What is the process of alcohol metabolism and how can it be managed?

Alcohol Metabolism: Process and Management

Alcohol is metabolized primarily in the liver through three enzymatic pathways—alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1), and catalase—with ADH being the predominant route, converting ethanol to acetaldehyde, which is then metabolized by aldehyde dehydrogenase (ALDH) to acetate. 1, 2

Primary Metabolic Pathways

The metabolism of alcohol follows a sequential two-step process:

• First oxidation step: Ethanol is converted to acetaldehyde through three enzymatic systems 1, 3:

  • Alcohol dehydrogenase (ADH) in the cytosol (predominant pathway) 1, 2
  • Cytochrome P450 2E1 (CYP2E1) in the microsomes (becomes more important with chronic alcohol use) 1, 3
  • Catalase in the peroxisomes (minor contribution) 1, 2

• Second oxidation step: Acetaldehyde is metabolized by mitochondrial aldehyde dehydrogenase (ALDH) to acetate, which then leaves the liver and is converted to acetyl-CoA in peripheral tissues 1, 2

Pathogenic Mechanisms of Alcohol Metabolism

The metabolic process itself generates liver injury through four primary mechanisms:

• Increased NADH production: Alcohol oxidation increases the NADH/NAD+ ratio, leading to enhanced triglyceride and fatty acid synthesis while suppressing mitochondrial β-oxidation 1, 4

• Enhanced hepatic influx of free fatty acids: Increased delivery from adipose tissue and chylomicrons from the intestinal mucosa 1, 4

• AMPK pathway suppression: Ethanol suppresses adenosine-monophosphate-activated protein kinase (AMPK), resulting in increased lipid biosynthesis, suppression of PPARα, and activation of SREBP1c 1, 4

• Acetaldehyde-induced organelle damage: Direct mitochondrial and microtubule damage causes decreased NADH oxidation and VLDL accumulation 1, 4

Toxic Effects of Acetaldehyde

Acetaldehyde is the primary toxic metabolite responsible for alcohol-related tissue damage:

• Direct cellular injury: Acetaldehyde binds to proteins and DNA, altering their function and affecting protein synthesis 1, 4

• Oxidative stress generation: Produces oxygen free radicals, causes lipid peroxidation, and decreases mitochondrial glutathione and S-adenosyl-L-methionine (SAMe) levels 1, 4

• Immune system activation: Acetaldehyde-protein adducts act as auto-antigens, activating the immune system and increasing lymphocyte infiltration 1

• Carcinogenic effects: Both ethanol and acetaldehyde are classified as carcinogenic to humans by IARC, with no safe level of exposure for cancer prevention 4

Genetic Variations Affecting Metabolism

Critical genetic polymorphisms significantly impact alcohol metabolism and disease risk:

• ALDH2 deficiency: The ALDH2*2 allele, particularly common in East Asian populations, produces an enzyme with greatly reduced activity, causing toxic acetaldehyde accumulation 5, 6, 7

  • Clinical manifestations include facial flushing, nausea, palpitations, and headache after alcohol consumption 5
  • Paradoxically provides protection against alcohol dependence but increases cancer risk when alcohol is consumed 5

• ADH polymorphisms: Variations in ADH2 and ADH3 genes affect the initial step of alcohol metabolism, influencing both alcohol dependence risk and liver disease susceptibility 5, 7

  • Women exhibit decreased gastric ADH activity compared to men, resulting in higher blood alcohol concentrations after equivalent alcohol intake 5

• CYP2E1 polymorphisms: Confer minor risk for alcoholic liver disease but contribute to oxidative stress through ROS generation 8, 5, 3

Clinical Management Strategies

Assessment of Alcohol Use

Accurate quantification of alcohol consumption is essential for proper classification and management 1:

• Obtain detailed information on recent and lifetime alcohol intake, quantified in grams per week 1
• Use validated questionnaires such as AUDIT-C (Alcohol Use Disorders Identification Test Consumption) 1
• Employ alcohol biomarkers, particularly phosphatidylethanol, to improve accuracy and overcome underreporting 1
• Obtain collateral information from friends and relatives when necessary 1

Risk Thresholds and Recommendations

Specific alcohol consumption thresholds define risk categories:

• Excessive drinking is defined as average consumption exceeding 40 g/day in men and 20 g/day in women, which increases risk of alcoholic liver injury 1
• Weekly thresholds of 140 g for women and 210 g for men should trigger heightened clinical vigilance 1
• Daily or binge drinking patterns increase ALD risk and should be avoided 1

Longitudinal Monitoring

Reassess metabolic dysfunction and alcohol use over time, especially after periods of change in risk factor exposure 1:

• This is particularly important in individuals exceeding weekly alcohol use thresholds 1
• Monitor for alcohol's causal relationship with hypertension, hypertriglyceridemia, and hyperglycemia 1
• In cases where only one metabolic criterion is present, liver damage might be linked solely to alcohol use 1

Pharmacological Intervention

Disulfiram blocks alcohol oxidation at the acetaldehyde stage, producing a highly unpleasant reaction when alcohol is ingested 9:

• Acetaldehyde concentrations may be 5 to 10 times higher than during normal alcohol metabolism 9
• The disulfiram-alcohol reaction persists as long as alcohol is being metabolized 9
• Effects can last one to two weeks after the last dose, as disulfiram is eliminated slowly from the body 9
• Prolonged administration increases sensitivity to alcohol rather than producing tolerance 9

Adjunctive Measures

• Alcohol abstinence is necessary for patients with chronic viral hepatitis 1
• Weight control and smoking cessation are recommended, as obesity and smoking increase ALD risk 1
• Probiotics have shown benefits in improving gut barrier function, reducing endotoxemia, and reducing TLR4 activation 4

Common Pitfalls and Caveats

Avoid misclassifying alcohol-related metabolic abnormalities as primary metabolic syndrome:

• Heavy alcohol use can directly cause hypertension, hypertriglyceridemia, and hyperglycemia 1
• Exercise caution when applying only one metabolic dysfunction criterion to diagnose MASLD in individuals exceeding alcohol thresholds 1
• The combination of genetic susceptibility, obesity, diabetes, and binge drinking creates multiplicative rather than additive risk for severe liver disease 5

Recognize that alcohol metabolism does not occur at a fixed rate:

• Disulfiram does not influence the rate of alcohol elimination from the body 9
• More than 90% of ingested ethanol is metabolized in the body, with less than 10% excreted unchanged 2
• Chronic alcohol consumption induces CYP2E1, which generates additional reactive oxygen species and contributes to progressive liver damage 8, 3