can be concluded by observations during physical examination, such as hepatomegaly, jaundice, ascites and in severe cases, altered consciousness as a result of encephalopathy [4]. To confirm ALD, liver function tests that include liver transaminases (alanine aminotransferase and aspartate aminotransferase, or ALT and AST), gamma-glutamyl transferase (GGT), together with coagulation parameters and albumin. It is important to note that AST and ALT levels are not markedly elevated (< 300 IU/L) and the AST to ALT ratio is ≥ 2, as ALT is low due to deficiency of vitamin B6 as a result of ethanol effects on the liver [4]. A definite diagnosis, however, can be made by biopsy and subsequent histopathological examination that shows various changes in hepatocytes depending on the stage of illness.

Early initiation of absolute cessation of alcohol intake is pivotal in management of ALD, as even marked pathological changes may regress with total abstinence [6]. This method directly correlates with longer survival rates, while adjunctive therapy with pharmacological agents that promote abstinence such as naltrexone, an opioid antagonists ot acamprosate (GABA inhibitor) have shown some benefit [4]. Because patients are often in poor general condition at the time of diagnosis, supportive care is equally important in achieving normal patient status. Restoration of normal body weight, administration of vitamin B complex, including B6 and B1 and diazepam during the period of alcohol withdrawal is important. B1 is known as thiamine, and its deficiency is the main factor in development of Wernicke-Korsakoff syndrome. Glucocorticoids and various antioxidants (pentoxifylline, N-acetyl cysteine and anti-TNF agents) are also being used in therapy, but in severe cases where significant irreversible liver damage has occurred, transplantation may be necessary [12].

The severity of liver damage directly influences patient outcomes. Approximately 90-100% of alcohol abusers develop hepatic steatosis [8], but it may completely regress with rigorous abstinence in a matter of weeks. On the other hand, 10-35% of individuals progress to alcoholic hepatitis and severe forms of this stage have mortality rates of up to 50% if untreated [6]. Finally, 8-20% of cases eventually result in liver cirrhosis, which has a poor overall prognosis [8]. When compensatory cirrhosis is present and persistent abstinence is achieved, 5-year survival rates reach up to 90%, whereas failed abstinence therapy lowers rates to 70% [2]. Moreover, liver cirrhosis is a significant risk factor for hepatocellular carcinoma (HCC), especially if concomitant hepatitis C infection is present, which increases the risk 20-fold [8]. Because early stages of liver damage can be reversed, it is essential to make the diagnosis in early stages.

Prolonged abuse of significant amounts of alcohol is the cause of ALD. Excessive alcohol intake facilitates upregulation of all metabolic pathways and consequent release of numerous ROS, including hydrogen peroxide, superoxide and hydroxyl radical [7]. Approximately 30 g of alcohol is considered a "safe dose", which corresponds to two 8-oz glasses of wine or 5-6 12-oz glasses of beer [3] [4], but patients often consume much higher daily doses. Because only 10-35% of heavy drinkers progress to ALD, however, other factors are thought to play a role in the development of this disease [4]. Genetic polymorphisms of enzymes responsible for alcohol degradation, obesity, concomitant hepatitis C infection, smoking and familial factors are shown to be important in the pathogenesis of ALD [4] [8].

Epidemiology studies across the world suggest that ALD, together with hepatitis C, is the most common cause of liver disease, especially in the Western World [9]. In 2007, almost 30,000 deaths from liver cirrhosis occurred in the United States, of which almost 50% were due to alcohol abuse [1], while similar data are obtained in Germany, where 50% of 18,000 deaths due to chronic liver disease are attributed to ALD [9]. The most obvious risk factor heavy alcohol abuse, but substantially increased rates of ALD and liver cirrhosis are seen in individuals who consume > 80 g/day for > 10 years [4]. Moreover, a 50% chance of developing irreversible liver disease is established in those who intake > 230 g/day for > 20 years [4]. In general, guidelines suggest that 10-12 year consumption of 40-80 g/day for males and 20-40 g/day for females is enough to cause ALD [9]. Although this condition is more commonly encountered in males, females are much more likely to develop ALD due to their increased susceptibility to ethanol toxicity [2]. Additional risk factors include genetic polymorphisms of CYP2E1 and ADH, but also ethnicity, as prevalence rates are shown to be higher in African Americans and Hispanics [2].

The pathogenesis model of ALD is complex and starts with absorption of alcohol through the gastrointestinal tract, mainly in the small intestine. Normally, metabolism of ethanol starts with activation of ADH located in the cytoplasm of hepatocytes, which converts ethanol into acetaldehyde, a process that requires conversion of nicotinamide-adenine dinucleotide (NAD) to NADH+, a more reactive substance. Acetaldehyde is then converted to acetate in mitochondria by acetaldehyde dehydrogenase (ALDH), which also requires formation of NADH+ [10]. In the setting of heavy alcohol intake, the ADH-mediated ethanol degradation is not sufficient to metabolize ingested quantities and calls for activation of alternative pathways. The microsomal ethanol oxidative system (MEOS) attempts to degrade ethanol via upregulation of CYP2E1 in the liver, but as a cost, it generates ROS and causes marked oxidative stress [10]. Consequently, free radicals exert deleterious effects on liver hepatocytes, including lipid peroxidation and cell membrane damage, deficiency of vitamins and antioxidants, as well as accumulation of proinflammatory products and leukocytes [4]. Tumor necrosis factor-α (TNF-α) is shown to play a pivotal role in liver injury as a result of alcohol abuse and it is secreted in Kupffer cells [3]. Disruption of normal microbial flora and increased endotoxin production by bacteria is also shown to occur [3]. As consumption of alcohol continues over time, accumulation of lipids in hepatocytes followed by diffuse inflammation and fibrosis develops. The end-stage of ALD is liver cirrhosis, in which extensive irreversible fibrosis of the liver parenchyma occurs and disrupts normal cellular architecture [4].

Adequate changes in alcohol intake and support of individuals with alcohol abuse issues should be taken seriously, as they are of crucial importance. Various forms of rehabilitation and support groups may be useful as well, but identification of heavy drinking in its initial stages is the single most important preventive strategy. Studies have established that only 50% of heavy alcohol abusers are recognized by their physicians, whereas 25% actively seek medical care [8], which is why various physician guidelines have been proposed in order to facilitate higher identification rates. Direct questioning regarding daily intake, the CAGE questionnaire (need to cut down, annoyed by criticism, guilty about drinking, need for an eye-opener in the morning) and several other inquiries are recommended for use during patient interviews [8]. Since certain studies have established that up to 70% of drinkers relapse after one year, the use of pharmacological agents such as acamprosate and naltrexone have shown mixed results, but acamprosate seems to substantially reduce the risk of relapse [6].

Severe and prolonged alcohol abuse can lead to various forms of alcoholic liver disease (ALD), one of the leading causes of liver failure in the Western world [1]. According to various epidemiological studies, almost 30,000 individuals die every year from liver cirrhosis in the United States, with almost half being attributed to alcohol abuse, and previous decades have shown increased numbers of cases worldwide [1] [2]. Although the single most important factor for ALD is excessive alcohol consumption, several other factors are implicated in this disease, including genetic, dietary and presence of additional comorbidities (for ex. hepatitis C). Despite the fact that ALD is more frequently encountered in men (an approximate 2:1 ratio is observed), women are more susceptible to alcohol-induced changes due to their lower capacity for metabolism of ethanol [3]. Under physiological conditions, alcohol cannot be stored in the body and is metabolized via three pathways upon its absorption from the small intestine (and from the stomach in a smaller percentage). Liver hepatocytes contain alcohol dehydrogenase (ADH) in their cytoplasm, which converts ethanol to acetaldehyde [3]. Formation of acetate follows, as a result of acetaldehyde oxidation mediated by acetaldehyde dehydrogenase (ALDH) in the mitochondria [4]. This pathway, however, has a limited capacity for ethanol uptake and the microsomal ethanol oxidizing system (MEOS) in the endoplasmic reticulum of hepatocytes is activated in the setting of very high alcohol intake. Through cytochrome P2E1 (CYP2E1), this pathway aids in further degradation of ethanol, but is often insufficiently effective in chronic abuse. Throughout this entire process, abundant formation of free radicals occurs, which is the main mechanism of damage seen in ALD. Proinflammatory cytokines, alterations in normal microbial flora and release of bacterial endotoxins, as well as genetic polymorphisms in liver enzymes are thought to be additional culprits in liver injury [3] [4]. Three stages of ALD are described. Firstly, hepatic steatosis (fatty liver) develops, characterized by accumulation of lipid droplets in hepatocytes that results in hepatomegaly. Although this condition is relatively benign, persistent alcohol abuse can further lead to alcoholic hepatitis (or steatohepatitis), featured by marked inflammation and necrosis of the liver parenchyma. At this stage, symptoms such as fever, jaundice, fatigue, abdominal pain and altered mental state may be encountered. Finally, liver cirrhosis may ensue - an irreversible and often fatal form of liver damage, as it may lead to terminal liver disease and the appearance of portal hypertension, Wernicke-Korsakoff syndrome and gastrointestinal bleeding, as well as formation of esophageal varices. In fact, alcoholic liver disease is shown to be the second most common indication for liver transplantation in the US [5]. Having in mind the fact that mortality rates from severe alcoholic hepatitis reach 50% and that hepatocellular carcinoma may arise on the grounds of profound liver cirrhosis [6], recognizing ALD in its early stages is detrimental. The diagnosis can be made based on detailed patient history that includes information obtained from both the patient and his/her family and friends regarding alcohol consumption, whereas a thorough physical examination may be sufficient to make an initial diagnosis. Liver function tests, together with basic laboratory studies including complete blood count (CBC) can confirm liver damage, while biopsy may be indicated as well. The main form of treatment is total alcohol abstinence supported by vitamin B supplementation, diazepam during withdrawal and glucocorticoids.

Alcoholic liver disease (ALD) encompasses numerous changes in the liver caused by chronic intake of alcohol, since our body cannot store it and possesses limited capacity for degradation. Ethanol, once ingested through alcoholic-rich beverages, is absorbed from the gastrointestinal tract and transported to the liver, the principal organ of alcohol metabolism. Through several pathways and mechanisms, the liver attempts to degrade ethanol into other compounds that may be excreted, but under circumstances of excessive alcohol ingestion, constant degradation leads to accumulation of free radicals that are created during this process. Consequently, severe damage to liver cells (hepatocytes) occurs over time and impairs numerous functions of this organ. Not only alcohol abuse, however, is important for the development of this syndrome. Genetic factors, gender and presence of comorbidities significantly determine the outcome of patients. It was shown that certain individuals have mutations in genes that code for enzymes that degrade alcohol, which may either make them more or less susceptible to toxic effects, whereas female gender is shown to be a risk factor due to lower tolerance to ethanol. There are three main stages of ALD: Fatty liver, the first stage where fat accumulation inside hepatocytes occurs; Alcoholic hepatitis, characterized by diffuse inflammation and degradation of liver cells; and finally, liver cirrhosis, an irreversible change in the structure of hepatocytes that can progress to end-stage liver disease. Symptoms may be completely absent in initial stages, while yellow skin color (jaundice), fever, abdominal pain, weight loss, nausea and fatigue may be encountered in milder cases. Altered consciousness, enlarged spleen and liver, as well as hypertension and development of esophageal varices are observed in severe cases. Because almost complete regression may result with early therapy and because advanced disease may either be fatal or predispose patients to liver cancer, an early diagnosis significantly prolongs the life of the patient. Interview with the patient is the crucial part of the diagnostic workup, as information regarding drinking habits and previous history of abuse may be obtained, but not all individuals will openly discuss their issues, which is why family and friends should be inquired with these questions as well, especially in the setting of high suspicion. Physical examination and liver function tests may can confirm liver damage, whereas a definite diagnosis can be made by biopsy. Treatment principles are based on complete abstinence from alcohol and has shown to be the most important modality. Supportive therapy through vitamin supplementation, administration of diazepam during withdrawal and use of various antioxidants has been recommended. This condition is one of the most common causes of end-stage liver disease that ends fatally within years in virtually all patients, but its prevention through early identification, supportive care and encouragement may substantially prolong survival rates or even induce complete regression of changes in the liver.

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