Normal Uric Acid Metabolism
In humans, uric acid is the end product of purine base degradation. Its primary production occurs in the liver and intestines. In a healthy body, the serum concentration of this metabolite is maintained within a strict range of 0.15–0.47 mmol/L. Excess uric acid is excreted predominantly by the kidneys (daily urine contains 400 to 600 mg), with small amounts eliminated via the gastrointestinal tract.
Biochemical synthesis of uric acid concludes in two steps, both catalyzed by the enzyme xanthine oxidase:
- Oxidation of hypoxanthine to yield xanthine and hydrogen peroxide.
- Further oxidation of xanthine directly into uric acid (also releasing $H_2O_2$).
Pathogenesis of Gouty Arthritis
Hyperuricemia is diagnosed when the uric acid concentration exceeds 0.42 mmol/L. It can result from excessive dietary intake of purines, impaired endogenous synthesis, or defective renal excretion.
The core issue with uric acid is its extremely poor solubility. When the solubility threshold is crossed, it crystallizes into sodium urate. These crystals deposit in the synovial fluid of articular cartilage, ligaments, and soft tissues, forming specific nodules called tophi.
The mechanism of acute symptom development is as follows:
- Urate crystals are recognized by the immune system and phagocytosed by neutrophils.
- Sharp crystals damage intracellular lysosomal membranes.
- Massive release of lysosomal enzymes occurs into the surrounding tissue.
- Acute inflammation develops, accompanied by severe pain, pronounced swelling, local erythema, and fever.
Concurrently, excess urates frequently lead to renal calculi formation (nephrolithiasis).
Genetic Causes of the Pathology
Epidemiological data show that gout affects 0.3% to 1.7% of the population. Because men naturally have a higher serum urate pool, they develop the disease 20 times more frequently than women. Genetic factors play a significant role in primary hyperuricemia:
- PRPP synthetase anomalies. Mutations can cause hyperactivation of this enzyme or loss of its feedback inhibition by end products of purine synthesis, leading to uncontrolled purine production.
- Decreased hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity. Partial loss of this enzyme's function impairs the salvage pathway of purine bases, shunting excess purines into catabolic pathways.
Biochemical Principles of Treatment
Therapeutic management of gout aims to reduce the purine load and inhibit urate synthesis:
- Dietary therapy: Strict restriction of purine-rich foods (meat, organ meats, chocolate, coffee). Alkaline hydration is recommended to shift urinary pH and improve salt solubility.
- Pharmacological inhibition: The gold standard is allopurinol.
Mechanism of action of allopurinol: Allopurinol is a structural analog of hypoxanthine. It acts as a competitive and "suicide" inhibitor of xanthine oxidase. The enzyme recognizes the drug as a substrate and oxidizes it into oxypurinol. The resulting oxypurinol binds tightly and irreversibly to the active site of the enzyme, blocking its function. Consequently, purine catabolism halts at the hypoxanthine and xanthine stages. These intermediates are 10 times more soluble in body fluids than uric acid and are easily excreted by the kidneys without forming crystals.