Gout

David A. Ross, MD Reviewed 06/2017
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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

  • Overall prevalence of 3.9% (8.3 million) in the United States in 2008 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

  • Congestive heart failure

  • Coronary artery disease

  • Dyslipidemia

  • Renal disease

  • Organ transplant

  • Hypertension

  • Smoking

  • Diabetes mellitus

  • Urate-elevating medications:

GENERAL PREVENTION

  • Maintain optimal weight.

  • Regular exercise

  • Diet modification purine-rich foods)

  • Reduce alcohol consumption (beer and liquor).

  • Smoking cessation

  • Maintain fluid intake and avoid dehydration.

COMMONLY ASSOCIATED CONDITIONS

  • Hypertension

  • Dyslipidemia

  • Nontraumatic joint disorders

  • Heart 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 present.

  • Subcutaneous or intraosseous nodules, referred to as tophi, can be seen.

  • 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 olecranon 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 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.

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

  • Radiograph's are 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.

  • Ultrasound evidence of urate deposition—hyperechoic enhancement over surface of hyaline cartilage 4.

  • Dual-energy CT (DECT) imaging can show urate deposition at articular or periarticular sites 4.

  • ACR-EULAR Gout Classification calculator: (goutclassificationcalculator.aukland.ac.nz) validated classification criteria with sensitivity 92%, specificity 89% [with clinical criteria only sensitivity of 85% and specificity of 78%] 4.

TREATMENT

GENERAL MEASURES

Topical ice as needed 5[B

MEDICATION

  • Acute treatment

    • ▪ General principles:
      • * Acute gouty arthritis attacks should be treated with pharmacologic therapy 5[C].
      • * Pharmacologic treatment should be initiated within 24 hours of acute gout attack 5[C].
      • * Ongoing pharmacologic urate-lowering therapy should not be interrupted during an acute gout attack 5[C].
      • * Choice of agent is based on severity of pain and the number of joints involved 5.
    • ▪ 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 5[A]
        • Indomethacin (Indocin): 50-150 mg/day for 2-7 days 5[A]
        • Sulindac (Clinoril): 200 mg BID for 7-10 days 5[A]
        • Celecoxib (Celebrex)
        • ▪ Not FDA approved but can be considered in selected patients with contraindications or intolerance to NSAIDs 5[B].
          • □ Dose: 800 mg once, then 400 mg on day 1, then 400 mg BID for 1 week 5[B]
      • * Corticosteroids
        • ▪ Those with an acute flare involving one to two large joints can consider intra-articular corticosteroids; can consider using oral corticosteroids in combination
        • ▪ Corticosteroids are useful in patients with acute gout flare who cannot tolerate NSAIDs or have contraindications to NSAIDs such as chronic kidney disease (CKD)
        • ▪ For other acute flares, use oral corticosteroids:
          • Prednisone (Sterapred): 0.5 mg/kg/day for 5 to 10 days followed by discontinuation 5 [A] or alternately 2 to 5 days at full dose followed by tapering for 7 to 10 days and then discontinuing 5[C]
          • Methylprednisolone (Medrol) dose pack 5[C]
          • Triamcinolone acetonide (Trivaris): 60 mg IM single dose followed by oral corticosteroids 5[C]
      • * Colchicine (Colcrys)
        • ▪ Used for gout attacks where the onset was ≪36 hours prior to treatment initiation 5[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 5[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) 5.
    • ▪ Severe gout (≥7 of 10 on visual analog pain scale, involving ≥4 joints with arthritis involving >1 region, or involving three separate large joints)
      • * Initial combination therapy is an option and includes the use of full doses of the following 5[C]:
    • ▪ For patients not responding to initial pharmacologic monotherapy, add a second agent 5[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]
      • * 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 antiinflammatory prophylaxis has been initiated prior to urate-lowering therapy 1[C].
    • ▪ Anti-inflammatory prophylaxis required when initiating urate-lowering therapy:
      • * First line
      • * Second line: If use of colchicine and NSAIDs both are not tolerated, contraindicated, or ineffective:
      • * Treatment duration for the greater of
        • ▪ At least 6 months 5[A] or
        • ▪ 3 months after achieving serum urate appropriate for the patient with no tophi on exam 5[B], or for 6 months after achieving serum urate appropriate for the patient with ≥1 tophi on exam 5[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 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

    • Losartan possesses uricosuric properties; therefore, it may be an excellent agent if patient is also hypertensive.
    • ▪ Acute treatment: adrenocorticotropic hormone (ACTH): 25 to 40 IU SC 5[A]
    • 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 and good hydration
    • ▪ Smoking cessation
  • 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, sweetened beverages and desserts
    • ▪ Table salt, including in sauces and gravies
    • ▪ Alcohol (particularly beer) in all patients 1[B]
  • Encourage

    • ▪ Low-fat or nonfat dairy products
    • ▪ Vegetables

PATIENT EDUCATION

  • Dietary and lifestyle modifications 1[B]

  • 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  PP, et 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.  [View Abstract]
Doghramji  PP. Managing your patient with gout: a review of treatment options. Postgrad Med.  2011;123(3):56–71.  [View Abstract]
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.  [View Abstract]
Neogi  T, Jansen  T, Dalbeth  N, et al. 2015 Gout Classification Criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheumatol.  2015;67(10):2557–2568.  [View Abstract]
Khanna  D, Khanna  PP, Fitzgerald  JD, et 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.  [View Abstract]

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.

  • Pharmacologic treatment should begin within 24 hours of acute gout flare.

  • Asymptomatic hyperuricemia does not require treatment.

 
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