Overview
Gout is a common inflammatory arthritis that is increasing in prevalence. Gout (monosodium urate crystal deposition disease) is characterized biochemically by extracellular fluid urate saturation. Tends to occur earlier in life in men than women, and is rare in childhood. Prevalence is increasing. It is associated with many serious comorbidities such as hypertension, chronic kidney disease, obesity, diabetes and cardiovascular disease.
Definition
Gout: Defective metabolism of uric acid can build up in joints causing arthritis, especially in the smaller bones of the feet, deposition of chalk-stones, and episodes of acute pain.
Pseudogout: Deposits of calcium pyrophosphate dihydrate crystals in the fluid and tissues of the joints, leading to intermittent attacks of arthritis.
Tophi: Firm, painless deposits of urate crystals in soft tissues, seen in chronic gout. Common sites include fingers, toes, elbows, and ears. They may ulcerate or deform joints and indicate long-standing uncontrolled hyperuricaemia.
Podagra: Classic first presentation of gout in the first MTP joint
Anatomy and Physiology
Physiology of Monosodium Urate Production and Excretion
- Uric acid is the final breakdown product of purine metabolism (from DNA/RNA turnover and dietary intake)
- In the body, uric acid exists mainly as monosodium urate in extracellular fluid
- Humans lack the enzyme uricase, so uric acid is not converted to allantoin (more soluble)
- Production occurs primarily in the liver via the enzyme xanthine oxidase
- Excretion:
- ~2/3 via kidneys (glomerular filtration, tubular reabsorption, secretion, and post-secretory reabsorption)
- ~1/3 via the gut (enzymatic degradation by gut flora)
- Renal underexcretion is the most common cause of hyperuricaemia
Remember
Hyperuricaemia results from either overproduction or, more commonly, underexcretion of urate. Xanthine oxidase inhibitors (e.g. allopurinol) reduce uric acid production
Aetiology and Risk Factors
Aetiology
There is a causal relationship between hyperuricaemia (high urate level) and gout.
- Underexcretion of uric acid (90% of cases): due to renal impairment, diuretics, alcohol
- Overproduction of uric acid: enzyme defects (e.g. Lesch-Nyhan), high purine intake
Risk Factors
| Risk Factors |
| Older age |
| Male sex |
| Consumption of meat, seafood, alcohol |
| Menopausal status |
| Medications (Diuretics, cyclosporine/tacrolimus, pyrazinamide, aspirin) |
| Genetics |
| Haematological Malignancies (High cell turn over) |
| Chemotherapy (High cell turn over) |
| Diabetes |
Pathophysiology
- Chronic hyperuricaemia leads to supersaturation of urate in plasma
- Monosodium urate crystals precipitate in synovial fluid and tissues
- Crystals are phagocytosed by neutrophils → release of inflammatory mediators (IL-1, TNF-α)
- Inflammation peaks within 24 hours and resolves over days
- Recurrent flares → chronic tophaceous gout, joint damage, and bone erosions
Remember
Crystal phagocytosis is central to triggering acute inflammation
Clinical Manifestation
Three classic stages in the natural history of progressive urate crystal deposition disease (gout):
- Acute gouty arthritis
- Intercritical (or interval) gout
- Chronic articular and tophaceous gout
Remember
Gout does not occur only in the great toe (podagra), although this is a common site for the initial episode.
1. Acute gouty arthritis
- Monoarthritic joint – 80% (usually big toe podagra or the knee)
- Severe pain, redness, warmth, swelling, and disability
- Polyarticular gouty arthritis is the initial manifestation in less than 20 percent of patients with gout, but occurs with increasing frequency in later flares.
2. Intercritical gout
- Intervals between attacks of acute gouty arthritis are of variable duration
- Tophi can already develop bony erosions causing chronic gout arthropathy
3. Chronic articular and tophaceous gout
- Polyarthritic joints
- Uric acid nephrolithiasis
- Tophaceous deposits – Tophi are typically not painful or tender
Diagnosis
| Monoarthropathy | Oligoarthropathy | Polyarthropathy |
| Septic arthritis | Crystal arthritis | Rheumatoid arthritis |
| Crystal arthritis (Gout or Pseudogout) | Psoriatic arthritis | Viral Arthritis |
| Osteoarthritis (can be mono-poly) | Reactive arthritis | Autoimmune connective tissue disease (ie. SLE) |
| Trauma (Haemarthrosis) | Ankylosing spondylititis | Vasculitides (ie. Polymyalgia Rheumatica) |
Investigations
Side note
The chance of developing gout increases with increasing serum concentrations of uric acid.
- Joint aspiration: gold standard — negatively birefringent, needle-shaped MSU crystals under polarised light
- Serum urate: may be normal during acute flare; measure later
- Inflammatory markers: ↑ ESR/CRP during flare
- X-ray: late findings — punched-out erosions with overhanging edges (“rat bite”)
- Dual-energy CT (DECT): non-invasive detection of urate crystals
- Ultrasound: “double contour sign” (urate deposition over cartilage)
Remember
With any monoarthritic presentation, septic arthritis should be ruled out. This can be done with a Joint aspirate.
| Synovial fluid analysis | |||
| Aetiology | Colour and Clarity | WBC (mm³) | |
| Normal | Normal | Clear and transparent | <200 |
| Non-Inflammatory | Osteoarthritis | Yellow and transparent | 0 to 2000 |
| Inflammatory | Gout | Yellow and traslucent-opaque | 2000-100,000 |
| Septic | Bacteria | Yellow/green and opaque | >25,000 – >100,000 |
| Haemorrhage | Trauma | Red and Bloody | 200-2000 |
Diagnosis For a definitive diagnosis of gout, urate crystals must be demonstrated in synovial fluid or in the tophus
- Synovial fluid should be analysed by polarised light microscopy for monosodium urate crystals
Treatment
Acute Attacks
- Colchicine: best if <36 hours; inhibits neutrophil activation
- NSAIDs: e.g. indomethacin
- Corticosteroids: oral or intra-articular if NSAIDs contraindicated
- IL-1 inhibitors: anakinra (off-label) for refractory cases
Urate-lowering therapy (long-term):
- First-line: Allopurinol (xanthine oxidase inhibitor)
- Alternatives: febuxostat, probenecid (if underexcretor)
- Colchicine/NSAIDs for prophylaxis during initiation to prevent flares
Management plan
- Set urate target
- Start urate-lowering therapy with prophylaxis
- Ensure patient has acute flare plan
- Monitor serum urate until target reached
- Titrate urate-lowering therapy to achieve target
- Once target achieved, monitor 6–12 monthly
Side note
Allopurinol should not be stopped during acute flares of gout. Stopping allopurinol during an acute flare means therapeutic effect is lost and the urate level will rise. Historically, there has been concern that starting urate-lowering therapy such as allopurinol could worsen or prolong the acute gout flare, now this is not the case.
Pharmacology
Allopurinol inhibits the enzyme xanthine oxidase, blocking the conversion of the oxypurines hypoxanthine and xanthine to uric acid. Side effects: mild to severe rash.
Pharmacology
Colchicine inhibits microtubule assembly in leukocytes by binding tubulin, reducing chemotaxis, phagocytosis, and release of inflammatory mediators during urate crystal ingestion. It has no analgesic or urate-lowering effect. Side effects: Diarrhoea (usually dose dependent), GI upset, myopathy and cytopaenias in rare cases.
Complications and Prognosis
Complications
- Nephrolithiasis (kidney stones)
- Chronic urate nephropathy
Prognosis
- Acute gout attacks is painful and debilitating but self limiting
- Appropriate treatment can suppress gout attacks and their recurrence, and prevent long-term consequences of the disease
- Chronic articular and tophaceous gout may be associated with renal insufficiency
References
- Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76(1):29–42.
- Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet. 2016;388(10055):2039–2052.
- Neogi T, Jansen TL, Dalbeth N, et al. 2015 Gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2015;74(10):1789–1798.
- Stamp LK, Dalbeth N. Prevention and treatment of gout in the context of chronic kidney disease. Nat Rev Nephrol. 2019;15(5):271–283.
Discussion