Hyperuricemia - Gout

Diagnosis

Indications for Testing

Swollen, erythematous joint(s)

Criteria for Diagnosis

• Diagnosis based on the American College of Radiology/European League against Rheumatism (ACR/EULAR) 2015 guidelines
  • Step 1: sufficient criterion (if met, can classify as gout)
    • Presence of tophus – monosodium urate (MSU) crystals in a symptomatic joint or bursa (ie, in synovial fluid)
  • Step 2: ACR/EULAR gout classification criteria
    • Entry criterion – ≥1 episode of swelling, pain, or tenderness in a peripheral joint or bursa
    • Score of 8 confirms gout
    • ACR/EULAR gout classification criteria and scoring

      ACR/EULAR Gout Classification Criteria^a

      	Criteria	Categories	Score
      Clinical	Clinical	Ankle or midfoot	1
      	Pattern of joint/bursa involvement during symptomatic episode(s) everb	Involvement of the first metatarsophalangeal joint	2
      Characteristics of symptomatic episode(s) ever	Erythema overlying affected joint (patient reported or physician observed) Can't bear touch or pressure to affected joint Great difficulty with walking or inability to use affected joint	One characteristic	1
      		Two characteristics	2
      		Three characteristics	3
      Time course of episode(s) ever	Presence (ever) of ≥2, irrespective of anti-inflammatory treatment Time to maximal pain <24 hours Resolution of symptoms in ≤14 days Complete resolution (to baseline level) between symptomatic episodes	One typical episode	1
      		Recurrent typical episodes	2
      Tophus	Clinical evidence of tophus	Present	4
      Laboratory	Serum urate	<4 mg/dL (<0.24 mmol/L)c	-4
      		6–<8 mg/dL (0.36–<0.48 mmol/L)	2
      		8–<10 mg/dL (0.48–<0.60 mmol/L)	3
      		≥10 mg/dL (≥0.60 mmol/L)	2
      	Synovial fluid analysis of a symptomatic (ever) joint or bursa	Monosodium urate (MSU) negative	-2
      Imagingd	Imaging evidence of urate deposition in symptomatic (ever) joint or bursa	Present	4
      	Imaging evidence of gout-related joint damage	Present	4
      aA web-based calculator can be accessed at: https://goutclassificationcalculator.auckland.ac.nz, and through the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) web sites. bSymptomatic episodes are periods of symptoms that include any swelling, pain, and/or tenderness in a peripheral joint or bursa. cIf serum urate level is <4 mg/dL (<0.24 mmol/L), subtract 4 points; if serum urate level is ≥4−<6 mg/dL (≥0.24−<0.36 mmoles/L), score this item as 0. dIf imaging is not available, score these items as 0.

Laboratory Testing

• Serum uric acid
  • Elevated in only 50% of patients during an acute attack
    • Lack of elevation does not rule out gout
  • Ideally measured >4 weeks after an acute attack
    • If normal value found during an attack, repeat when joint normalizes
  • Ideal method – uricase (ACR/EULAR, 2015)
• Synovial fluid examination
  • Essential if main differential diagnosis is between gout and septic joint – otherwise not used very often
  • Cell count – predominance of polymorphonuclear cells
    • Absolute white blood cell (WBC) count usually <50,000
  • Crystals – presence of uric acid crystals in fluid as viewed by polarized light microscopy is diagnostic
  • Gram stain and culture to rule out septic arthritis
• CBC – modest leukocytosis may be present
  • Significant leukocytosis suggests septic joint
• Blood urea nitrogen (BUN) and creatinine – to evaluate renal function
  • Drugs used to treat acute and chronic gout may be affected by renal function
    • Uricosuric drugs less effective; other drugs need dosing modifications
• HLA-B*5801 genotyping – recommended prior to initiation of allopurinol therapy (Saito, Clinical Pharmacogenetics Implementation Consortium, 2016)
  • To ​identify patients at increased risk for developing severe cutaneous adverse reactions to allopurinol (allopurinol hypersensitivity reaction)
    • Highest HLA-B*58:01 allele frequencies are found in Asian populations – up to 20% in Taiwan, Singapore, and among Han Chinese

Imaging Studies

•  Acute gout – not useful
• Chronic gout – may demonstrate tophi or erosive joint disease

Differential Diagnosis

• Calcium pyrophosphate dihydrate disease (pseudogout)
• Reactive arthritis (eg, Campylobacter jejuni)
• Septic arthritis
• Cellulitis
• Osteoarthritis
• Rheumatoid arthritis, other arthritides
• Internal ligament derangement
• Hemarthropathy
• Traumatic arthritis

Monitoring

• Serum urate should  be lowered to improve signs and symptoms of gout, with a minimum target of 6 mg/dL, and often <5 mg/dL (American College of Radiology [ACR], 2012; European League against Rheumatism [EULAR], 2016)
• Current evidence is not sufficient to recommend a goal serum uric acid level in terms of the benefits of higher dosing versus the harms of higher doses (American College of Physicians [ACP],  2017)
• Evidence does support a decreased number of gout flares with preventative dosing below a serum urate level of 7 mg/dL, although the benefits are not seen for 6 months (ACP,  2017)
• Serum uric acid level ≤3 mg/dL not recommended for long-term treatment (EULAR, 2016)

Background

Epidemiology

• Prevalence – 3.9% in U.S. (American College of Radiology/European League against Rheumatism [ACR/EULAR], 2015)
• Age – unusual <30 years; peaks at 12% >80 years
• Sex – M>F; 4-9:1

Risk Factors

• Obesity (body mass index [BMI] ≥30 kg/m²)
• Medications – thiazide and loop diuretics, niacin, and calcineurin inhibitors
• Diet high in fructose corn syrup (eg, sweetened beverages)
• High purine diet (red meat, wild game, or organ meats)
  • Nuts, oats, asparagus, legumes are high in purine but do not seem to increase risk
• Alcohol consumption (particularly beer)
• Male sex
• Poor kidney function
• Common acute attack triggers in patients with preestablished gout
  • Trauma
  • Surgery
  • Psoriasis exacerbation
  • Diuresis
  • Starting or stopping allopurinol
  • Infections

Pathophysiology

• Uric acid – final byproduct of purine metabolism; poorly soluble
• Hyperuricemia – often caused by altered purine metabolism; leads to increased levels of uratic acid
  • Decreased excretion, increased production, or a combination of factors may be involved as etiology of hyperuricemia
  • When solubility limits are exceeded, MSU crystals precipitate in joints, kidneys, and soft tissues
    • Crystal deposition triggers immune activation with release of inflammatory cytokines and neutrophils
    • Tophi – MSU crystals in a matrix of lipids, protein, and mucopolysaccharides

Clinical Presentation

• Typically a clinical diagnosis
• Nonspecific – fever
• Monoarticular arthritis
  • More common in lower extremities – typical joints include first metatarsophalangeal, midfoot, ankle
• Pain, erythema, and swelling of joint
  • Abrupt onset
  • Usually takes <24 hours to go from asymptomatic to maximum pain
  • Complete remission between episodes
  • Resolution of symptoms usually ≤14 days
• May cause fever, leukocytosis, and/or cellulitis over joint
• Chronic gout
  • Tophi – subcutaneous nodules
    • Typical locations – joints, ears, finger pads, olecranon bursa
  • Joint erosion and destruction
    • Typically visible on x-ray of affected joint
  • Increased susceptibility to septic joints – knee and olecranon bursa most common