Alcoholic liver disease (ALD) refers to liver diseases caused by excessive alcohol consumption. The spectrum of ALD includes alcoholic hepatitis, alcoholic fatty liver, alcoholic liver fibrosis, and cirrhosis, which may further progress to liver cancer.
Etiology and Pathogenesis
Ethanol-induced liver damage involves several mechanisms:
Acetaldehyde, an intermediate metabolite of ethanol, is a highly reactive molecule that binds to proteins to form acetaldehyde-protein adducts. These adducts not only directly damage hepatocytes but also act as neoantigens, inducing cellular and humoral immune responses, which result in immune-mediated attacks on hepatocytes.
The oxygen-consuming process of ethanol metabolism causes hypoxia in the central zone of the hepatic lobule.
The microsomal ethanol oxidation pathway in hepatocytes generates reactive oxygen species, leading to liver injury.
Excessive alcohol consumption disrupts gut microbiota and impairs the intestinal barrier, resulting in endotoxemia that exacerbates liver damage.
Chronic heavy drinking leads to high blood alcohol levels, hepatic vasoconstriction, reduced hepatic blood flow and oxygen supply, and increased oxygen consumption during alcohol metabolism, causing microcirculatory disturbances and hypoxemia, which further worsen liver function.
Risk factors that increase the likelihood of developing alcoholic liver disease include:
- Alcohol consumption and duration: Repeated heavy drinking over a short period (e.g., daily ethanol intake >80 g for two weeks) can lead to alcoholic hepatitis. Chronic alcohol consumption (e.g., daily ethanol intake >40 g for more than five years) can result in chronic alcoholic liver disease.
- Genetic predisposition: Variants in genes encoding alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are closely associated with the development of alcoholic liver disease.
- Gender: Women are more susceptible to alcoholic liver disease than men at equivalent alcohol intake levels, likely due to lower ADH levels in women.
- Other liver diseases: Coexisting HBV or HCV infections increase the risk of alcoholic liver disease and exacerbate alcohol-induced liver damage.
- Obesity: Obesity is an independent risk factor for alcoholic liver disease.
- Malnutrition: Nutritional deficiencies also contribute to the development of ALD.
Pathology
The pathological changes in ALD are primarily characterized by macrovesicular or mixed macrovesicular and microvesicular steatosis of hepatocytes. Depending on the presence of inflammatory responses and fibrosis, ALD can be classified into alcoholic fatty liver, alcoholic hepatitis, alcoholic liver fibrosis, and alcoholic cirrhosis.
Alcoholic Fatty Liver
The initial manifestation of ethanol-induced liver damage is fatty degeneration of hepatocytes. Mild cases involve scattered individual hepatocytes or small clusters of hepatocytes, predominantly in the central zone (zone 3) of the lobule. As the condition progresses, the distribution becomes diffuse. There is no inflammation or necrosis of hepatocytes, and the lobular structure remains intact.
Alcoholic Hepatitis and Liver Fibrosis
Alcoholic hepatitis is characterized by hepatocyte necrosis, neutrophil infiltration, and the presence of alcoholic hyaline inclusions (Mallory bodies) in hepatocytes in the central zone of the lobule. Severe cases may exhibit confluent necrosis and/or bridging necrosis. Perisinusoidal/pericellular fibrosis and perivenular fibrosis may extend to the portal area, leading to perivenular sclerosing hyaline necrosis, focal or widespread stellate fibrosis in the portal area, and in severe cases, focal or widespread bridging fibrosis.
Alcoholic Cirrhosis
The lobular architecture is completely disrupted and replaced by pseudolobules and extensive fibrosis, resulting in macroscopic nodular cirrhosis. Based on the presence or absence of interface hepatitis in fibrous septa, alcoholic cirrhosis can be classified into active and inactive forms.
Clinical Manifestations
The clinical manifestations of ALD are generally related to the amount and duration of alcohol consumption. Some patients may remain asymptomatic for prolonged periods, with no signs or symptoms of liver disease.
Alcoholic Hepatitis
Symptoms are associated with the severity of histological damage and often occur after recent heavy drinking (over hours to weeks). Common symptoms include general malaise, loss of appetite, nausea, emesis, fatigue, and pain in the liver region. Fever, jaundice, and hepatomegaly with tenderness may also occur. Severe cases can develop acute liver failure.
Alcoholic Fatty Liver
Symptoms are usually absent or mild, including fatigue, loss of appetite, vague discomfort, or dull pain in the right upper abdomen. Hepatomegaly of varying degrees may be observed.
Alcoholic Cirrhosis
Clinical manifestations resemble those of cirrhosis caused by other etiologies and may be accompanied by signs of chronic alcohol intoxication, such as neuropsychiatric symptoms and chronic pancreatitis.
Some individuals with alcohol dependence may experience withdrawal symptoms after ceasing alcohol consumption. These symptoms include tremors, perspiration, insomnia, agitation, restlessness, and incoherent speech. Severe withdrawal symptoms, if not managed promptly, can result in death.
Laboratory and Other Examinations
Laboratory Tests
In alcoholic fatty liver disease, mild elevations in serum AST and ALT levels may be observed. In alcoholic hepatitis, AST levels are significantly higher than ALT levels, with an AST/ALT ratio often greater than 2. γ-GT levels are commonly elevated, and changes in TB, PT, and mean corpuscular volume (MCV) may also occur to varying degrees. Combined testing of these parameters aids in the diagnosis of alcoholic liver disease. Characteristic findings include an AST/ALT ratio >2, elevated γ-GT, and increased MCV.
Imaging Examinations
Imaging findings are similar to those seen in non-alcoholic fatty liver disease.
Pathological Examination
Liver biopsy is a reliable method for confirming the diagnosis and staging of alcoholic liver disease. It provides important information about disease severity and prognosis. However, it is often difficult to distinguish alcoholic liver disease from liver damage caused by other etiologies.
Diagnosis and Differential Diagnosis
A history of alcohol consumption is essential for diagnosing alcoholic liver disease. Details regarding the type of alcohol consumed, daily intake, duration of consumption, and drinking patterns should be thoroughly assessed. The safe threshold for alcohol intake remains controversial. The diagnostic criteria for alcoholic liver disease include: a long-term history of alcohol consumption (>5 years), with an average daily ethanol intake of ≥40 g for men and ≥20 g for women, or a history of heavy drinking within two weeks, with ethanol intake >80 g/day. The formula for calculating ethanol intake is as follows:
Ethanol intake (g)=Amount of alcohol consumed (ml)×Ethanol content (%)×0.8
The diagnostic approach for alcoholic liver disease involves the following considerations:
- Determining whether liver disease is present.
- Assessing whether the liver disease is related to alcohol consumption.
- Evaluating for the presence of other liver diseases.
- Identifying the clinical and pathological stage if alcoholic liver disease is confirmed.
Diagnosis is based on a combination of alcohol consumption history, clinical manifestations, and relevant laboratory and other examinations. Liver biopsy and histological examination may be performed if necessary.
Differential diagnosis includes non-alcoholic fatty liver disease, viral hepatitis, drug-induced liver injury, autoimmune liver disease, and cirrhosis caused by other etiologies. Alcoholic liver disease is closely associated with chronic viral hepatitis. Patients with chronic hepatitis B or C are more sensitive to alcohol and are at an increased risk of developing alcoholic liver disease. Conversely, patients with alcoholic liver disease are also more susceptible to viral hepatitis.
Treatment
Patient Education
Abstinence from alcohol is the most important measure in the treatment of alcoholic liver disease. Alcohol cessation significantly improves histological changes and survival rates in patients at all stages of the disease. It also reduces portal hypertension and slows the progression to cirrhosis. For patients with alcoholic liver disease, encouragement and support from healthcare providers and family members play a critical role in helping them achieve early alcohol cessation.
Nutritional Support
Chronic alcohol consumption often replaces caloric intake from food, leading to protein and vitamin deficiencies and resulting in malnutrition. Patients with alcoholic liver disease require adequate nutritional support. In addition to abstinence from alcohol, they should receive a high-calorie, high-protein, and low-fat diet, along with supplementation of multiple vitamins (e.g., vitamins B, C, and K).
Pharmacological Treatment
Polyene phosphatidylcholine stabilizes sinusoidal endothelial and hepatocyte membranes, reduces lipid peroxidation, and alleviates hepatocyte steatosis, inflammation, and fibrosis.
Metadoxine accelerates ethanol metabolism.
N-acetylcysteine replenishes intracellular glutathione and has antioxidant effects.
The use of glucocorticoids in the treatment of alcoholic liver disease remains controversial, but they may alleviate symptoms and improve biochemical indices in severe alcoholic hepatitis.
Other medications, such as S-adenosylmethionine and glycyrrhizin preparations, may also have therapeutic effects.
In cases of severe alcohol withdrawal symptoms, symptomatic treatment may be supplemented with naloxone, benzodiazepines, and vitamins.
Management of Portal Hypertension and Liver Transplantation
Portal hypertension occurs early in patients with alcoholic cirrhosis and requires monitoring and management (refer to the "Cirrhosis" section for details). For patients with severe alcoholic cirrhosis, liver transplantation may be considered. However, candidates are required to abstain from alcohol for 3–6 months prior to transplantation and must not have severe alcohol-induced damage to other organs.
Prognosis
The prognosis of alcoholic fatty liver disease is generally favorable, with partial recovery possible after alcohol cessation. Alcoholic hepatitis can also recover in most cases with timely treatment and alcohol abstinence. Without alcohol cessation, alcoholic fatty liver disease may progress directly to alcoholic cirrhosis, either with or without passing through the stage of alcoholic hepatitis, and may even lead to liver cancer. The primary causes of death include liver failure and complications related to cirrhosis.