Normal Oxidation of Lactate
Lactate produced in tissues can be utilized as an energy substrate or a precursor for glucose synthesis.
In the liver, a portion of the pyruvate derived from lactate is oxidized to carbon dioxide and water. This process yields energy in the form of ATP molecules, which is consumed during gluconeogenesis.
Lactate is also actively consumed by other tissues, primarily the kidneys and myocardium, where it is oxidized to $CO_2$ and $H_2O$ with the generation of ATP.
At rest in skeletal muscle, the $NAD^+/NADH$ ratio increases. This allows lactate to be converted back to pyruvate, which is then fully oxidized.
Lactic Acidosis
If lactate is not utilized for glucose synthesis (e.g., due to defects in gluconeogenic enzymes), lactic acid accumulates in the blood. This causes a drop in pH and the development of lactic acidosis.
Physiological (short-term) lactic acidosis occurs in healthy individuals during intense muscle exertion. The body compensates for this state via pulmonary hyperventilation, accelerating the elimination of carbon dioxide. The primary mechanism involves the buffer reaction converting hydrogen ions and bicarbonate into carbonic acid, and then into $CO_2$ and water.
In uncompensated lactic acidosis, blood lactate levels exceed 5 mmol/L (normal is up to 2 mmol/L), and blood pH drops below 7.25.
Causes of pathological lactate elevation include:
- Tissue hypoxia, which activates anaerobic oxidation.
- Liver damage (cirrhosis, toxic dystrophies), reducing lactate utilization.
- Hereditary defects (glucose-6-phosphatase deficiency, pyruvate dehydrogenase complex defects).
- Vitamin deficiencies ($B_1$, $B_2$, $PP$) that impair coenzyme functions.
Ethanol Metabolism
About 90% of all ethanol is metabolized in the liver. The main enzyme involved is alcohol dehydrogenase, the vast majority of which (95%) is localized in hepatocytes (with the remainder in the brain, kidneys, lungs, and intestines).
Alcohol catabolism involves two dehydrogenation reactions. The resulting acetyl-CoA is oxidized in the citric acid cycle. A fraction of ethanol is oxidized via microsomal enzymes. Alcohol oxidation requires a massive amount of coenzymes: 125 g of ethanol consumes as much $NAD^+$ as 500 g of carbohydrates.
Effect of Ethanol on Carbohydrate Metabolism
Ethanol catabolism leads to a sharp increase in NADH concentration.
This excess of reducing equivalents shifts the equilibrium of the reaction catalyzed by lactate dehydrogenase (LDH) toward lactate production. As a result, pyruvate concentration decreases, leading to the suppression and inhibition of gluconeogenesis.
In acute alcohol intoxication in an unconscious patient, laboratory findings reveal hypoglycemia (glucose reduced to 50 mg/dL) and hyperlactatemia (lactate elevated to 2 mmol/L with a normal of 1 mmol/L), while blood alcohol levels vastly exceed normal limits. The excessively high $NADH/NAD^+$ ratio shifts the conversion of pyruvate to lactate, while the deficit of pyruvate and oxaloacetate inhibits glucose synthesis, causing severe hypoglycemia.