Ethanol Metabolism

How the liver oxidizes ethanol

Two enzymes, both making NADH. Ethanol is oxidized to acetaldehyde by alcohol dehydrogenase (ADH) in the cytosol, then to acetate by aldehyde dehydrogenase (ALDH) in mitochondria. Both steps reduce NAD⁺ to NADH, so the hepatic NADH/NAD⁺ ratio climbs sharply. Acetate is converted to acetyl-CoA and enters general metabolism.

Zero-order kinetics. ADH is saturated even at low ethanol levels, so a fixed amount of ethanol is cleared per hour regardless of concentration — which is why blood alcohol falls at a steady rate, a straight line rather than an exponential decay.

MEOS. Chronic drinking induces microsomal CYP2E1 (the microsomal ethanol-oxidizing system), which adds clearance capacity and generates reactive oxygen species. Because CYP2E1 also converts acetaminophen to its toxic metabolite NAPQI, chronic drinkers are more vulnerable to acetaminophen hepatotoxicity.

Acetaldehyde. Acetaldehyde is the toxic intermediate; ALDH normally keeps it low. People with a low-activity ALDH2 variant, common in East Asian populations, accumulate acetaldehyde and flush after small amounts of alcohol — a natural version of the disulfiram reaction.

Consequences of a high NADH/NAD⁺ ratio

One ratio drives all the damage. Surplus NADH pushes every NAD-linked equilibrium toward its reduced partner. Reason from the ratio and each hallmark of the binge drinker follows.

Lactic acidosis and gout. High NADH drives lactate dehydrogenase toward lactate, causing lactic acidosis and pulling pyruvate away from gluconeogenesis. Lactate also competes with urate for renal excretion, raising uric acid and precipitating gout.

Fasting hypoglycemia. Oxaloacetate shunted to malate strips gluconeogenesis of a key substrate. A drinker who has not been eating has already exhausted liver glycogen, so blood glucose falls — a classic emergency department scenario.

Fatty liver. Elevated NADH converts DHAP to glycerol-3-phosphate, the backbone for triglycerides, while suppressing fatty acid oxidation. The result is macrovesicular hepatic steatosis, the earliest alcoholic liver lesion, which is reversible if drinking stops.

Alcoholic ketoacidosis. High NADH also blocks the TCA cycle, diverting acetyl-CoA to ketone bodies. After a binge with poor intake, patients develop an anion-gap ketoacidosis with predominant beta-hydroxybutyrate (so the nitroprusside ketone test may be only weakly positive) and a normal or low glucose. Treat with saline, dextrose, and thiamine.

Give thiamine BEFORE glucose in a malnourished drinker: a glucose load in a thiamine-depleted patient can precipitate Wernicke encephalopathy.

Drugs that act on the pathway

Disulfiram. Disulfiram inhibits aldehyde dehydrogenase, so acetaldehyde accumulates when the patient drinks: flushing, throbbing headache, nausea, vomiting, and palpitations. The aversive reaction deters drinking in alcohol use disorder. Metronidazole, certain cephalosporins, and sulfonylureas cause a similar disulfiram-like reaction, so patients on them are told to avoid alcohol.

Fomepizole. Fomepizole inhibits alcohol dehydrogenase and is first-line for methanol and ethylene glycol poisoning: it stops the parent alcohol from being converted into its toxic acids, and the unmetabolized alcohol is then excreted or dialyzed. Ethanol is an alternative when fomepizole is unavailable; it works as a competing substrate for ADH.

Toxic alcohols

Methanol. Found in windshield washer fluid and illicit spirits. ADH converts it to formaldehyde, then formic acid, which causes an anion-gap metabolic acidosis and retinal/optic nerve toxicity: blurred vision progressing to blindness, with optic disc hyperemia. Treat with fomepizole plus folinic acid (which speeds formate breakdown), and dialysis if severe.

Ethylene glycol. The sweet-tasting ingredient in antifreeze. It is metabolized to glycolic and oxalic acids: anion-gap acidosis, CNS depression, flank pain, and acute kidney injury from calcium oxalate crystals (envelope-shaped) in the urine; oxalate binding can also lower serum calcium. Treat with fomepizole, adding dialysis for renal failure or severe acidosis.

Gaps over time. Both toxic alcohols raise the osmolar gap and the anion gap. The osmolar gap appears first (the parent alcohol is osmotically active), and the anion gap follows once the acids form — so a late presenter may have a large anion gap with a normal osmolar gap.