• Primary hyperuricemia
  • Uric acid saturation arises without coexisting diseases or drugs that alter uric acid production or excretion

• Secondary hyperuricemia
  •  Excessive uric acid production or diminished renal clearance occurs as a result of a disease, drug, dietary product or toxin

Causes of Secondary Hyperuricemia

• Excessive uric acid production:
  • Inherited enzyme defects (eg hypoxanthine-guanine phosphoribosyltransferase deficiency ,phosphoribosylpyrophosphate synthetase overactivity, glycogen storage diseases, fructose-1-phosphate aldolase deficiency, myoadenylate deaminase deficiency, carnitine palmitoyltransferase II deficiency)
  • Clinical disorders (eg myeloproliferative & 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 &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)

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, wrist, elbow & finger joints

• Extra-articular sites (eg olecranon bursa & Achilles tendon) may also be involved
• Attacks may occur & last from a few days to 2-3 week, 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

• After intermittent attacks (>3 acute attacks/year) & remissions, the chronic phase follows
• Polyarticular flares of gouty arthritis occur, & associated with bony erosions & deformities
• Chronic tophaceous gout:
  • Marked by polyarticular arthritis & 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 >0.54 mmol/L (9 mg/dL), age of ≥40 years old at disease onset

• Presence of urate nephropathy or urate renal calculi

• A rare form of gout
• Gout due to chronic lead exposure & "moonshine" whiskey consumers
• Commonly seen in plumbers & those exposed to lead-based paints

Gout Classification Criteria¹

• Developed by the American College of Rheumatology (ACR) & the European League Against Rheumatism (EULAR) in 2015
• The new criteria is based on the presence of monosodium urate (MSU) monohydrate crystals, imaging modalities, & 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

 Indications for referral to specialist:

• Difficulty in determining hyperuricemia etiology
• Refractory clinical manifestations of gout
• Reaching serum urate level difficulty in patients with renal impairment under xanthine oxidase inhibitor treatment trial
• Multiple &/or severe adverse effects due to urate lowering medications

Specific investigations for confirmation of gouty arthritis

Synovial fluid analysis

• Demonstration of MSU crystals in synovial fluid or tophus aspirates gives a definitive diagnosis of gout
  • MSU crystals are needle-shaped & they exhibit strong birefringence under polarized light

• It is recommended to search for MSU crystals in all synovial fluid samples obtained from undiagnosed inflamed joints
• Identification of MSU 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 >6.8-7 mg/dL or >0.40-0.41 mmol/L
• Although hyperuricemia is the most important risk factor for gout, this does not confirm or exclude 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
• Upper limit of serum urate level:
  • Male & postmenopausal women: 0.42 mmol/L or 7 mg/dL
  • Premenopausal women: 0.36 mmol/L or 6 mg/dL

• Upon detection of associated risk factors & comorbidities, these 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 & low HDL cholesterol
  • Urinalysis showing presence of blood &/or protein may suggest renal disorders
  • Rapid polymerase chain reaction-based HLA-B*5801 screening detects patients at high risk for severe Allopurinol hypersensitivity reaction (eg Koreans with > stage 3 CKD, Han Chinese, Thai)

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 & 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 & typical erosions
  • MSU 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 MSU crystals

Computed Tomography (CT)

• Allows excellent visualization of tophi
• May assist in differentiating tophi from other subcutaneous nodules & scoring bone erosions

Magnetic Resonance Imaging (MRI)

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