Gout

Ryan B. Feeney, PharmD, Michael C. Barros, PharmD, BCPS, BCACP and Paul N. Williams, MD, FACP Reviewed 07/2016
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Subject: Gout

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BASICS

DESCRIPTION

  • Gout is an inflammatory arthritis related to a hyperuricemia (serum uric acid [SUA] level >6.8 mg/dL) (1).

  • Acute gouty arthritis can affect ≥1 joints; the first metatarsophalangeal joint is most commonly involved at presentation (podagra).

  • Although hyperuricemia is necessary for the development of gout, it is not the only determining factor.

  • Characterized by deposition of monosodium urate (MSU) crystals that accumulate in joints and soft tissues, resulting in acute and chronic arthritis, soft-tissue masses called tophi, urate nephropathy, and uric acid nephrolithiasis

  • After an initial flare, a second flare occurs in ∼60% of patients within 1 year and 78% within 2 years of the initial attack (2).

  • Management involves treating acute attacks and preventing recurrent disease by long-term reduction of SUA levels through pharmacology and lifestyle adjustments

EPIDEMIOLOGY

Incidence

Annual incidence of gout (3): 
  • Uric acid 7 to 8.9 mg/dL is 0.5%.

  • Uric acid >9 mg/dL is 4.5%.

Prevalence

  • Increasing prevalence over the past decades (3)

  • 2007 to 2008 prevalence of gout in the United States (3)

    • Men 5.8% (6.1 million)

    • Women 2.0% (2.2 million)

  • 2008 prevalence of hyperuricemia in the United States (3)

    • Men 21.2% (SUA >7.0 mg/dL)

    • Women 21.6% (SUA >5.7 mg/dL)

ETIOLOGY AND PATHOPHYSIOLOGY

  • Hyperuricemia results from urate overproduction, underexcretion, or often a combination of the two.

  • Gout occurs when MSU, a product of purine metabolism, precipitates out of solution and accumulates in joints and soft tissues.

  • Transient changes in urate solubility caused by local temperature decrease, trauma, or acidosis may lead to an acute gouty attack.

  • Urate crystals that precipitate trigger an immune response.

  • Left untreated, this crystal deposition leads to permanent joint damage and tophus formation.

Genetics

  • Phosphoribosyl pyrophosphate (PRPP) deficiency and hypoxanthine-guanine-phosphoribosyltransferase (HGPRT) deficiency (Lesch-Nyhan syndrome) are inherited enzyme defects associated with overproduction of uric acid.

  • Polymorphisms in the URAT1 and SLC 2A9 (GLUT9) renal transporters are hereditary enzyme defects resulting in primary underexcretion of uric acid.

RISK FACTORS

  • Age >40 years

  • Male gender

  • Increased purine uptake (meats and seafood)

  • Alcohol intake (especially beer)

  • High fructose intake

  • Obesity

  • Hyperuricemia

  • Congestive heart failure

  • Coronary artery disease

  • Dyslipidemia

  • Renal disease

  • Organ transplant

  • Hypertension

  • Hyperinsulinemia

  • Metabolic syndrome

  • Diabetes mellitus

  • Urate-elevating medications:

GENERAL PREVENTION

  • Maintain optimal weight.

  • Regular exercise

  • Diet modification (purine-rich foods)

  • Reduce alcohol consumption (beer and liquor).

  • Maintain fluid intake and avoid dehydration.

COMMONLY ASSOCIATED CONDITIONS

  • Hypertension

  • Dyslipidemia

  • Nontraumatic joint disorders

  • Heart disease

  • Urinary tract disease

  • Diabetes mellitus

  • Metabolic syndrome

  • Obesity

  • Renal disease

DIAGNOSIS

HISTORY

  • Classic presentation of acute gouty arthritis:

    • Intense pain and tenderness in the first metatarsophalangeal joint (podagra)

    • Can occur in the midtarsal, ankle, or knee joints

    • Joint may be swollen, warm, and red

    • Often awakes patients from sleep due to an intolerance to contact with clothing or bed sheets

    • There is a rapid onset of intense pain, often beginning in the early morning and progressing rapidly over 12 to 24 hours.

    • In the absence of treatment, flares can last up to 10 days.

  • Fever can be seen.

  • SC or intraosseous nodules, referred to as tophi

  • Pain with urination secondary to uric acid renal stones

PHYSICAL EXAM

  • Examine suspected joint(s) for tenderness, swelling, and range of motion (ROM).

  • Assess for presence of firm nodules known as tophi.

  • In patients with chronic gout, tophi can frequently be found in the helix of the ear, over the olacrenon process, or on the Achilles tendon.

  • Patients with untreated chronic gout can have evidence of joint inflammation and deformity.

DIFFERENTIAL DIAGNOSIS

Acute bursitis, tendonitis, septic arthritis, pseudogout (calcium pyrophosphate deposition disease), cellulitis, osteoarthritis 

DIAGNOSTIC TESTS & INTERPRETATION

  • SUA (may be normal during an acute flare)

  • CBC (can see elevation of WBC during an acute gout flare)

  • Synovial fluid analysis: urate crystals (negatively birefringent under polarizing microscopy), cell count (WBC usually 2,000 to 5,000 cells/mm3); culture to rule out infection. Some guidelines suggest that gout can be diagnosed clinically without synovial fluid analysis.

  • Screen for uric acid overproduction 24-hour urinary uric acid in those patients with gout onset before the age of 25 years or had a history of urolithiasis (1)[C].

  • Radiograph is normal early in disease but can reveal

    • Swelling in acute gout

    • Periarticular erosions with periosteum overgrowth in chronic gout

  • Urate kidney stones are radiolucent and thus invisible on radiograph.

TREATMENT

GENERAL MEASURES

Topical ice as needed (4)[B

MEDICATION

  • Acute treatment

    • General principles:

      • Acute gouty arthritis attacks should be treated with pharmacologic therapy (4)[C].

      • Pharmacologic treatment should be initiated within 24 hours of acute gout attack onset (4)[C].

      • Ongoing pharmacologic urate-lowering therapy should not be interrupted during an acute gout attack (4)[C].

      • Choice of agent is based on severity of pain and the number of joints involved (4).

    • Mild/moderate gout severity (≤6 of 10 on visual analog pain scale, particularly for an attack involving only one or a few small joints or one to two large joints)

      • NSAIDs:

        • Naproxen (Naprosyn, Anaprox, Aleve): 750 mg followed by 250 mg q8h for 5–8 days (4)[A]

        • Indomethacin (Indocin): 50–150 mg/day for 2–7 days (4)[A]

        • Sulindac (Clinoril): 200 mg BID for 7–10 days (4)[A]

        • Celecoxib (Celebrex)

        • Not FDA approved but can be considered in selected patients with contraindications or intolerance to NSAIDs (4)[B].

          • Dose at 800 mg once followed by 400 mg on day 1, then 400 mg BID for 1 week (4)[B]

      • Corticosteroids

        • Those with an acute flare involving one to two large joints can consider intra-articular corticosteroids; can consider using PO corticosteroids in combination.

        • For other acute flares, use PO corticosteroids:

          • Prednisone (Sterapred): 0.5 mg/kg/day for 5–10 days followed by discontinuation (4)[A] or alternately 2–5 days at full dose followed by tapering for 7–10 days and then discontinuing (4)[C]

      • Colchicine (Colcrys)

        • Used for gout attacks where the onset was <36 hours prior to treatment initiation (4)[A]

        • Begin a loading dose of 1.2 mg followed by 0.6 mg 1 hour later, followed by 0.6 mg once or twice daily 12 hours later, until the gout attack resolves (4)[C].

        • Dose reduction recommended in moderate to severe kidney disease and in those on inhibitors of cytochrome P450 3A4 and P-glycoprotein (clarithromycin, erythromycin, cyclosporine, and disulfiram) (4).

    • Severe gout (≥7 of 10 on visual analog pain scale, involving ≥4 joints with arthritis involving >1 region, or involving 3 separate large joints)

      • Initial combination therapy is an option and includes the use of full doses of the following (4)[C]:

        • Colchicine and NSAIDs

        • PO corticosteroids and colchicine

        • Intra-articular steroids with all other modalities

    • For patients not responding to initial pharmacologic monotherapy, add a second agent (4)[C].

  • Chronic treatment

    • Indications for pharmacologic urate-lowering therapy include any patient with

      • Tophus or tophi by clinical exam or imaging study (1)[A]
      • Frequent attacks of acute gouty arthritis (≥2 attacks/year) (1)[A]
      • Chronic kidney disease (CKD) stage 2 or worse (1)[C]

      • Past urolithiasis (1)[C]

    • Treat to the serum urate:

      • Minimum serum urate target is <6 mg/dL (1)[A].
      • Serum urate target may need to be <5 mg/dL to improve gout signs and symptoms (1)[B].

    • Urate-lowering agents can be prescribed during an acute attack provided that effective anti-inflammatory prophylaxis has been initiated prior to urate-lowering therapy (1)[C].

    • Anti-inflammatory prophylaxis required when initiating urate-lowering therapy include the following:

      • First line

        • Low-dose colchicine: 0.6 mg once or twice daily (4)[A]

        • Low-dose NSAIDs with proton pump inhibitor if indicated: naproxen 250 mg PO BID (4)[C]

      • Second line: Use of colchicine and NSAIDs both are not tolerated, contraindicated, or ineffective:

      • Treatment duration for the greater of

        • At least 6 months (4)[A] or

        • 3 months after achieving serum urate appropriate for the patient with no tophi on exam (4)[B], or for 6 months after achieving serum urate appropriate for the patient with ≥1 tophi on exam (4)[C]

    • Pharmacologic urate-lowering agents:

      • Allopurinol (Zyloprim): xanthine oxidase inhibitor (1)[A]
        • Starting dose should be no higher than 100 mg/day (1)[B]
        • Starting dose should be 50 mg/day in stage 4 CKD or worse
        • Gradually titrate the dose upward q2–5wk to appropriate maximum dose (1)[C]
        • Dose can be >300 mg/day, even with renal impairment, as long as accompanied by patient education and monitoring of drug toxicity; maximum FDA-approved dosage is 800 mg/day (1)[B].
        • Regularly monitor for allopurinol hypersensitivity syndrome (AHS), pruritus, rash, elevated hepatic transaminases, and eosinophilia.
        • Screening for the HLA-B*5801 allele for AHS should be performed in those of Korean descent with stage 3 CKD or worse and Han Chinese or Thai descent irrespective of renal function (1)[A].
      • Febuxostat (Uloric): selective xanthine oxidase inhibitor (1)[A]
        • No renal or hepatic adjustments needed for mild-to-moderate hepatic or renal impairment
        • Starting dose 40 mg/day; may be titrated to 80 mg/day
        • In select instances, may dose up to 120 mg/day (not FDA approved) (1)[A]
      • Probenecid: uricosuric agent (1)[B]
        • Alternative first line urate-lowering therapy; use if at least one xanthine oxidase inhibitor is contraindicated or not tolerated (1)[B].
        • May be used in addition to allopurinol or febuxostat if serum urate target not achieved
        • Multiple drug interactions exist, as well as risk of urolithiasis with this agent.
        • Not recommended if creatinine clearance (CrCl) is <50 or with patient history of urolithiasis (1)[C].
        • Starting dose is 250 mg BID; gradually titrate to 2,000 mg/day

  • Other treatment

    • Acute treatment: adrenocorticotropic hormone (ACTH): 25 to 40 IU SC (4)[A]; especially in those NPO

    • Pegloticase in select severe instances (1)

SURGERY/OTHER PROCEDURES

Large tophi that are infected or interfering with joint motion may need to be surgically removed. 

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

  • SUA q2–5wk while titrating urate-lowering treatment to goal (1)[C]

  • Regularly monitor CBC, renal function, liver function test, and urinalysis.

DIET

  • General lack of evidence regarding specific recommendations, although the American College of Rheumatology has outlined the following (1)[C]:

  • General measures:

    • Weight loss for obese patients

    • Healthy overall diet

    • Exercise

    • Smoking cessation

    • Stay well hydrated

  • Avoid

    • Organ meats high in purine content (sweetbreads, liver, kidney) (1)[A]

    • High-fructose corn syrup–sweetened sodas, other beverages, or foods

    • Alcohol overuse (>2 servings per day for men and >1 serving per day for women) (1)[A]

    • Any alcohol use in gout during periods of frequent gout attacks or advanced gout under poor control

  • Limit

    • Serving sizes of beef, lamb, pork, and seafood with high purine content such as sardines and shellfish (1)[B]

    • Servings of naturally sweetened fruit juices

    • Table sugar and sweetened beverages and desserts

    • Table salt, including in sauces and gravies

    • Alcohol (particularly beer) in all gout patients (1)[B]

  • Encourage

    • Low-fat or nonfat dairy products

    • Vegetables

PATIENT EDUCATION

  • Dietary and lifestyle modifications (1)[B]

  • Patient instructions on initiating treatment on signs and symptoms of an acute gout attack without the need to consult health care provider for each attack (1)[B]

  • Discussion that gout is caused by excess uric acid and that effective urate-lowering therapy is essential treatment (1)[B]

PROGNOSIS

Gout can usually be successfully managed with proper treatment. 

COMPLICATIONS

  • AHS

  • Increased susceptibility to infection

  • Urate nephropathy

  • Renal stones

REFERENCES

Khanna D, Fitzgerald JD, Khanna PPet al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res.  2012;64(10):1431–1446.
Doghramji PP. Managing your patient with gout: a review of treatment options. Postgrad Med.  2011;123(3):56–71.
Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007–2008. Arthritis Rheum.  2011;63(10):3136–3141.
Khanna D, Khanna PP, Fitzgerald JDet al. 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res.  2012;64(10):1447–1461.

CODES

ICD10

  • M10.9 Gout, unspecified

  • M10.00 Idiopathic gout, unspecified site

  • M10.30 Gout due to renal impairment, unspecified site

  • M1A.30X0 Chronic gout due to renal impairment, unsp site, w/o tophus

  • M1A.9XX1 Chronic gout, unspecified, with tophus (tophi)

  • M10.09 Idiopathic gout, multiple sites

  • M10.39 Gout due to renal impairment, multiple sites

  • M10.079 Idiopathic gout, unspecified ankle and foot

  • M10.072 Idiopathic gout, left ankle and foot

  • M10.40 Other secondary gout, unspecified site

  • M10.49 Other secondary gout, multiple sites

  • M10.071 Idiopathic gout, right ankle and foot

  • M1A.9XX0 Chronic gout, unspecified, without tophus (tophi)

  • M10.379 Gout due to renal impairment, unspecified ankle and foot

  • M10.479 Other secondary gout, unspecified ankle and foot

  • M1A.30X1 Chronic gout due to renal impairment, unsp site, with tophus

ICD9

  • 274.9 Gout, unspecified

  • 274.00 Gouty arthropathy, unspecified

  • 274.10 Gouty nephropathy, unspecified

  • 274.19 Other gouty nephropathy

  • 274.89 Gout with other specified manifestations

  • 274.11 Uric acid nephrolithiasis

  • 274.03 Chronic gouty arthropathy with tophus (tophi)

  • 274.02 Chronic gouty arthropathy without mention of tophus (tophi)

  • 274.01 Acute gouty arthropathy

SNOMED

  • 90560007 Gout (disorder)

  • 190828008 gouty arthropathy (disorder)

  • 239844009 Gout secondary to renal impairment (disorder)

  • 190829000 chronic urate nephropathy (disorder)

  • 24595009 Primary gout (disorder)

  • 48440001 Articular gout (disorder)

  • 402469004 Gouty tophus (disorder)

CLINICAL PEARLS

  • MSU crystals found in synovial fluid aspirate are pathognomonic for gout.

  • Acute gout and sepsis can coexist.

  • Asymptomatic hyperuricemia does not require treatment.

  • Losartan possesses uricosuric properties, therefore it may be an excellent agent if patient is hypertensive.

 
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