Definition

Gout is a systemic metabolic disease. Humans do not express the enzyme urate oxidase (uricase), which converts urate to the more soluble and easily excreted compound allantoin. This may lead to hyperuricemia. Gouty arthritis has four clinical stages¹: asymptomatic hyperuricemia, acute gouty flares, intercritical gout (intervals between acute flares), and chronic tophaceous gout. Acute flares in patients with gout are caused by inflammation from monosodium urate (MSU) crystal deposition as a result of chronically elevated levels of urate in plasma and extracellular fluids.

Gout is a common inflammatory arthritis. An estimated 8.3 million adults in the United States (prevalence of 3.9%) have gout.² The prevalence of gout is increasing. This is occurring because of increasing life expectancy and increases in prevalence of risk factors for gout such as greater use of diuretics and low-dose aspirin (acetylsalicylic acid) as well as an increase in prevalence of comorbidities such as obesity, renal disease, hypertension, and the metabolic syndrome.³

In the asymptomatic hyperuricemia stage, the patient has elevated levels of serum urate (SU) but no previous acute flares. During this phase, however, MSU crystals may “silently” be deposited in the tissues and joints and possibly other organs and result in “hidden damage,” which can occasionally occur over time even in the absence of clinically apparent gout. Hyperuricemia is often present for many years in the absence of clinical signs of gout. Acute flares occur as a result of the deposition of MSU crystals and activation of an inflammatory response leading to intense pain and other signs of inflammation, such as swelling, redness, and warmth of the involved joints. Over time, or with the help of drugs to terminate the acute flare, the flare will subside. At that point, even though the patient is not experiencing a flare, he or she is still considered to have gout and is in the intercritical stage until another flare occurs. Uncontrolled hyperuricemia and resultant gout can eventually evolve into the destructive chronic tophaceous gout.

The SU level is the single most important risk factor for development of gout.⁴ The SU level is elevated when it exceeds 6.8 mg/dL, the limit of solubility of MSU in serum at 37° C (98.6° F). A sustained elevation of SU is virtually essential for the development of gout but by itself is insufficient to cause the disease. In fact, most patients with hyperuricemia never develop gout.

It is now suspected that hyperuricemia may be a risk factor for cardiovascular disease as well as for hypertension, renal insufficiency, and nephrolithiasis.

Gouty arthritis is the most common inflammatory arthritis in adults. An estimated 8.3 million adults in the United States have gouty arthritis, corresponding to a prevalence of 3.9%.² Prevalence increases with age, peaking at about 10% among men aged 70 to 79 years, and 6% in women aged 80 years or older.² With the aging of populations in most developed countries, various studies have reported that the incidence of gout is increasing^2,3; this is probably driven not only by the increasing life expectancy in most countries but also by increases in the prevalence of risk factors for gout, including greater use of diuretics and low-dose aspirin (acetylsalicylic acid), and the increasing prevalence of comorbidities such as obesity, renal disease, hypertension, and metabolic syndrome.

Pathophysiology

Uricase, an end product of purine metabolism, is an enzyme that converts uric acid to allantoin, the soluble form. Its gene is silent in humans. The solubility of MSU crystals is related to temperature. At 37° C (98.6° F), the maximum solubility of urate in physiologic saline is 6.8 mg/dL; but at 30° C (86° F), it is only 4.5 mg/dL. If SU concentration is increased for a sustained period, MSU will come out of solution to form crystals. Microtophi may subsequently form, particularly in the cooler parts of the body as well as at points of mechanical pressure, such as fingers and toes, olecranon bursae, and ears. Sustained hyperuricemia is a risk factor for gout; however, most patients with hyperuricemia will never have a gout flare, and current guidelines suggest that no treatment is required, although it is prudent to determine the cause of hyperuricemia and to correct it if possible.

Uric acid production is increased in males after puberty and in females after menopause. The predominant cause of hyperuricemia in most patients is undersecretion of urate by the kidneys. Lower clearance of urate is seen in all gout patients compared with normal controls; it is therefore not surprising that up to 73% of all gout patients have mild to severe renal insufficiency.⁵

Clinical Presentation

Acute gout is characterized by a rapid onset and buildup of pain. The first flare often begins at night and wakes the patient from sleep. During an acute gouty flare, the patient experiences exquisite pain associated with warmth, redness, swelling, and decreased range of motion of the affected joint or joints. The initial episode is usually monoarticular in men. The first metatarsophalangeal (MTP) joint is the initial one involved in approximately half the patients. Acute synovitis of the first MTP joint of the big toe is referred to as podagra. Other joints involved (in decreasing order of frequency) are insteps, heels, knees, wrists, fingers, and elbows.⁶

In his classic description of the onset of an acute flare, Thomas Sydenham (London, 1683), a long-time sufferer from gout, wrote, “The victim goes to bed and sleeps quietly. About two in the morning he is awakened by a pain in the great toe; rarely in the heel, ankle or instep. The pain resembles that of a dislocated bone… [It] becomes so exquisitely painful as not to endure the weight of clothes nor the shaking of the room by a person walking in.”⁷

Systemic symptoms and signs of fatigue, fever, and chills may accompany the acute arthritis because of increased production of proinflammatory cytokines such as interleukin-1. The natural course of the untreated flare lasts several hours to several weeks.

Chronic tophaceous gout usually develops after 5 to 10 years of acute intermittent gout, although rarely patients have tophi as their initial manifestation of the disease. Tophus means “chalk stone” in Latin. Tophi appear as firm swellings. They may appear at any site. The most common sites for the tophi to appear are the digits of the hands and feet and in the olecranon bursa. Tophi of the helix or antihelix of the ear are classic but less common. Tophi may be associated with a destructive deforming arthritis and may rarely ulcerate, in which case secondary infection may be a problem.⁸ Local trauma and binges of alcohol, overeating, or fasting have been implicated as factors that precipitate an acute flare. Use of diuretics may also increase the risk of gout flares. In the hospital setting, acute flares of gout often occur postoperatively or are associated with severe acute medical illnesses. Changes in the body’s total uric acid pool also can precipitate a disease flare because homeostatic mechanisms mobilize the deposited MSU crystals. This is commonly seen in patients newly initiated on urate-lowering therapy (ULT) and can be mitigated by slow titration of the dose upward and the addition of concomitant prophylactic therapy, such as nonsteroidal anti-inflammatory drugs (NSAIDs) or colchicine.⁸ Finally, seasonal factors have been noted to relate to acute flares—for example, increased gout flares in the spring.⁹

Diagnostics

A definitive diagnosis of gout is achieved by needle aspiration of the acutely inflamed joint or suspected tophus. Even when clinical appearance strongly suggests gout, diagnosis has to be confirmed by needle aspiration.¹⁰ MSU crystals can be observed in more than 95% of patients experiencing attacks of acute gout.¹¹ However, this method is invasive and diagnosis is not always possible.

The typical clinical history includes sudden (reaching its pain peak within 2 to 4 hours) and severe, exquisite pain in a joint, most classically the first MTP joint (toe), that may wake the patient. The patient may have renal disease or be taking medications that can elevate SU. Elevated SU level, however, in up to 49% of patients may be normal during the acute flare.¹²

Advanced radiology can help with the diagnosis of gout. On ultrasonography, the double-contour sign or urate icing is highly specific for diagnosis of gout.¹³ The double-contour sign is observed on ultrasound examination as a hyperechoic band over anechoic cartilage and is believed to be indicative of MSU crystals overlying articular cartilage. Dual-energy computed tomography (DECT) is an advanced imaging modality that enables visualization of MSU crystal deposits by analysis of the chemical composition of the scanned materials. DECT provides good diagnostic accuracy for detection of MSU deposits in patients with gout. However, sensitivity is lower in patients with recent-onset disease.

Differential Diagnosis

Difficulties in the clinical diagnosis of gout occur because the disease can be polyarticular and chronic, especially in the elderly. Atypical joint involvement can also occur, such as in Heberden nodes, especially in elderly women. It can cause diagnostic confusion with rheumatoid arthritis. However, gout tends to be less symmetric than typical rheumatoid arthritis. Tophi sometimes tend to be confused with rheumatoid nodules, and therefore, when in doubt, the provider should perform needle aspiration to look for MSU crystals. It is sometimes difficult to determine whether the patient with acute arthritis has gout or pseudogout. Almost half of acute attacks of calcium pyrophosphate deposition disease (CPPD) affect the knees, but the wrists, metacarpophalangeal joints, elbows, and shoulders may be involved. However, under compensated polarized light, the difference between the two types of crystals is evident, and the correct diagnosis can be made. The CPPD crystals are rhomboid and have weakly positive birefringence.