Alcohol Metabolism in Humans: Effects and Disorders
Primary Metabolic Pathways
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
The Three-Step Process:
- Step 1: Ethanol → Acetaldehyde (via ADH, CYP2E1, or catalase) 3, 1, 4
- Step 2: Acetaldehyde → Acetic acid (via ALDH) 3, 1
- Step 3: Acetic acid → CO₂ + H₂O 4
The gut also plays important roles in alcohol metabolism, not just the liver 2
Toxic Mechanisms of Alcohol Metabolism
Direct Metabolic Injury
The metabolic process itself generates liver injury through four primary mechanisms 3, 1:
- Increased NADH production from alcohol oxidation, which favors fatty acid and triglyceride synthesis while inhibiting mitochondrial β-oxidation of fatty acids 3, 1
- Enhanced hepatic influx of free fatty acids from adipose tissue and chylomicrons from intestinal mucosa 3
- AMPK pathway suppression resulting in increased lipogenesis and decreased lipolysis by inhibiting PPARα and stimulating SREBP1c 3
- Acetaldehyde-induced organelle damage to mitochondria and microtubules, reducing NADH oxidation and causing VLDL accumulation 3, 1
Acetaldehyde Toxicity
Acetaldehyde is the primary toxic metabolite responsible for alcohol-related tissue damage, causing direct cellular injury, oxidative stress generation, immune system activation, and carcinogenic effects. 1, 5
Specific toxic effects include 3:
- Protein binding: Forms adducts with proteins causing functional alterations and autoantigen formation 3
- DNA damage: Binds to DNA creating mutagenic adducts 3
- Mitochondrial damage: Impairs glutathione function leading to oxidative stress and apoptosis 3
- Direct hepatic stellate cell activation: Promotes fibrosis 3
Oxidative Stress
Reactive oxygen species (ROS) generation occurs through multiple sources 3:
- CYP2E1-dependent microsomal ethanol oxidizing system (MEOS) 3
- Mitochondrial electron transport chain 3
- NADH-dependent cytochrome reductase and xanthine oxidase 3
Chronic alcohol intake markedly up-regulates CYP2E1, which metabolizes ethanol to acetaldehyde while generating ROS and hydroxyl-ethyl radicals. 3
Inflammatory Cascade
Alcohol metabolites and ROS activate pro-inflammatory pathways 3:
- Signaling activation: NFκB, STAT-JAK, and JNK pathways in hepatic cells 3
- Cytokine production: TNFα, interleukin-8, and osteopontin 3
- Gut-liver axis disruption: Changes in colonic microbiota and increased intestinal permeability lead to elevated lipopolysaccharides that activate Kupffer cells via CD14/TLR4 3
- PMN infiltration: Results in additional ROS formation and hepatocellular damage 3
Genetic Variations Affecting Metabolism
ALDH2 Deficiency
The deficit in aldehyde dehydrogenase 2 (ALDH2) is the principal enzymatic deficit associated with problems metabolizing alcohol, especially common in East Asian populations. 6, 1
The ALDH2*2 allele produces a variant enzyme with greatly reduced activity, preventing efficient conversion of toxic acetaldehyde to non-toxic acetic acid 6, 1:
Clinical manifestations of ALDH2 deficiency include 6:
- Nausea after alcohol consumption 6
- Palpitations after alcohol consumption 6
- Headache after alcohol consumption 6
- Facial flushing (the "Asian flush" reaction) 6
Paradoxically, ALDH2 deficiency provides protection against alcohol dependence and alcoholic liver disease by making alcohol consumption highly unpleasant. 6
Health Risks of ALDH2 Deficiency
Despite protective effects against alcoholism, ALDH2 deficiency carries significant health risks 6:
- Increased cancer risk: Higher risk of upper digestive tract cancers, especially when combined with alcohol and tobacco use 6
- Glaucoma risk: Increased risk of open-angle glaucoma in Asian populations 6
- Hypertension: Overweight men with alcohol-related facial flushing have greater risk of ocular hypertension at lower alcohol consumption levels 6
ADH Polymorphisms
Genetic variations in ADH2 and ADH3 enzymes affect the initial step of alcohol metabolism, influencing both alcohol dependence risk and liver disease susceptibility 6:
- Sex differences: Women exhibit decreased gastric ADH activity compared to men, resulting in higher blood alcohol concentrations after consuming equivalent amounts of alcohol 6
- CYP2E1 polymorphisms: Confer minor risk for alcoholic liver disease 6
- Heritability: Twin studies suggest approximately 50% heritability for alcohol use disorders 6
Spectrum of Alcohol-Related Liver Disease
Alcoholic Steatosis (Fatty Liver)
The earliest stage results from the metabolic mechanisms described above, with fat accumulation in hepatocytes 3
Alcoholic Steatohepatitis (ASH)
Alcoholic fatty livers can develop parenchymal inflammation (mainly by PMN cells) and hepatocellular damage, a prerequisite for progression to fibrosis and cirrhosis. 3
Contributing factors include 3:
- Acetaldehyde-induced toxic effects 3
- ROS generation and lipid peroxidation 3
- Pro-inflammatory cytokine production 3
- Impaired ubiquitin-proteasome pathway leading to Mallory-Denk body formation 3
Fibrosis and Cirrhosis
Patients with ASH may develop progressive fibrosis, typically located in pericentral and perisinusoidal areas, eventually progressing to bridging fibrosis, regeneration nodules, and cirrhosis. 3
Fibrogenic mechanisms 3:
- Direct HSC activation: Acetaldehyde directly activates hepatic stellate cells (the main collagen-producing cells) 3
- Paracrine activation: Damaged hepatocytes, activated Kupffer cells, and infiltrating PMN cells release TGFβ1, PDGF, leptin, angiotensin II, interleukin-8, TNFα, nitric oxide, and ROS 3
- ROS signaling: Stimulates pro-fibrogenic pathways (ERK, PI3K/AKT, JNK) and up-regulates TIMP-1 while decreasing metalloproteinase activity 3
- Multiple cell sources: Portal fibroblasts and bone marrow-derived cells also synthesize collagen 3
Impact of Cirrhosis on Metabolism
Total ALDH activity is significantly lower in cirrhotics than in controls, both among alcoholics and non-drinkers, with the reduction due mainly to decreased low Km ALDH activity. 7
This reduction is clearly a consequence of liver damage itself, not chronic alcohol abuse 7
Metabolic Dysfunction and Alcohol-Related Liver Disease (MetALD)
The New Nomenclature
The 2023 nomenclature update recognizes a spectrum of steatotic liver disease (SLD) from metabolic-predominant (MASLD) to alcohol-predominant (ALD), with MetALD representing the coexistence of metabolic dysfunction and alcohol use. 3
Synergistic Effects
Obesity and metabolic syndrome create a synergistic effect with alcohol that accelerates liver injury and impairs metabolic capacity, with insulin resistance, diabetes, and dyslipidemia worsening alcohol-related liver disease progression. 6
The combination creates multiplicative rather than additive risk for severe liver disease and hepatic decompensation 6
Alcohol's Direct Effects on Metabolic Parameters
Chronic high alcohol intake and binge drinking directly disrupt metabolic parameters, making diagnosis of metabolic syndrome challenging in active drinkers. 3
Specific effects 3:
- Hypertension: Alcohol is a major cause of high blood pressure; reducing intake returns blood pressure toward normal 3
- Hypertriglyceridemia: Alcohol directly elevates triglyceride levels 3
- Hyperglycemia: Complex J-shaped relationship with type 2 diabetes, varying by sex and BMI 3
Critical caveat: In cases where only one metabolic criterion is present (especially hypertension, hypertriglyceridemia, or hyperglycemia), liver damage might be linked solely to alcohol use, not true metabolic syndrome. 3
Diagnostic Thresholds
MetALD is defined by 3:
- Alcohol consumption: 140-350 g/week for women, 210-420 g/week for men 3
- Plus: At least one metabolic dysfunction criterion 3
Caution should be exercised in applying only one metabolic dysfunction criterion to diagnose MASLD in individuals exceeding weekly alcohol thresholds of 140 g for women and 210 g for men, particularly with isolated hypertension, hypertriglyceridemia, or hyperglycemia. 3
Clinical Assessment and Management
Accurate Alcohol Quantification
Detailed information on recent and lifetime alcohol intake should be obtained in all individuals with metabolic dysfunction and steatotic liver disease, as this is crucial for prognosis and management. 3, 1
- Validated questionnaires: AUDIT-C (Alcohol Use Disorders Identification Test Consumption) 3, 1
- Alcohol biomarkers: Phosphatidylethanol 3, 1
- Collateral information: From friends and relatives 3
Risk Thresholds
Excessive drinking is defined as average consumption exceeding 40 g/day in men and 20 g/day in women. 1
Weekly thresholds of 140 g for women and 210 g for men should trigger heightened clinical vigilance. 3, 1
Longitudinal Monitoring
Metabolic dysfunction and alcohol use should be reassessed over time, especially after periods of change in risk factor exposure, particularly in individuals exceeding weekly alcohol thresholds. 3, 1
This allows for 3:
- Adjustments in management strategies 3
- Reassessment of prognosis 3
- Detection of alcohol's causal relationship with hypertension, hypertriglyceridemia, and hyperglycemia 3, 1
Treatment Strategies
Alcohol abstinence is necessary for patients with chronic viral hepatitis, and weight control and smoking cessation are recommended as obesity and smoking increase ALD risk. 1
Additional interventions 1:
- Probiotics: Shown to improve gut barrier function, reduce endotoxemia, and reduce TLR4 activation 1
- Weight management: Should be implemented immediately upon alcohol cessation, particularly in overweight or obese patients with metabolic syndrome 8
- Physical activity: 12-week programs show decreased body fat and increased lean body mass 8
Pharmacological Intervention: Disulfiram
Disulfiram blocks the oxidation of alcohol at the acetaldehyde stage; during alcohol metabolism following disulfiram intake, the concentration of acetaldehyde in blood may be 5 to 10 times higher than that found during metabolism of the same amount of alcohol alone. 9
Key characteristics 9:
- Produces highly unpleasant disulfiram-alcohol reaction proportional to dosage of both disulfiram and alcohol 9
- Does not influence the rate of alcohol elimination from the body 9
- Effects persist 1-2 weeks after last dose 9
- Prolonged administration does not produce tolerance; patients become more sensitive to alcohol over time 9
Common Pitfalls and Caveats
Underestimating Metabolic Consequences of Cessation
Weight gain after stopping alcohol is primarily driven by loss of alcohol's metabolic acceleration effects, combined with increased appetite and compensatory eating behaviors. 8
Proactive dietary counseling and exercise programs can prevent weight gain if implemented at cessation—metabolic effects of chronic alcohol consumption reverse after only 3 days of abstinence, meaning weight gain can begin immediately. 8
Misattributing Metabolic Criteria
The diagnosis of cardiometabolic risk factors in the context of alcohol use must account for alcohol's causal relationship with hypertension, hypertriglyceridemia, and hyperglycemia. 3
Ignoring metabolic syndrome components can accelerate liver disease progression even after alcohol cessation 8
Underestimating Synergistic Risk
High BMI and fasting glucose are independent risk factors for liver fibrosis progression even after correcting for alcohol quantity and duration. 6
The combination of genetic susceptibility (particularly ALDH2 or ADH variants), obesity, diabetes, and binge drinking creates multiplicative risk 6
Assuming Chronic Alcohol Depresses ALDH
Chronic alcohol abuse does not depress ALDH activity—reduction in ALDH activity detected in patients with severe liver disease is clearly a consequence of liver damage, not alcohol exposure itself. 7