Pathophysiology

Pathophysiology

II-6. Acute alcohol intoxication

急性アルコール中毒

Acute Alcohol Intoxication

Severity set by blood ethanol concentration, primarily via CNS effects. Chronic alcoholics tolerate higher levels (induced CYP2E1) — can exceed 500 mg/dL non-lethally.

Concentration → CNS Effects

  • 10–100 mg/dL: mild euphoria, ↓judgment/attention/coordination, numbness.
  • 100–300 mg/dL: mild intoxication (confusion, slurred speech, disorientation, loss of balance).
  • 300–400 mg/dL: moderate (stupor, incontinence, delayed/absent reactions).
  • 400–500 mg/dL: severe (coma, circulatory/respiratory failure, hypothermia).
  • >500 mg/dL: death.

Other (non-CNS) Symptoms

  • Nausea/vomiting (gastric irritation), tachyarrhythmia (AF), hypoglycemia (inhibits gluconeogenesis), hyperosmolarity, ↑diuresis → hypovolemia → hypotension/tachycardia, respiratory depression, peripheral vasodilation, hypothermia.

Therapy

  • No specific antidote (treat symptoms): IV rehydration, electrolytes (Mg²⁺), glucose + thiamine, airway/respiration management, antiemetics.

Pathomechanism

Depends on ethanol amount, metabolism, risk factors (genetics, gender, comorbidity).

Metabolic Effects

  • Unregulated ethanol metabolism → overproduction of NADH, acetate, acetyl-CoA (toxic): membrane damage (ethanol/acetaldehyde/acetate), intracellular acidosis (acetate), protein denaturation (acetaldehyde), ROS (CYP2E1).
  • Redox imbalance (↑NADH): → lactate (EC acidosis), ↓glucose breakdown, TAG synthesis, ↓fatty acid β-oxidation, ↓citric acid cycle → fatty acid synthesis.

Oxidative Stress

  • ↑Free radicals/ROS: mitochondria (defective respiratory chain from NADH load + denatured enzymes), ER (CYP2E1 induction); ↓antioxidants (GSH, tocopherol).
  • Consequences: membrane damage → lipid peroxidation (vicious cycle), protein damage, DNA damage (carcinogenesis).

Acetaldehydemia

  • Acetaldehyde accumulation (ALDH polymorphism or CYP induction) = hepatotoxic; forms covalent adducts with proteins:
    • ↓DNA repair, ↑immune response (worsens liver damage), binds procollagen → ↑collagen synthesis (fibrosis), ↓vesicular transport (tubulin), ↓glutathione (→ oxidative stress).

一問一答

▶Why does acute alcohol intoxication cause hypoglycemia?

Ethanol inhibits gluconeogenesis.

▶What blood ethanol level causes coma and respiratory/circulatory failure, and what level is lethal?

400–500 mg/dL causes severe effects (coma, circulatory/respiratory failure, hypothermia); >500 mg/dL causes death.

▶What primarily determines the severity of acute alcohol intoxication?

Blood ethanol concentration, acting mainly via CNS effects.

▶What CNS effects occur at 100–300 mg/dL blood ethanol?

Mild intoxication: confusion, slurred speech, disorientation, and loss of balance.

▶Why can chronic alcoholics tolerate higher blood ethanol levels?

Induced CYP2E1 lets them tolerate higher levels, sometimes exceeding 500 mg/dL non-lethally.

▶How does alcohol lead to hypovolemia and hypotension acutely?

Increased diuresis causes hypovolemia, leading to hypotension and tachycardia (with peripheral vasodilation worsening it).

▶What is the therapy for acute alcohol intoxication?

No specific antidote — treat symptoms: IV rehydration, electrolytes (Mg²⁺), glucose + thiamine, airway/respiration management, and antiemetics.

▶Which toxic products are overproduced by unregulated ethanol metabolism?

NADH, acetate, and acetyl-CoA.

▶How does the redox imbalance (↑NADH) from alcohol affect metabolism?

It shifts pyruvate to lactate (extracellular acidosis), reduces glucose breakdown and fatty acid β-oxidation, reduces the citric acid cycle, and promotes TAG/fatty acid synthesis.

▶Which agents cause membrane damage in alcohol toxicity?

Ethanol, acetaldehyde, and acetate.

▶Which alcohol metabolites cause intracellular acidosis and protein denaturation?

Acetate causes intracellular acidosis; acetaldehyde causes protein denaturation.

▶What are the sources of oxidative stress in alcohol toxicity?

Mitochondria (defective respiratory chain from NADH load and denatured enzymes) and ER (CYP2E1 induction), with reduced antioxidants (GSH, tocopherol).

▶What is acetaldehydemia and how does it damage cells?

Accumulation of acetaldehyde (from ALDH polymorphism or CYP induction) that is hepatotoxic and forms covalent adducts with proteins.

▶How do acetaldehyde-protein adducts promote fibrosis?

Acetaldehyde binds procollagen, increasing collagen synthesis and driving fibrosis.

▶List additional harmful effects of acetaldehyde adducts besides fibrosis.

Reduced DNA repair, increased immune response (worsening liver damage), impaired vesicular transport (tubulin), and decreased glutathione (oxidative stress).

▶What CNS effects occur at 10–100 mg/dL blood ethanol?

Mild euphoria, reduced judgment/attention/coordination, and numbness.

▶What effects occur at 300–400 mg/dL blood ethanol?

Moderate intoxication: stupor, incontinence, and delayed/absent reactions.

▶Why does lipid peroxidation form a vicious cycle in alcohol toxicity?

Membrane damage from ROS triggers lipid peroxidation, which further damages membranes, perpetuating the cycle (alongside protein and DNA damage/carcinogenesis).

▶Which non-CNS cardiac and GI symptoms occur in acute intoxication?

Nausea/vomiting from gastric irritation and tachyarrhythmia (atrial fibrillation).

▶What factors influence the pathomechanism of alcohol intoxication?

Ethanol amount, metabolism, and risk factors (genetics, gender, comorbidity).