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.

Tabs Content

Clinical Overview

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
Clinical	Pattern of joint/bursa involvement during symptomatic episode(s) ever^b	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
Time course of episode(s) ever		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
Imaging^d	Imaging evidence of urate deposition in symptomatic (ever) joint or bursa	Present	4
Imaging^d	Imaging evidence of gout-related joint damage	Present	4
^aA web-based calculator can be accessed at: http://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

ARUP Lab Tests

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Uric Acid, Serum or Plasma 0020026
Method: Quantitative Spectrophotometry

Recommended Use

Aid in diagnosis and monitoring of gout or kidney stones

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

Limitations

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

Cell Count, Body Fluid 0095019
Method: Cell Count/Differential

Recommended Use

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

Gram Stain 0060101
Method: Stain/Microscopy

Recommended Use

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

Body Fluid Culture and Gram Stain 0060108
Method: Stain/Culture/Identification

Recommended Use

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

Limitations

Anaerobe culture is NOT included with this order

HLA-B*58:01 Genotyping, Allopurinol Hypersensitivity 3001393
Method: Polymerase Chain Reaction/Sequence Specific Oligonucleotide Probe Hybridization

Recommended Use

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

CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Recommended Use

Aid in differentiating gout from septic arthritis

Test Fact Sheet(s)

HLA-B*58:01 Genotyping, Allopurinol Hypersensitivity

Medical Experts

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

Genzen, Jonathan R., MD, PhD, Laboratory Section Chief, Clinical Chemistry, and Medical Director, Automated Core Laboratory, at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Lehman, Christopher M., MD, Co-Medical Director, University Hospitals and Clinics Clinical Laboratory; Professor of Clinical Pathology, University of Utah

References

Guidelines

Wallace SL, Robinson H, Masi AT, Decker JL, McCarty DJ, Yü TF. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum. 1977; 20(3): 895-900. PubMed
Neogi T, Jansen TL, Dalbeth N, Fransen J, Schumacher HR, Berendsen D, Brown M, Choi H, Edwards NL, Janssens HJ, Lioté F, Naden RP, Nuki G, Ogdie A, Perez-Ruiz F, Saag K, Singh JA, Sundy JS, Tausche AK, Vaquez-Mellado J, Yarows SA, Taylor WJ. 2015 Gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2015 Oct;74(10):1789-98.
Qaseem A, McLean RM, Starkey M, Forciea MA, Clinical Guidelines Committee of the American College of Physicians. Diagnosis of Acute Gout: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2017; 166(1): 52-57. PubMed
Richette P, Doherty M, Pascual E, Barskova V, Becce F, Castañeda-Sanabria J, Coyfish M, Guillo S, Jansen TL, Janssens H, Lioté F, Mallen C, Nuki G, Perez-Ruiz F, Pimentão J, Punzi L, Pywell T, So A, Tausche AK, Uhlig T, Zavada J, Zhang W, Tubach F, Bardin T. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017; 76(1): 29-42. PubMed
Saito Y, Stamp LK, Caudle KE, Hershfield MS, McDonagh EM, Callaghan JT, Tassaneeyakul W, Mushiroda T, Kamatani N, Goldspiel BR, Phillips EJ, Klein TE, Lee MT, Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for human leukocyte antigen B (HLA-B) genotype and allopurinol dosing: 2015 update. Clin Pharmacol Ther. 2016; 99(1): 36-7. PubMed

General References

Courtney P, Doherty M. Joint aspiration and injection and synovial fluid analysis. Best Pract Res Clin Rheumatol. 2009; 23(2): 161-92. PubMed

Eggebeen AT. Gout: an update. Am Fam Physician. 2007; 76(6): 801-8. PubMed

Hainer BL, Matheson E, Wilkes T. Diagnosis, treatment, and prevention of gout. Am Fam Physician. 2014; 90(12): 831-6. PubMed

Lillicrap M. Crystal arthritis: contemporary approaches to diseases of antiquity. Clin Med. 2007; 7(1): 60-4. PubMed

Mandell BF. Clinical manifestations of hyperuricemia and gout. Cleve Clin J Med. 2008; 75 Suppl 5: S5-8. PubMed

Minisola S, Pepe J, Piemonte S, Cipriani C. The diagnosis and management of hypercalcaemia. BMJ. 2015; 350: h2723. PubMed

Pascual E, Sivera F, Andrés M. Synovial fluid analysis for crystals. Curr Opin Rheumatol. 2011; 23(2): 161-9. PubMed

Underwood M. Diagnosis and management of gout. BMJ. 2006; 332(7553): 1315-9. PubMed

Content Review:

May 2017

Last Update: February 2019

Hyperuricemia - Gout

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Imaging Studies

Differential Diagnosis

Monitoring

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Test Fact Sheet(s)

Medical Experts

References

Guidelines

General References

ARUP Laboratories

ARUP Websites

ARUP Consult


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	Hyperuricemia - Gout. ARUP Consult^©. Retrieved June 20, 2019, from: https://arupconsult.com/content/hyperuricemia

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Hyperuricemia - Gout

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Imaging Studies

Differential Diagnosis

Monitoring

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Test Fact Sheet(s)

Medical Experts

References

Guidelines

General References

ARUP Laboratories

ARUP Websites

ARUP Consult