Gout

Overview

Gout is a metabolic disorder that can yield recurrent acute bouts of excruciating arthritis due to deposition of highly inflammatory urate crystals within joints. In the absence of treatment, urate crystals can continue to deposit, growing to large sizes, termed tophi, that can ultimately result in joint deformities. Treatment involves identifying the cause of excess blood uric acid and either preventing its excessive synthesis or improving inadequate urinary excretion.

Etiology

Ultimately, deposition of monosodium urate crystals in tissues requires their precipitation out of body fluid, a direct consequence of excessive uric acid levels or hyperuricemia. Excess uric acid can be caused either by its over-production or under-excretion. In most cases, over-production is the culprit, although the precise cause of excess uric acid production will remain unknown, termed primary gout. It should be pointed out that only a small percentage of hyperuricemic individuals will develop gout and thus additional mechanisms must exist to prevent uric acid precipitation. It is likely that these precipitation-inhibiting mechanisms are deranged or ineffective in individuals with primary gout.

Uric Acid is the final product of the purine nucleotide metabolism pathway. As mentioned, in most cases of gout the cause for uric acid over-production will remain unknown. That being said, for some patients, a bout of idiopathic gout will be precipitated by a large nucleotide-rich meal such as a juicy steak or alcohol consumption, both of which temporarily enhance uric acid production.
In a minority of cases, the cause for excess uric acid production can be identified, termed secondary gout. The most common context for development of secondary gout occurs in patients harboring rapidly dividing tumors such as lymphomas or leukemias. Here, lysis of rapidly dividing tumor cells can release large amounts of purine which is metabolized to uric acid, thus generating hyperuricemia and predisposing to gout. In rare cases, such as Lesch-Nyhan Syndrome genetic defects in the purine metabolism pathway will cause congenital uric acid over-production and thus a near guarantee for development of secondary gout.

Uric acid is primarily eliminated by the kidneys, and reduced renal excretion can be identified as the cause in a minority of patients. These individuals frequently have chronic renal failure or insufficiency. In some cases, a bout of gout may be precipitated by thiazide diuretics which reduce urice acid excretion.

Pathogenesis

Whatever the precise mechanism of hyperuricemia, precipitation of monosodium urate crystals is highly inflammatory. In general, precipitation is favored by lower temperatures and thus crystals tend to deposit in the feet, with a predilection for the metatarsophalangeal joint of the first toe. The potent inflammatory milieu appears to be generated by neutrophils and macrophages which are triggered to release large amounts of inflammatory cytokines after phagocytosing urate crystals.
With repeated bouts of unresolved acute gout, a chronic inflammatory picture evolves with granuloma development surrounding large deposits of urate, heralding "tophaceous gout". These walled-off tophi tend to be less inflammatory than individual urate crystals; however, they may take long periods of time to dissolve and eliminate.

Pathology

Urate cyrstals tend to deposit within the synovium and appear long, needle-like crystals on join aspirates. The acutely inflamed synovium will contain large numbers of neutrophils attempting to engulf the urate crystals

Tophi appear as large, grossly visible deposits of urate surrounded by granulomatous inflammation. Tophi can exist within the synovium and other soft tissues such as the skin and tendons. Although rarely seen now, over time, tophi can trigger significant fibrosis and profound deformation of joints.

Clinical Consequences

Gout tends to occur more commonly in men during the adult years. The disease can be thought of progressing through several stages described below.

Those that eventually develop gout are thought to harbor asymptomatic hyperuricemia for over 10-30 years, explaining why gout is a disease of adulthood. As mentioned, only a small percentage of those with hyperuricemia will develop gout; therefore, hyperuricemia itself is a poor predictor of disease development.

Gout will typically present as an intensely painful monoarticular arthritis. The affected joint will be swollen, red, and hot, thus commonly confused with an infectious arthritis. Indeed, a joint aspiration demonstrating needle-shaped crystals is the only definitive method of differentiating between the two. As mentioned, the first joint affected is typically the MTP of the great toe although any distal joint of the extremities is possible. Although medications can accelerate resolution, most cases of acute gout will self-resolve, leading to the "intercritical preiod"

In between episodes of gout, termed the intercritical period, the patient will remain completely asymptomatic. However, urate deposition appears to continue and for a subset of patients further episodes acute gout will occur followed by intercritical periods lasting weeks to months. Over time, more and more joints will become involved and the intercritical period will shorten, ultimately leading to development of tophi.

Over time, patients will develop large, palpable tophi in joints or surrounding soft tissues. Because tophi are walled-off by granulomas, they tend to be less painful, although they frequently ulcerate and can lead to significant joint deformity

Patients who suffer from gout often develop renal complications. Most predictably, urate crystals can precipitate within the renal tubules, generating uric acid calculi and thus precipitating nephrolithiasis. However, uric acid crystals can also deposit within the renal interstitium, eventually generating interstitial tophi and ultimately renal fibrosis, a process termed urate nephropathy.

Treatment

Treatment of gout occurs in two stages. Initially, the goal is to reduce acute inflammation and centers around administration of anti-inflammatories. Once the acute inflammation is controlled, the second step is to prevent further episodes by correct the underlying problem of uric acid over-production or under-excretion.

Bouts of acute gout are treated with either colchicine or NSAIDs such as indomethacin, with the goal of controlling the acute inflammation triggered by precipitating urate crystals. Importantly, aspirin is not used as it has effects on uric acid production and excretion itself.

Only a subset of patients will have repeated bouts of acute gout and thus practitioners may not begin prophylactic therapy until the second or possibly third episode of acute gout. However, once begun, prophylaxis is aimed at correcting the underlying problem of uric acid over-production or under-excretion, which can be distinguished by evaluating the urine uric acid levels. Over-producers are treated with agents that inhibit the purine metabolism pathway such as allopurinol. Under-excretors are treated with agents such as probenecid that improve urinary excretion.

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