Pathology of alcohol-related disorders

1. Metabolism of ethanol

Alcohol is absorbed in the stomach/small intestine and distributed in body water. Blood levels: ~80 mg/dL = drunk, ~200 mg/dL = drowsiness; chronic alcoholics tolerate higher levels (accelerated metabolism).

Ethanol → acetaldehyde by 3 hepatic systems:

• Alcohol/acetaldehyde dehydrogenase (cytosol) — main, uses NAD⁺.
• CYP2E1 (microsomal, sER) — induced at high ethanol levels; generates ROS.
• Catalase (peroxisomes).

Acetaldehyde → acetate by mitochondrial aldehyde dehydrogenase (ALDH). (~50% of East Asians have a defective ALDH → slow metabolism, flushing.)

2. Mechanisms of injury

• ↑ NADH / ↓ NAD⁺ → inhibits fatty-acid β-oxidation → hepatic steatosis; impairs lactate→pyruvate → lactic acidosis.
• CYP2E1 → ROS → lipid peroxidation of membranes.
• Gut endotoxin → TNF release → hepatocyte injury.

3. Acute alcoholism

• CNS — depressant; medullary respiratory centers → respiratory arrest.
• Liver — reversible hepatic steatosis (fat droplets).
• Stomach — acute gastritis, erosions.

4. Chronic alcoholism

Liver (main chronic target) — progression:

Stage	Features
Fatty liver (steatosis)	Macrovesicular fat; reversible with abstinence
Alcoholic hepatitis	Hepatocyte ballooning, Mallory-Denk bodies (keratin), neutrophils, pericellular “chicken-wire” fibrosis
Cirrhosis	Micronodular → mixed; regenerative nodules + bridging fibrosis → portal HTN, HCC risk

• GI — massive bleeding from gastritis, gastric ulcer, esophageal varices.
• Pancreas — acute & chronic pancreatitis.
• Cardiovascular — dilated (congestive) cardiomyopathy; hypertension, ↑ CHD risk.
• Neurological — thiamine deficiency → peripheral neuropathy, Wernicke encephalopathy (confusion, ophthalmoplegia, ataxia) and Korsakoff syndrome (irreversible memory loss); cerebellar degeneration.
• Carcinogenesis — oral cavity, esophagus, liver, breast.
• Pregnancy — fetal alcohol syndrome: growth retardation, mental impairment, facial anomalies (microcephaly, short palpebral fissures, thin upper lip, maxillary hypoplasia).

💡 High-yield: Ethanol → acetaldehyde (ADH/CYP2E1/catalase) → acetate (ALDH). ↑ NADH → fatty liver + lactic acidosis; CYP2E1 → ROS. Liver: steatosis → alcoholic hepatitis (Mallory-Denk bodies) → cirrhosis. Also pancreatitis, dilated cardiomyopathy, Wernicke-Korsakoff (thiamine), fetal alcohol syndrome.