Gout - Musculoskeletal Medicine for Medical Students

Contents

Description

In gout, excessive levels of serum uric acid (sUA) result in the formation of monosodium urate (MSU) crystals, triggering acute and chronic inflammation in joints and forming MSU masses (tophi) that damage tissues and joints.

Clinical manifestations

Gout manifestations vary with disease stage. Patients with asymptomatic hyperuricemia have no signs or symptoms whatsoever. In contrast, the patient suffering an acute gouty attack has one or more swollen, warm, red, and painful joint. In most first attacks, the involved joint is the first metatarsophalangeal joint (podagra). Subsequently, other joints may be involved; later attacks are often polyarticular. Attacks come on rapidly (typically, from several hours to 1 day). Between attacks, patients typically show no evidence of the presence of gout (intercritical period).

Chronic gouty arthritis occurs after years of inadequate treatment, particularly when sUA levels have remained high. Affected patients may develop deposited masses of urate (tophi, Latin for stone). Tophi may be visible in the helix of the ear, the bursa of the elbow, or on the hands or feet, and can grow large enough to impair motion and cause severe joint damage. In addition, chronic gout patients experience acute attacks more frequently, and often experience persistent inflammation between acute attacks.

Red flags

A single gout attack is extremely painful but usually self-limited. A missed diagnosis at that time will be of little long-term consequence. However, a missed diagnosis of an infected joint can be catastrophic; because gout and infection are often clinically indistinguishable, diagnostic joint aspiration should almost always be performed. On the other hand, chronic gout can be debilitating and accompanied by increased morbidity and mortality. Therefore, the importance of long-term treatment should not be underestimated.

Epidemiology

Gout prevalence has doubled over the past several decades, and gout is now the most common inflammatory arthritis. Factors contributing to this rise include:

The obesity epidemic and the rising prevalence of metabolic syndrome
The aging of the population
An increase in chronic kidney disease

Gout results from elevated sUA. Because sUA in males but not females rises at puberty, gout before older age is almost exclusively a male disease. At menopause, sUA rises in women as well; consequently gout is not uncommon in the older female population. Gout is distinctly rare in children, but may occur when genetic mutations affect urate metabolism. Currently the overall prevalence of gout in the US is 2-4%, but is 10% or greater in older adults.

Pathology and pathophysiology

Hyperuricemia — Uric acid derives from the breakdown of purines. Serum uric acid is determined by the intersection of purine synthesis/turnover and subsequent urate excretion. In most patients (90%), hyperuricemia derives primarily from a failure to adequately excrete urate. Urate is excreted mainly via the kidneys via a complex process: Urate is filtered at the glomerulus, then both resorbed and re-secreted by the proximal tubule so that only approximately 10% of filtered urate is finally excreted. Aberrancies in renal urate transport are common and can impede the kidney’s excretory ability. Moreover, chronic kidney disease (decreased filtration rate) on whatever basis reduces renal urate delivery and excretion. In a minority of patients (10%), hyperuricemia results from increased production of urate. This usually occurs with other conditions in which there is high cell turnover; rarely, inborn (genetic) errors can result in excessive purine, and, hence, urate synthesis (primary overproduction).

Gouty Inflammation — Gout requires three distinct but related events:

First, patients must experience a chronic state of elevated (supersaturated) sUA (>6.8 mg/dL).
Second, hyperuricemia permits MSU crystallization in joints and other structures.
Finally, MSU crystals then induce acute inflammatory responses, most often in joints.

The induction of inflammation by MSU crystals occurs through multiple mechanisms. Within a joint, crystals interact with synovial lining macrophages and induce them to produce inflammatory cytokines. Recent work implicates the macrophage NLRP3 inflammasome as a critical player in these responses. The inflammasome is a macromolecular complex that activates IL-1 and several other interleukins. IL-1 then activates both vascular endothelial cells and intravascular neutrophils. Simultaneously, MSU crystals activate complement and other soluble inflammatory mediators. These mediators induce neutrophils to migrate to crystals and phagocytose them, further stimulating the neutrophils to produce additional inflammatory markers. The result is an explosive inflammatory process.

Tophaceous deposition — Patients with longstanding gout, whose sUA levels have been inadequately controlled, may accrue masses of MSU in soft tissue, cartilage and bone. These tophi consist of dense deposits of MSU, surrounded by fibrous and inflammatory rinds. Depending on their size and location, tophi may be asymptomatic or even go unrecognized; they can also be large, painful, and disabling. Without management, tophi tend to enlarge progressively over time. Because of their space-filling capacity and their inflammatory rinds, tophi can destroy tissue, resulting in significant damage to bone and joints (Figure 1).

Figure 1. X-ray of the hand from a patient with tophaceous gout. The solid arrows indicate two examples of erosion of the bone, demonstrating the classic punched-out lesions with overhanging edges seen in chronic gout. The dashed arrow indicates an area of tophaceous deposition; calcification of the monosodium urate allows its visualization on x-ray.

Differential diagnosis

Differential diagnosis of acute gout depends on the patient history, physical examination, and laboratory testing. The most important alternative diagnosis to consider, particularly in monoarticular attacks, is septic joint because infection can rapidly and permanently damage joints. Other crystals, particularly calcium crystals, can cause attacks mimicking gout. Gout can also mimic virtually any inflammatory arthritis, depending on the pattern of presentation. For example, rheumatoid arthritis may need to be considered if the gouty attack is polyarticular and involves the hands.

Etiology

As noted above, the etiology of hyperuricemia may be genetic, but multiple acquired conditions can push the level of sUA beyond its saturation point. Undoubtedly, both genetic and environmental factors affect the extent to which MSU induces inflammatory responses, but such processes are poorly understood.

Radiographic and laboratory findings

Patients with gout will almost invariably have urate levels > 6.8 mg/dL, although these values can fluctuate and transiently appear within the normal range. However, many hyperuricemic patients never experience gout, so the sUA by itself cannot be used to make a diagnosis. During acute attacks, inflammatory markers (ESR, CRP) will be elevated — often markedly – but these are non-specific and only confirm inflammation. Chronic gout will commonly be accompanied by the presence of “punched-out” erosions seen on X-rays, representing tophi within peri-articular bone, as shown in Figure 1, above.

The only definitive way to diagnose an acute gouty attack is to aspirate the joint. Patients with gout will demonstrate synovial fluid leukocytosis (predominantly neutrophils) and the presence of negatively birefringent, needle-shaped crystals viewed using a polarizing microscope. Even with these findings, a simultaneous infection is not definitively excluded. Accordingly, synovial fluid aspirated for gout should always be assessed for infection by Gram stain and culture.

Risk factors and prevention

Multiple risk factors promote hyperuricemia and subsequently gout. Diets rich in purines, or high in alcohol or fructose (promoting purine turnover and urate synthesis), can raise sUA. Diseases of high cell turnover such as leukemia and lymphoma also promote hyperuricemia (secondary overproduction). Diuretics and certain other drugs can inhibit renal urate excretion and promote hyperuricemia. Obesity is also associated with hyperuricemia, but the relative contributions of diet versus adiposity are unclear. Nonetheless, weight loss reduces sUA and is advisable in overweight gout patients.

Treatment options

Treatment of acute gout focuses on suppressing inflammation, and three classes of agents are used — non-steroidal anti-inflammatory drugs, glucocorticoids, and colchicine. All are effective; the choice of agent depends on which will be best tolerated in the individual patient. Intra-articular glucocorticoid injections are effective but should be eschewed if infection is not definitively excluded. Changing the dose of urate-lowering drugs during an acute attack — either by initiating or discontinuing them — should generally be avoided because acute urate shifts may worsen the attacks.

For patients with established gout (?2 attacks/year) who are between attacks, urate-lowering should be initiated to reduce the urate burden and the risk of both attacks and tophi. First-line agents include allopurinol and febuxostat, which block urate production by inhibiting the synthesis enzyme xanthine oxidase. A recombinant uricase enzyme (pegloticase) is FDA-approved for refractory patients and can lower urate dramatically. In contrast to targeting urate production, probenecid promotes urate excretion from the kidneys. All patients starting urate-lowering therapy must receive anti-inflammatory prophylaxis (usually colchicine) for 6 or more months, since urate lowering transiently increases the risk of gouty attack. The goal is to drive the serum urate level to <6.0 mgs/dL (lower to resolve tophi). Drugs promoting hyperuricemia, including diuretics, should be substituted out whenever feasible.

Outcomes

With aggressive treatment, it should be possible to keep the serum urate below 6.0 mg/dL. If this target is achieved, most patients will eventually become free of acute attacks. Resolution of tophi can take years and may require more aggressive urate lowering. Unfortunately, studies suggest that in a surprising majority of cases, gout is inadequately treated, leading to increasingly frequent attacks and joint damage.

Holistic

Although not usually sufficient in itself, the importance of diet in reducing sUA should not be underestimated. High purine foods (meat, seafood), fructose, and alcohol should be limited. Cherries, eaten in large quantities daily, may help reduce gout risk, but the fructose load may undesirable. Increased consumption of dairy has been suggested to both lower serum urate levels and possibly decrease inflammation. Weight loss is beneficial.

Miscellany

Patients with gout commonly experience multiple co-morbidities, similar to those seen in the metabolic syndrome. Hyperuricemia and/or gout may directly contribute to some of these co-morbidities, including renal and cardiovascular disease. If these observations are confirmed, the treatment of gout will take on increased urgency.

Key terms

Gout, hyperuricemia, colchicine, allopurinol, febuxostat

Skills and competencies

Bedside skills for the diagnosis of gout include the ability to take a detailed but focused history and to perform a thorough musculoskeletal examination. More advanced skills include the ability to aspirate and/or inject joints (students should be able to aspirate easily accessible joints such as the knee under expert supervision), and to identify crystals in joint fluid.