Gout Diagnosis

Diagnosis

Classification

Causes of Hyperuricemia

Excessive uric acid production:
- Inherited enzyme defects (eg hypoxanthine-guanine phosphoribosyltransferase deficiency, phosphoribosyl pyrophosphate synthetase overactivity, glycogen storage diseases, fructose-1-phosphate aldolase deficiency, myoadenylate deaminase deficiency, carnitine palmitoyltransferase II deficiency)
- Clinical disorders (eg myeloproliferative and lymphoproliferative disorders, malignancies, psoriasis, Down syndrome)
- Induced by diet, drugs, or toxins (eg ethanol, excessive purine in diet, fructose, vitamin B12 deficiency, Nicotinic acid, cytotoxic drugs, Warfarin)

Decreased renal clearance:
- Genetic disorders such as medullary cystic kidney disease, familial juvenile hyperuricemic nephropathy and uric acid transportasome mutations
- Chronic renal insufficiency, volume depletion (eg heart failure, volume loss), obesity, diabetic or starvation ketoacidosis, lactic acidosis, hyperparathyroidism, hypothyroidism, sarcoidosis
- Induced by diet or drugs (eg Aspirin, diuretics, Ciclosporin, Tacrolimus, Ethambutol, Pyrazinamide, ethanol, Levodopa)
- Saturnine gout is a rare form of gout due to chronic lead exposure
  - Commonly seen in plumbers and those exposed to lead-based paints

Clinical Phases of Gout

Acute Gout

Usually manifests as an acute, self-limiting, monoarticular inflammatory arthritis in majority of patients
Lower extremity joints are affected more often than upper extremity joints
- Joints most commonly affected include the 1st metatarsophalangeal joint (podagra), forefoot, ankle, knee
Extra-articular sites (eg olecranon bursa and Achilles tendon) may also be involved
Attacks may occur and last from a few days to 2-3 weeks, with resolution of all inflammatory signs
- Early attack: <12 hours after onset of attack
- Well-established attack: 12-36 hours after onset of attack
- Late attack: >36 hours after attack onset

Intercritical Gout

Periods in between attacks when patient is free of symptoms
Asymptomatic joints may still have crystals detected in the synovial fluid

Chronic Gout

If hyperuricemia is not treated properly, intermittent acute gouty attack can develop into chronic gouty arthritis
There is persistent inflammation in the joints and connective tissues associated with bony erosions and deformities
Polyarticular flares of gouty arthritis occur and associated with bony erosions and deformities
Chronic tophaceous gout:
- Marked by polyarticular arthritis and the formation of tophi which are chalky deposits of monosodium urate
- Tophi are usually painless, appearing as firm, nodular or fusiform masses located subcutaneously
- Risk factors include polyarticular presentation, serum urate level 9 mg/dL (>0.54 mmol/L)
Presence of urate nephropathy or urate renal calculi

Gout Classification Criteria¹

Developed by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) in 2015
The new criteria is based on the presence of monosodium urate monohydrate crystals, imaging modalities, and clinical parameters
Provides a scoring system for a patient’s symptomatic episode, regardless of the clinical phase
A total score of ≥8 confirms the diagnosis of gout
Entry criterion is defined as at least 1 episode of swelling, pain, or tenderness in a peripheral joint or bursa
Sufficient criterion should be considered with the presence of urate crystals in a symptomatic joint or bursa, or a positively-identified tophus
The classification criteria should be used if sufficient criterion is not met

Criteria	Categories	Score
Clinical Parameters (Per Symptomatic Episode)
Pattern of joint or bursa involvement	Ankle or midfoot 1st metatarsophalangeal joint	1 2
Characteristics Erythema overlying affected joint Unable to tolerate touch or pressure on the affected joint Difficulty with walking or unable to use affected joint	1 characteristic 2 characteristics 3 characteristics	1 2 3
Time course: Presence of ≥2 of the following regardless of anti-inflammatory treatment: Time to maximal pain <24 hours Resolution of symptoms happen in ≤14 days Complete resolution between symptomatic episodes	1 typical episode Recurrent typical episode	1 2
Clinical evidence of tophus²	Present	4
Laboratory Parameters
Serum urate^3,4	<4 mg/dL (<0.24 mmol/L) 6-<8 mg/dL (0.36-<0.48 mmol/L) 8-<10 mg/dL (0.48-<0.60 mmol/L) ≥10 mg/dL (≥0.60 mmol/L)	-4 2 3 4
Synovial fluid analysis per symptomatic episode	Monosodium urate monohydrate negative	-2
Radiologic Parameters⁵
Evidence of urate deposition: Double-contour sign seen with ultrasound or urate deposition seen by dual-energy computed tomography (DECT)	Present	4
Evidence of gout-related joint damage: At least 1 erosion seen using conventional radiography of the hands and/or feet	Present	4
¹Adapted from Neogi T, Jansen TL, Dalbeth N, et al. 2015 Gout Classification Criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheumatol. 2015 Oct;67(10):2557-2568. ²Tophus characterized as a draining or chalk-like subcutaneous nodule under transparent skin, often with overlying vascularity, usually located in joints, ears, olecranon bursae, finger pads, and/or tendons. ³Obtained using the uricase method; scoring should be done while the patient is not taking urate-lowering drugs and >4 weeks have passed since the occurrence of symptoms. ⁴For serum urate results of >4-<6 mg/dL (>0.24-<0.36 mmol/L), score to be given is 0. ⁵A score of 0 is given if imaging modalities are unavailable.

Diagnosis

EULAR Recommendations for the Diagnosis of Gout

Look for crystals in the synovial fluid or tophus aspirates in suspected gout patients as presence of monosodium citrate is a definitive diagnosis of gout
In any acute arthritis in an adult, gout should be considered in the diagnosis
In patients with undiagnosed inflammatory arthritis, it is recommended to have synovial fluid aspiration and crystals examination
Presence of hyperuricemia alone is not diagnostic of gout
In patients with uncertain clinical diagnosis of gout and identification of crystal is not possible, patients should be investigated by imaging to search for monosodium urate crystal deposition and features of any alternative diagnosis
To search for imaging evidence of monosodium urate by the use of plain radiographs. Ultrasound scanning is used to establish gout diagnosis in patients with suspected gout flare or chronic gouty arthritis
Risk factors for chronic hyperuricemia should be investigated in patients with gout

Laboratory Tests

Specific investigations for confirmation of gouty arthritis

Synovial Fluid Analysis

Demonstration of monosodium urate monohydrate crystals in synovial fluid or tophus aspirates gives a definitive diagnosis of gout
- Monosodium urate crystals are needle-shaped and they exhibit strong birefringence under polarized light
It is recommended to search for monosodium urate crystals in all synovial fluid samples obtained from undiagnosed inflamed joints
Identification of monosodium urate monohydrate crystals from asymptomatic joints may allow definite diagnosis in intercritical periods wherein patients are free of symptoms

Serum Urate Levels

Hyperuricemia defined as serum urate level >6.8 mg/dL (>0.40 mmol/L)
- Definition of hyperuricemia may vary between countries
Although hyperuricemia is the most important risk factor for gout, presence of it alone is not diagnostic of gout
- Many patients with hyperuricemia do not develop gout
- During acute attacks, serum urate levels may be normal in about 10% of cases
It will be best to measure serum urate levels 2-3 weeks after an attack

Additional Laboratory Exams to Detect the Presence of Associated Comorbidities in Patients with Gout

Upon detection of associated risk factors and comorbidities, the following should be addressed as an important part of the management of gout:
- Complete blood count to exclude infection, lymphoproliferative or myeloproliferative disorders
- Serum creatinine/urea to exclude renal disease leading to hyperuricemia or to detect renal disease secondary to urate nephropathy or nephrolithiasis
- Blood glucose to detect the presence of diabetes/insulin resistance
- Lipid profile to detect hypertriglyceridemia and low HDL cholesterol
- Urinalysis showing presence of blood and/or protein may suggest renal disorders

Imaging

Plain Radiography/Skeletal X-ray

Usually normal in acute gouty arthritis, although there may be reversible soft tissue swelling around the involved joint
In chronic tophaceous gout, typical radiographic findings include erosions with sclerotic margins and overhanging edges of bones or calcification in some tophi
- Presence of a thin, overhanging, calcified edge is highly suggestive of gout
- Joint space is usually preserved until late stages of the disease

Ultrasonography (US)

Can detect crystals deposited on cartilaginous surfaces as well as tophaceous material and typical erosions
- Monosodium urate monohydrate crystals may appear as “double contour sign” meaning there are deposits on superficial articular cartilage or as “snow storm appearance” denoting presence wtihin the synovial fluid of monosodium urate monohydrate crystals

Dual-Energy Computed Tomography (DECT)

Allows visualization of tophi or urate deposits in articular and periarticular locations and can distinguish urate from calcium deposition

Magnetic Resonance Imaging (MRI)

Findings are not specific for the diagnosis of gout but allow early detection of tophi and bone erosion
Method of determining the extent of disease in tophaceous gout and may provide information regarding the patterns of deposition and spread of monosodium urate monohydrate crystals