Purine metabolism and development of hyperuricemia
Uric acid (uric acid) is the end product of purine degradation. The metabolic pathway includes two main branches:
- Adenine branch: Adenosine is transformed into inosine, then into hypoxanthine, and finally into xanthine.
- Guanine branch: Guanosine is converted into guanine, and then directly into xanthine.
At the final stage, xanthine is converted into uric acid. This key step is catalyzed by the enzyme xanthine oxidase (xanthine oxidase).
The development of hyperuricemia (a pathologically high uric acid level) is caused by two main mechanisms: either purine breakdown increases, or the renal excretion (elimination) of uric acid decreases. When the concentration of urates in the blood exceeds the solubility threshold (about 6.8 mg/dL), precipitation begins — the deposition of monosodium urate crystals.
Pathogenesis of inflammation
The deposition of monosodium urate crystals in the joint cavity acts as a trigger for the immune system. Phagocytes engulf the crystals, which triggers a powerful inflammatory cascade. Proteases, prostaglandins, leukotrienes, and oxygen free radicals are released in the focus. This exact process forms the full-blown clinical picture of an acute attack.
With frequent relapses, the disease transitions into a chronic phase: constant crystal deposition leads to the formation of tophi (tophi) — dense accumulations in soft tissues, which ultimately causes persistent joint damage and destruction.
Clinical presentation and stages of gout
The course of gout is traditionally divided into three distinct stages:
- Acute attack. Debuts as a monoarticular lesion, most commonly affecting the 1st metatarsophalangeal joint (the historical name for such a lesion is podagra). The attack usually begins early in the morning. Within 24–48 hours, symptoms rapidly escalate: the joint becomes erythematous, hot, edematous, and extremely painful. Marked hypersensitivity is characteristic — pain occurs with the slightest touch or movement.
- Intercritical period. The patient has no complaints, and upon examination, the joints appear completely normal.
- Chronic tophaceous gout. Develops in the absence of adequate treatment. Tophi localize in the soft tissues near the interphalangeal joints of the feet and hands, on the olecranon, and the helix of the ear. At this stage, periarticular erosions occur, leading to end-stage arthritis.
Diagnostic criteria and methods
A comprehensive approach is used to confirm the diagnosis:
- Gold standard: Examination of synovial fluid or tophus contents using polarizing microscopy. Monosodium urate crystals have a characteristic needle-like shape and demonstrate strong negative birefringence.
- Clinical diagnosis: When microscopy is not feasible, the ACR/EULAR (2015) criteria are applied. The following are taken into account: hyperuricemia (level > 6 mg/dL), asymmetric swelling, erythema, and tenderness of the 1st metatarsophalangeal joint.
- Laboratory markers: Inflammation markers and leukocytosis may be detected in the blood. It is important to remember that a normal serum uric acid level does not rule out an acute gout attack. Asymptomatic hyperuricemia is also not a hundred-percent sign of the disease.
- Radiography: In the early stages, only asymmetric soft tissue swelling can be noticed. In the chronic course, specific periarticular erosions with sclerotic overhanging margins and tophus shadows are revealed.
Differential diagnosis: Pseudogout
Pseudogout (pseudogout) is clinically very similar to gout, but has a different pathogenesis. It is caused by the deposition of calcium pyrophosphate dihydrate (CPPD) crystals.
Unlike gout, pseudogout more frequently affects the upper extremities (wrists) as well as large proximal joints (knees, pelvic joints). The condition is often associated with metabolic disorders: in 40% of cases, CPPD deposition accompanies hemochromatosis, and a connection with hyperparathyroidism and local joint trauma is also traced.
Briefly: answers to topical questions
Which enzymes are involved in the catabolism of purines to uric acid?
Several key enzymes are involved in the catabolism of purines to uric acid.
- 5'-nucleotidase — catalyzes the formation of adenosine from AMP via dephosphorylation.
- Adenosine deaminase — deaminates adenosine to inosine.
- Purine nucleoside phosphorylase — converts a nucleoside into a nitrogenous base.
- Guanase — deaminates guanine to xanthine.
- Xanthine oxidase (xanthine oxidase) — catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid.
Which groups of pharmacological agents are used to manage an acute gout attack?
Three main groups of pharmacological agents are used to manage an acute gout attack.
- Nonsteroidal anti-inflammatory drugs (NSAIDs) — inhibit crystal phagocytosis and reduce the inflammatory response (e.g., indomethacin, naproxen, sulindac).
- Glucocorticoids — used as intra-articular injections for rapid symptom relief, but are strictly contraindicated in septic arthritis.
- Colchicine (colchicine) — suppresses the acute inflammatory response by reducing neutrophil motility and inhibiting inflammatory mediators.
Which clinical, laboratory, and instrumental parameters are included in the full ACR/EULAR (2015) gout classification criteria system?
In available sources, the ACR/EULAR (2015) criteria system is described partially, including the following parameters.
- Absolute criterion — visual detection of monosodium urate crystals in synovial fluid or a tophus.
- Clinical parameters — presence of an episode of swelling or pain in a peripheral joint; tenderness or swelling of the first metatarsophalangeal joint (1st metatarsophalangeal joint); erythema (redness) over the joint.
- Laboratory parameters — hyperuricemia (uric acid level greater than 6 mg/dL).
- Instrumental parameters — asymmetric swelling and signs of joint damage on radiography; the ultrasound "double contour" sign; urate deposits according to dual-energy computed tomography.
To memorize metabolism: Adenine and Guanine (AG) merge into Xanthine, which under the blow of Xanthine Oxidase (XO) is converted into Uric Acid. The XO inhibitor is allopurinol.
Class and exam questions
Can an acute gout attack be ruled out if blood uric acid levels are within the normal range?
No. A normal serum uric acid level during a flare-up is common and does not contradict the diagnosis of gout.
With which diseases is it most difficult to differentiate an acute gout attack?
Due to pronounced erythema, swelling, local temperature rise, and leukocytosis in the blood, an acute attack is difficult to distinguish from infectious cellulitis or septic arthritis.
What are the radiological signs of chronic tophaceous gout?
Radiographs reveal soft tissue thickenings (tophi) and periarticular erosions, which have characteristic sclerotic overhanging margins.
What else to study on this topic
- Mechanisms of renal uric acid excretion and causes of its decrease
- Association of pseudogout with hemochromatosis and hyperparathyroidism
- Acute bursitis and tenosynovitis as complications of uncontrolled gout
- Differential diagnosis of subcutaneous tophi and rheumatoid nodules
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