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:
- Thiazide diuretics: ethambutol
- Loop diuretics (less of a risk vs. thiazides)
- Niacin
- Calcineurin inhibitors (cyclosporine and tacrolimus)
- Acetylsalicylic acid (not recommended in high doses)
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]
- Methylprednisolone (Medrol) dose pack (4)[C]
- Triamcinolone acetonide (Trivaris): 60 mg IM single dose followed by oral corticosteroids (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:
- Low-dose prednisone or prednisolone at ≤10 mg/day (4)[C]
- 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
11 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):1431-1446.22 Doghramji PP. Managing your patient with gout: a review of treatment options. Postgrad Med. 2011;123(3):56-71.33 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):3136-3141.44 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.
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.