Hyperuricemia - Gout

Gout is a type of arthritis caused by hyperuricemia leading to deposits of monosodium urate (MSU) crystals in tissues and joints. Synovial fluid examination is essential if the main differential diagnosis is between gout and septic joint.

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

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

ARUP Lab Tests

Aid in diagnosis and monitoring of gout or kidney stones

Aid in monitoring uric acid levels in patients at risk for kidney stone development

Assay interference (negative) may be observed when high concentrations of N-acetylcysteine (NAC) are present

Negative interference has also been reported with NAPQI (an acetaminophen metabolite), but only when concentrations are at or above those expected during acetaminophen overdose

May assist in evaluating for joint disease, systemic disease, or inflammation

Detect white blood cells (WBCs) and presence and type of microorganisms in specimen

Identify bacteria in normally sterile body fluids

May assist in differentiating gout from septic arthritis

Anaerobe culture is recommended for body fluids, tissue, and deep wound/surgical cultures; refer to anaerobe culture and gram stain 

For CSF specimens, order CSF culture and gram stain

For blood specimens, order blood culture or blood culture, AFB and fungal

Anaerobe culture is NOT included with this order

Identify patients with increased risk for allopurinol-induced severe cutaneous adverse reactions (SCAR) based on the presence of HLA-B*58:01 allele

Refer to Test Fact Sheet for further information

Aid in differentiating gout from septic arthritis

Related Tests

Screening test to evaluate kidney function

Screening test to evaluate kidney function

Aid in diagnosis of kidney stones

Aid in monitoring uric acid levels in patients at risk for kidney stone development (eg, gout)

Aid in diagnosis of gout (synovial fluid)

For information on body fluid reference ranges and/or interpretive guidance visit http://aruplab.com/bodyfluids/

Medical Experts

Contributor

Fisher

Mark A. Fisher, PhD, D(ABMM)
Associate Professor of Clinical Pathology, University of Utah
Medical Director, Bacteriology, Special Microbiology, and Antimicrobial Susceptibility Testing, ARUP Laboratories
Contributor

Genzen

Jonathan R. Genzen, MD, PhD
Associate Professor of Clinical Pathology, University of Utah
Chief Operations Officer, Medical Director of Automated Core Laboratory and Farmington Health Center Clinical Laboratory, ARUP Laboratories
Contributor

Lehman

Christopher M. Lehman, MD
Associate Professor of Clinical Pathology, University of Utah
Medical Director, University of Utah Health Hospital Clinical Laboratory, ARUP Laboratories

References

Additional Resources