Gout

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

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.