istorically, gout has been considered a diseaseof affluent middle-aged men who eat anddrink to excess; however, gout does affectother segments of the population. Gout is a

systemic disease characterized by manifestations ofchronic underlying hyperuricemia, resulting in thedeposition of monosodium urate crystals in various tis-sues. Initially, inflammatory arthropathy is episodic,but it can become persistent if left untreated. Otherclinical signs of gout include tophi formation, renalcalculi, and urate nephropathy. This article reviews therisk factors, clinical features, and diagnostic evaluationof gout and discusses the management of gout andhyperuricemia.

RISK FACTORS

Gout has a strong male predominance, with an esti-mated 2% prevalence in men over age 30 years1 and apeak incidence in the fifth decade of life among men.2

Gout is rarely seen in premenopausal women but canbe found in postmenopausal women. The prevalenceof gout is higher in African Americans than in whites,3

and gout prevalence overall appears to have increasedin recent decades.4

Other risk factors for gout include older age, obesity,taking certain medications (eg, diuretics), and consum-ing purine-rich food and alcohol. Alcoholic beveragesnot only increase urate production but also decreaseurate elimination via the kidney. Beer has the highestpurine content of the alcoholic beverages and confersthe highest risk for developing gout. However, winedoes not increase the risk of developing gout. Interest-ingly, a recent study by Choi et al5 showed that consum-ing purine-rich vegetables had no correlation with goutdevelopment and increasing dairy intake decreasedgout incidence.

PATHOPHYSIOLOGY

Hyperuricemia is defined as a serum uric acid level

greater than 6.8 mg/dL. Baseline uric acid level ishigher among men (5.1 ± 1.0 mg/dL) than amongwomen (4.0 ± 1.0 mg/dL).6 Common causes of over-production or underexcretion of uric acid that canlead to hyperuricemia are shown in Table 1. When thelimit of solubility of monosodium urate in plasma isexceeded, urate crystals precipitate. Urate crystals arephagocytosed by neutrophils, which subsequentlyrelease potent inflammatory mediators, such as tumornecrosis factor-α, interleukin-1, and interleukin-6.These inflammatory mediators are responsible for sys-temic effects (eg, fever, leukocytosis) observed duringan acute attack of gout.

H

Dr. Sunkureddi is a rheumatology fellow, and Dr. Nguyen-Oghalai is anassistant professor of medicine, Division of Rheumatology. Dr. Karnathis an associate professor of medicine, Division of General Medicine. Allare at the University of Texas Medical Branch, Galveston, TX.

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R e v i e w o f C l i n i c a l S i g n s

Series Editor: Bernard M. Karnath, MD

Clinical Signs of Gout

Prashanth Sunkureddi, MDTracy U. Nguyen-Oghalai, MD

Bernard M. Karnath, MD

FEATURES OF GOUT

Gout has a strong male predominance.Asymptomatic hyperuricemia may be present for

decades.Risk factors for gout include: older age, obesity,

medications (eg, diuretics, niacin), and consump-tion of purine-rich foods and alcohol.

The metatarsophalangeal joint of the great toes isinvolved in 50% of initial attacks.

Nonsteroidal anti-inflammatory drugs (NSAIDs)are typically used as first-line therapy.

Corticosteroids are an effective alternative toNSAIDs.

CLINICAL FEATURES

Gout can be described in 4 stages: asymptomatichyperuricemia, intermittent acute gout, intercriticalgout, and advanced or chronic tophaceous gout. Thefirst stage, asymptomatic hyperuricemia, may be presentfor decades and is characterized by silent urate deposi-tion in tissue. The degree of hyperuricemia correlateswith the development of a gout attack in the secondstage.7 Acute gout attacks occur abruptly with severejoint pain and inflammation and are typically monoar-ticular. In 50% of the initial attacks, the metatarsopha-langeal joint of the great toes is involved, commonlyknown as podagra (Figure 1). Over time, attacks maybecome polyarticular and involve the ankles, knees,wrist, and joints in the hands. Impressive erythema ofthe surrounding area may also occur. Although theattack is often dramatic and painful, it is usually self-limited and lasts only several days. After each attack,long asymptomatic intervals may occur, which are re-ferred to as the intercritical period.8 This stage may lastmany years and, in some cases, patients have persistenthyperuricemia and low-grade inflammation in thejoints.9 Gout attacks can be precipitated by rapidchanges in the serum urate level caused by trauma,alcohol consumption, medications, and increased con-sumption of purine-rich foods (eg, hospitalized pa-tients such as those admitted for a myocardial infarc-tion or surgery who are not on their usual diet).

As the disease progresses, the intercritical periods ofgout become shorter and attacks occur more often,

eventually leading to the last stage, advanced or chronictophaceous gout. Patients often complain of constantpain and swelling in the joints. The clinical features ofchronic gouty arthritis can be similar to rheumatoidarthritis (Figure 2), but in gouty arthritis, plain radio-graphs of the joints show distinctive submarginal ero-sions with “overhanging edges,” atrophic and hyper-trophic features, and minimal periarticular osteopenia(Figure 3). Also, deposition of clusters of urate crystalsin soft tissues, known as tophi, can occur (Figure 4).While tophi can form anywhere in the body, commonlyinvolved sites are the olecranon bursa, fingers, wrists,and sometimes the helix of the ear.

In chronic gout, urate deposition in the kidneys canalso cause renal problems, such as urate renal stones(10%–25% of all patients with gout) and urate neph-ropathy, which can lead to progressive renal failure.6

DIAGNOSTIC EVALUATION

The definitive diagnosis of gout is made by verifyingthe presence of monosodium urate crystals in neutro-phils from synovial fluid obtained from the affectedjoint (via aspiration). Uric acid crystals are needle-shaped and, under a compensated polarizing micro-scope, are yellow and negatively birefringent when

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Figure 1. Acute arthritis of the right first metatarsopha-langeal joint in a patient with gout (known as podagra).

Figure 2. Arthritis of the hands. Note the distribution of thearthritis. The metacarpophalangeal and proximal interpha-langeal joints are predominantly affected, as in rheumatoidarthritis.

Table 1. Common Causes of Hyperuricemia

Overproduction

Foods with high purine content (eg, mussels, oysters, red meat, liver,anchovies)

Alcohol

Enzyme deficiencies (eg, hypoxanthine-guanine phosphoribosyltrans-ferase, phosphoribosyl pyrophosphate)

Obesity

Increased cell turnover

Malignancy

Psoriasis

Underexcretion

Renal disease

Lead intoxication (“saturnine gout”)

Medications (eg, diuretics, cyclosporine, low-dose aspirin, pyrazi-namide, niacin, ethambutol)

Metabolic acidosis (eg, ketoacidosis, lactic acidosis)

Alcohol

parallel to the plane of the polarizing lens (Figure 5).Cell count of the synovial fluid typically shows an in-flammatory exudate, with leukocyte counts rangingfrom 5000 to 80,000 cells/µL and with neutrophilic pre-dominance. The synovial fluid should also be evaluatedfor infection with Gram stain and culture because septicarthritis can rarely occur with acute gouty arthritis.

Serum uric acid levels should be checked, but anelevated serum uric acid level is not required to estab-lish the diagnosis of acute gout. Although most pa-tients will demonstrate hyperuricemia, a small numberof patients may have a normal uric acid level at thetime of an attack.10 A 24-hour urine collection for uricacid is not routinely performed in the initial evaluationbut can be done when uricosuric therapy is being con-sidered. Radiography of the affected joint in acute goutmay reveal soft tissue swelling but no characteristicbone or joint abnormalities.

The American College of Rheumatology criteria forthe classification of acute gouty arthritis state that thediagnosis of gout can be made based on clinical, labo-ratory, and/or radiographic findings without demon-stration of crystals (Table 2).11 However, if a synovialfluid analysis is not performed, other conditions thatcan mimic acute gout, such as rheumatoid arthritis,pseudogout, septic arthritis, trauma, and avascularnecrosis, cannot be definitively ruled out.

MANAGEMENT OF ACUTE GOUT

Nonsteroidal anti-inflammatory drugs (NSAIDs)can effectively treat acute gout attacks and are typicallyused as first-line therapy. Oral indomethacin has tradi-tionally been the NSAID of first choice, initially admin-istered at a dose of 50 to 75 mg and then 50 mg every 6 hours thereafter (maximum of 200 mg in 24 h). How-ever, other NSAIDs, including the cyclooxygenase-2selective agents, are effective as well.12 In general,NSAIDs should be started as soon as possible after a

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Figure 4. A large tophus at the olecranon in a patient withchronic gouty arthritis.

Figure 5. Under a compensated polarizing microscope, uratecrystals are needle-shaped, and they appear blue when perpen-dicular to the plane of the polarizing lens compensator (A), disap-pear when in the plane (B), and are yellow when parallel to theplane (C). (Reprinted with permission from American College ofRheumatology. ACR slide collection on the rheumatic diseases.3rd ed. Atlanta: The College; 2004. Copyright © 1972 – 2004American College of Rheumatology Clinical Slide Collection.)

Figure 3. Radiograph of the left hand in a patient withchronic gouty arthritis showing erosions in the second meta-carpophalangeal joint, third proximal interphalangeal joint,and the distal radius. Note the joint space narrowing, the cys-tic lesions, the lack of periarticular osteopenia, and the sub-marginal location of the erosions. (Reprinted with permissionfrom American College of Rheumatology. ACR slide collec-tion on the rheumatic diseases. 3rd ed. Atlanta: The College;2004. Copyright © 1972 – 2004 American College ofRheumatology Clinical Slide Collection.)

gout attack occurs and continued for 24 to 48 hoursafter the inflammation subsides. Because of the in-creased risk for gastrointestinal (GI) toxicity and renaldamage with NSAIDs, caution must be exercised inhigh-risk patients, such as the elderly and those withunderlying GI or renal disease.

For patients unable to tolerate NSAIDs, corticoster-oids are an effective alternative and can be given orally,intra-articularly, or intramuscularly. Intra-articular injec-tion of trimacinolone (10–40 mg) with lidocaine canprovide prompt relief in monoarticular gout. Systemiccorticosteroids (triamcinolone 80 mg given intramuscu-larly or 3–5 days of prednisone 20–40 mg) can be usedin patients with polyarticular gout. Adrenocorticotropichormone has also been used to treat acute gout.13

Although effective for treating acute gout, the use ofcolchicine is limited by serious side effects and a fre-quent administration schedule. Colchicine 0.6 mg oral-ly must be given every hour until symptoms have re-solved, side effects have developed, or a maximumdose of 6 g has been given. Most patients develop GIside effects, such as nausea, vomiting, abdominal pain,and diarrhea, prior to resolution of the arthritis. Use ofintravenous colchicine can avoid some GI toxicity, butthe risk for toxicity is still high; it is contraindicated in

patients with hepatic disease, renal failure, prior use ofcolchicine, or bone marrow suppression. For prophy-laxis against recurrent attacks, colchicine 0.6 mg dailyis effective and is usually continued until the serumuric level is below 6.0 mg/dL or after 6 months.

MANAGEMENT OF HYPERURICEMIA

The management of hyperuricemia is an essentialcomponent of the overall treatment of gout. Urate-lowering agents not only control hyperuricemia but alsocan reverse urate deposition. Many experts recommendtreatment of hyperuricemia with urate-lowering agentsif a patient has tophi, 2 or more arthritis attacks per year,erosive arthritis seen on radiography, or renal calculi.14

Allopurinol lowers serum urate levels by inhibitingurate production and is a competitive inhibitor of xan-thine oxidase, the last enzyme in the purine metabo-lism pathway that generates urate. The typical startingdose of allopurinol is 300 mg/d, and the dose can betitrated up to 800 mg/d to achieve the desired serumurate level of 6 mg/dL. Patients with renal insufficiencyshould be started at a lower dose (50–100 mg/dL)with slow titration as tolerated. There is a risk of precip-itating an acute gout attack when initiating allopurinol.It is recommended that patients start or continue pro-phylactic therapy with either NSAIDs or colchicinewhen starting urate-lowering therapy.15 One option isto continue colchicine 0.6 mg daily for 6 months forprophylaxis in addition to allopurinol. Febuxostat, anew nonpurine xanthine oxidase inhibitor, has beenreported to be efficacious and safe; US Food and DrugAdministration approval is pending.16

A less commonly used treatment of hyperuricemiais probenecid, a uricosuric agent. The typical startingdose is 500 mg/d, titrated up to 3000 mg/d. Prior tostarting therapy with a uricosuric agent, a 24-hoururine collection for uric acid should be performed.Typical indications for probenecid are urinary uricacid excretion of below 800 mg/24 h, age 60 years oryounger, normal renal function, and no history ofrenal calculi.6 Xanthine oxidase inhibitors and urico-suric agents can be combined if serum urate levels arenot reduced below 6 mg/dL on a single agent. Typic-ally, patients continue on urate-lowering therapy indef-initely. Currently, urate-lowering therapy is not indicat-ed for asymptomatic hyperuricemia.

ADVERSE EFFECTS OF GOUT THERAPY

Adverse reactions reported with allopurinol includeGI intolerance, bone marrow suppression, and skinrashes. Another severe adverse effect is the allopurinolhypersensitivity syndrome, which is characterized by a

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Table 2. Criteria for the Classification of Acute GoutyArthritis

A. The presence of characteristic urate crystals in the joint fluid, or

B. A tophus proved to contain urate crystals by chemical means or polarized light microscopy, or

C. The presence of 6 of the following clinical, laboratory, and/orradiographic features:

More than 1 attack of acute arthritis

Maximal inflammation developed within 1 day

Attack of monoarticular arthritis

Joint redness

First metatarsophalangeal joint painful or swollen

Unilateral attack involving first metatarsophalangeal joint

Unilateral attack involving tarsal joint

Suspected tophus

Hyperuricemia

Asymmetric swelling within a joint (shown on radiography)

Subcortical cysts without erosions (shown on radiography)

D. Negative culture of joint synovial fluid for microorganisms during attack of joint inflammation

Adapted with permission from Wallace SL, Robinson H, Masi AT, et al.Preliminary criteria for the classification of the acute arthritis of prima-ry gout. Arthritis Rheum 1977;20:895–900.

skin rash, hepatitis, eosinophilia, fever, renal failure,and possibly death. Patients with underlying renal insuf-ficiency and those taking diuretics are mostly likely todevelop the allopurinol hypersensitivity syndrome. Also,patients taking azathioprine or 6-mercaptopurineshould avoid allopurinol or substantially reduce theirdose because of the risk of bone marrow suppression.

Chronic colchicine therapy has been associated withrhabdomyolysis and a painful axonal neuromyopathyand should be avoided in patients with significant renalor hepatic disease.17 Probenecid is generally well toler-ated, with GI distress being the most common adverseeffect; however, it alters the metabolism of many drugs,including penicillin, heparin, and indomethacin.

CONCLUSION

Gout is a systemic disease characterized by manifesta-tions of hyperuricemia, such as inflammatory arthritis,tophi formation, nephropathy, and nephrolithiasis.When possible, diagnosis should be made by identifyingcharacteristic urate crystals in synovial fluid. Therapy forgout is effective and can dramatically change the courseof the disease. New drugs that are currently under devel-opment may provide additional options to treat gout inpatients not amenable to current therapies. HP

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